FGF19/FGF21 Polypeptides

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/931,683 filed November 6, 2019, and U.S. Provisional Application No. 63/000,948 filed March 27, 2020, the disclosure of each of which is incorporated by reference herein in its entirety.

SEQUENCE LISTING

This application incorporates by reference in its entirety a Sequence Listing submitted with this application as a text filed entitled “13370-112-228_SEQLIST.txt”, created on October 19, 2020, and is 256,719 bytes in size.

FIELD

[0001] Provided herein includes the treatment or prevention of a disease associated with universally elevated lactate levels with variants of fibroblast growth factor 19 (FGF19) proteins and peptide sequences (and peptidomimetics) and fusions of FGF19 and/or fibroblast growth factor 21 (FGF21) proteins and peptide sequences (and peptidomimetics), and variants of fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics).

INTRODUCTION

[0002] Lactate homeostasis is maintained at various levels. Generally, lactate levels are kept within a normal range due to clearance by the liver and kidney. Lactate can also be cleared by gut bacteria. It is important to regulate lactate levels because an elevation of lactate, also known as hyperlactemia, can exacerbate existing disease among other damaging effects. In fact, hyperlactemia is associated with many diseases and is used clinically to evaluate severity of disease. Such diseases include liver diseases. Examples of liver diseases that are associated with hyperlactemia include cirrhosis, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), and acute liver failure, among others. Therefore, there is a need in the art for a method of reducing lactate levels, e.g., to provide a protective effect in advanced liver disease. The present disclosure satisfies this and other needs.

SUMMARY [0003] The present disclosure is based, in part, on variants of fibroblast growth factor 19 (FGF19) peptide sequences, fusions of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21) peptide sequences and variants of fusions (chimeras) of fibroblast growth factor 19 (FGF19) and/or fibroblast growth factor 21 (FGF21) peptide sequences having one or more activities, such as modulating the gut microbiome. Such variants and fusions (chimeras) of FGF19 and/or FGF21 peptide sequences also include sequences that do not substantially or significantly increase or induce hepatocellular carcinoma (HCC) formation or HCC tumorigenesis.

[0004] The gut microbiome plays an important role in liver disease pathogenicity. Dysbiosis is a common feature of liver disease. The imbalance between harmful and beneficial bacteria can cause severe consequences for a patient with liver disease. The loss of beneficial bacteria can exacerbate certain liver diseases like cirrhosis. Veillonella , which ferments lactate to propionate and acetate, is a bacterium in the gastrointestinal tract that plays a role in lactate homeostasis. Lactate accumulation in liver disease may lead to acidosis, neurotoxicity and cardiac arrhythmia. It is known that the variants and fusions (chimeras) of FGF19 and/or FGF21 peptide sequences provided herein significantly inhibit bile acid synthesis. However, not much is known about the effects of the FGF19 and/or FGF21 peptide sequences on lactate accumulation. In some embodiments, provided herein are methods for enriching Veillonella in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein. In some embodiments, provided herein are methods for reducing lactate in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein. In some embodiments, provided herein are methods for treating or preventing disease associated with elevated lactate in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein. In some embodiments, the subject has liver disease. In further embodiments, the liver disease is cirrhosis. In further embodiments, the liver disease is NASH.

[0005] In various additional embodiments, a peptide sequence has amino-terminal amino acids 1-16 of SEQ ID NO: 100 (FGF21) fused to carboxy -terminal amino acids 21-194 of SEQ ID NO:99 (FGF19), or the peptide sequence has amino-terminal amino acids 1-147 of SEQ ID NO:99 (FGF19) fused to carboxy-terminal amino acids 147-181 of SEQ ID NO: 100 (FGF21) (M41), or the peptide sequence has amino-terminal amino acids 1-20 of SEQ ID NO: 99 (FGF19) fused to carboxy -terminal amino acids 17-181 of SEQ ID NO: 100 (FGF21) (M44), or the peptide sequence has amino-terminal amino acids 1-146 of SEQ ID NO: 100 (FGF21) fused to carboxy -terminal amino acids 148-194 of SEQ ID NO: 99 (FGF19) (M45), or the peptide sequence has amino-terminal amino acids 1-20 of SEQ ID NO: 99 (FGF19) fused to internal amino acids 17-146 of SEQ ID NO: 100 (FGF21) or fused to carboxy-terminal amino acids 148- 194 of SEQ ID NO:99 (FGF19) (M46).

[0006] In various further embodiments, a peptide sequence has at least one amino acid substitution to amino acid residues 125-129 of SEQ ID NO:99 (FGF19), EIRPD; at least one amino acid substitution to amino acid residues 126-128 of SEQ ID NO:99 (FGF19), IRP; or at least one amino acid substitution to amino acid residues 127-128 of SEQ ID NO:99 (FGF19),

RP, or at least one amino acid substitution to amino acid residues 1-124 of SEQ ID NO:99 (FGF19) and/or to amino acid residues 130-194 of SEQ ID NO:99 (FGF19). More specifically, for example, a peptide sequence with a substitution to one of amino acid residues 127-128 of SEQ ID NO:99 (FGF19), RP, wherein at least one amino acid substitution is R127L or P128E. Said substitutions within a corresponding FGF19 sequence (e.g., EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated. In certain embodiments, the peptide comprises both a R127L and P128E substitution to amino acid residues 127-128 of SEQ ID NO:99 (FGF19), RP, or the corresponding FGF19 sequence thereof in a variant peptide provided herein. In certain embodiments, the amino acid sequence of the peptide comprises at least one amino acid substitution in the Loop-8 region of FGF19, or the corresponding FGF19 sequence thereof in a variant peptide provided herein. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises four amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises five amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the IRP (amino acids 3-5 of SEQ ID NO:190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution. In other embodiments, the substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is a Pro (P) to Glu (E) substitution. In some embodiments, the substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution and a Pro (P) to Glu (E) substitution. In specific embodiments, the foregoing substitution(s) in the Loop-8 region of FGF19 is in the corresponding FGF19 sequence thereof in a variant peptide provided herein. That is, said substitutions within a corresponding FGF19 sequence (e.g., EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated.

[0007] Methods and uses provided herein can be practiced using a peptide or chimeric sequence, as set forth herein. For example, a sequence that comprises or consists of any peptide sequence set forth herein as Ml to M98, M101 to M160, or M200 to M207, or SEQ ID NOS: 1 to 98, 138 to 168, or 192 to 204. In other embodiments, the peptide sequence comprises or consists of any sequence set forth in Table 1. In yet other embodiments, the peptide sequence comprises or consists of any sequence set forth in the Sequence Listing herein.

[0008] Methods and uses provided herein can be practiced using a peptide or chimeric sequence of any suitable length. In particular, embodiments, the N-terminal or C-terminal region of the peptide or chimeric sequence is from about 20 to about 200 amino acid residues in length. In other particular aspects, a peptide or chimeric sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy-terminus or internally. In further particular embodiments, a peptide or chimeric sequence has an N-terminal region, or a C-terminal region that comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids. In additional more particular embodiments, a peptide or chimeric sequence has a FGF19 sequence portion, or a FGF21 sequence portion that comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids ofFGF19 or FGF21.

[0009] In yet additional embodiments, a peptide sequence or a chimeric peptide sequence has a WGDPI (SEQ ID NO: 170) sequence motif corresponding to the WGDPI (SEQ ID NO: 170) sequence of amino acids 16-20 of SEQ ID NO:99 (FGF19); has a substituted, mutated or absent WGDPI (SEQ ID NO: 170) sequence motif corresponding to FGF19 WGDPI (SEQ ID NO: 170) sequence of amino acids 16-20 of FGF19; has a WGDPI (SEQ ID NO: 170) sequence with one or more amino acids substituted, mutated or absent. In various other further aspects, the peptide sequence is distinct from a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the FGF19 WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20.

[0010] In yet further embodiments, a peptide sequence or a chimeric peptide sequence has N- terminal region comprises amino acid residues VHYG (SEQ ID NO: 101), wherein the N- terminal region comprises amino acid residues DASPHVHYG (SEQ ID NO: 102), or the N- terminal region comprises amino acid residues DSSPLVHYG (SEQ ID NO: 103). More particularly, in one aspect the G corresponds to the last position of the N-terminal region.

[0011] In various additional aspects, the N-terminal region comprises amino acid residues DSSPLLQ (SEQ ID NO: 104), where the Q residue is the last amino acid position of the N- terminal region, or comprises amino acid residues DSSPLLQFGGQV (SEQ ID NO: 105), where the V residue corresponds to the last position of the N-terminal region. [0012] In certain embodiments, an N-terminal region comprises or consists of (or further comprises or consists of): RHPIP (SEQ ID NO: 106), where R is the first amino acid position of the N-terminal region; or HPIP (SEQ ID NO: 107), where H is the first amino acid position of the N-terminal region; or RPLAF (SEQ ID NO: 108), where R is the first amino acid position of the N-terminal region; or PLAF (SEQ ID NO: 109), where P is the first amino acid position of the N- terminal region; or R, where R is the first amino acid position of the N-terminal region.

[0013] In various other aspects, a peptide or chimeric sequence has: amino acid residues HPIP (SEQ ID NO: 107), which are the first 4 amino acid residues of the N-terminal region. In still further aspects, a peptide or chimeric sequence has: an R residue at the first position of the N-terminal region, or the first position of the N-terminal region is an M residue, or the first and second positions of the N-terminal region is an MR sequence, or the first and second positions of the N-terminal region is an RM sequence, or the first and second positions of the N-terminal region is an RD sequence, or the first and second positions of the N-terminal region is an DS sequence, or the first and second positions of the N-terminal region is an MD sequence, or the first and second positions of the N-terminal region is an MS sequence, or the first through third positions of the N-terminal region is an MDS sequence, or the first through third positions of the N-terminal region is an RDS sequence, or the first through third positions of the N-terminal region is an MSD sequence, or the first through third positions of the N-terminal region is an MSS sequence, or the first through third positions of the N-terminal region is an DSS sequence, or the first through fourth positions of the N-terminal region is an RDSS (SEQ ID NO: 115), sequence, or the first through fourth positions of the N-terminal region is an MDSS (SEQ ID NO: 116), sequence, or the first through fifth positions of the N-terminal region is an MRDSS (SEQ ID NO: 117), sequence, or the first through fifth positions of the N-terminal region is an MSSPL (SEQ ID NO: 113) sequence, or the first through sixth positions of the N-terminal region is an MDSSPL (SEQ ID NO: 110) sequence, or the first through seventh positions of the N- terminal region is an MSDSSPL (SEQ ID NO: 111) sequence.

[0014] In various other particular aspects, a peptide or chimeric sequence has at the N- terminal region first amino acid position an “M” residue, a “R” residue, a “S” residue, a “H” residue, a “P” residue, a “L” residue or a “D” residue. In various alternative particular aspects, a peptide or chimeric sequence peptide sequence does not have a “M” residue or an “R” residue at the first amino acid position of the N-terminal region. [0015] In further various other aspects, a peptide or chimeric sequence has an N-terminal region with any one of the following sequences: MDSSPL (SEQ ID NO: 110), MSDSSPL (SEQ ID NO: 111), SDSSPL (SEQ ID NO: 112), MSSPL (SEQ ID NO: 113) or SSPL (SEQ ID NO: 114).

[0016] In still additional aspects, a peptide sequence or chimeric peptide sequence has a residue at the last position of the C-terminal region that corresponds to about residue 194 of SEQ ID NO:99 (FGF19). In still other embodiments, a peptide sequence or a chimeric peptide sequence an addition of amino acid residues 30-194 of SEQ ID NO: 99 (FGF19) at the C- terminus, resulting in a chimeric polypeptide having a residue at the last position of the C- terminal region that corresponds to about residue 194 of SEQ ID NO: 99 (FGF19). In further other embodiments, a chimeric peptide sequence or peptide sequence comprises all or a portion of a FGF19 sequence ( e.g ., SEQ ID NO: 99), positioned at the C-terminus of the peptide, or where the amino terminal “R” residue is deleted from the peptide.

[0017] In more particular embodiments, a chimeric peptide sequence or peptide sequence comprises or consists of any of M1-M98 variant peptide sequences, or a subsequence or fragment of any of the M1-M98 variant peptide sequences. Methods and uses provided herein can also be practiced using a peptide or chimeric sequence, as set forth herein. For example, a sequence that comprises or consists of any peptide sequence set forth herein as Ml to M98,

M101 to M160, or M200 to M207 or SEQ ID NOs: 1 to 98, 138 to 168, or 192 to 204, or a peptide sequence that comprises or consists of any sequence set forth in Table 1, or a peptide sequence that comprises or consists of any sequence set forth in the Sequence Listing herein. [0018] In various more particular aspects, a peptide sequence comprises or consists of any one of the following sequences:

RPL AF SD AGPHVHY GW GDPIRLRHL YTSGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHR LP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDPF GLVTGLEAVRSPSFEK (M3) (SEQ ID NO:3);

RPL AF SD AGPHVHY GW GDPIRLRHL YTSGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIREDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDP F GLVTGLEAVRSPSFEK (M140) (SEQ ID NO: 194); RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLE IKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKH RLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDP F GLVTGLEAVRSPSFEK (M160) (SEQ ID NO: 196);

RD S SPL VH Y GW GDPIRLRHL YT S GPHGL S S CFLRIRAD G V VD C ARGQ S AHSLLEIKAVA LRTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDCAFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSPSFEK (M69) (SEQ ID NO:69);

RD S SPLLQ W GDPIRLRHL YT S GPHGL S S CFLRIRADGVVD C ARGQ S AHSLLEIK A V ALRT VAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VT GL EAVRSPSFEK (M52) (SEQ ID NO:52);

RHPIPDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEI KAV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M5) (SEQ ID NO:5);

HPIPDS SPLLQF GGQVRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ SAHSLLEIKAVA LRTVAIKGVIIS VRYLCMGADGKMQGLLQ Y SEEDCAFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSPSFEK (M5-R) (SEQ ID NO: 160);

HPIPD S SPLLQF GGQ VRQRYL YTDD AQQTEAHLEIREDGT VGGAADQ SPESLLQLKALK PGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHSLPLHLP GNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVGPSQGRSPSY A S (M71) (SEQ ID NO:71);

HPIPD S SPLLQF GGQ VRQRYL YTDD AQQTEAHLEIREDGT VGGAADQ SPESLLQLKALK PGVIQILGVKT SRFLCQRPDGAL Y GSLHFDPEAC SFRELLLEDGYN VY Q SEAHGLPLHLP GNKSPHRDPAPRGPARFLPLPGLPPAPPEPPGILAPQPPDVGSSDPLSMVGPSQGRSPSY A S (M72) (SEQ ID NO: 72); HPIPD S SPLLQF GGQ VRQRYL YTDD AQQTEAHLEIREDGT VGGAADQ SPESLLQLKALK PGVIQILGVKT SRFLCQRPDGAL Y GSLHFDPEAC SFRELLLEDGYN VY Q SEAHGLPLHLP GNK SPHRDP APRGP ARFLPLPGLPP ALPEPPGIL APQPPD V GS SDPL SM V V QDELQGV GG EGCHMHPEN CKTLLTDIDRTHTEKP VWDGIT GE (M73) (SEQ ID NO:73);

RPL AF SD ASPHVHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDP F GLVTGLEAVRSPSFEK (Ml) (SEQ ID NO: l or 139);

RPL AF SD S SPL VH Y GW GDPIRLRHL YT S GPHGL S S CFLRIRADGVVDC ARGQ S AH SLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDP F GLVTGLEAVRSPSFEK (M2) (SEQ ID NO:2 or 140);

RDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVA LRT VAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VT GL EAVRSPSFEK (M48) (SEQ ID NO:48 or 6 or 148);

RPLAFSDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLE IKA VALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VTGLEAVRSPSFEK (M49) (SEQ ID NO:49 or 7 or 149);

RHPIPDSSPLLQFGDQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEI KAV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M50) (SEQ ID NO:50);

RHPIPDSSPLLQFGGNVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEI KAV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M51) (SEQ ID NO:51 or 36 or 155); MD S SPLLQW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AVALRT VAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VT GL EAVRSPSFEK (M53) (SEQ ID NO: 192);

MRD S SPL VHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M70) (SEQ ID NO:70);

RPL AF SD AGPHVHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ SAHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILPDGYNVYRSEKHR LP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GLVTGLEAVRSPSFEK (M139) (SEQ ID NO: 193); or

RPL AF SD AGPHVHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ SAHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILCDGYNVYRSEKH RLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDP F GL VT GLE A VRSP SFEK (M141) (SEQ ID NO: 195);

RPLAFSDAGPHVHYGWGDPIRQRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSL LE IKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDP F GLVTGLEAVRSPSFEK (Ml 60); or a subsequence or fragment thereof of any of the foregoing peptide sequences. In certain embodiments of any of the foregoing peptide sequences, the R terminal residue (R residue at the N-terminus) is deleted.

[0019] In other embodiments, the peptide comprises or consists of:

RDS SPLVHYGWGDPIRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ S AHSLLEIKAVA LRTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEILEDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSPSFEK (M200) (SEQ ID NO: 197); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0020] In some embodiments, the peptide comprises or consists of: RPL AF SD S SPL VH Y GW GDPIRLRHL YT S GPHGL S S CFLRIRADGVVDC ARGQ S AH SLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHR LP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDPF GLVTGLEAVRSPSFEK (M201) (SEQ ID NO: 198); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0021] In certain embodiments, the peptide comprises or consists of:

RPL AF SD ASPHVHY GW GDPIRLRHL YT S GPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHR LP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDPF GLVTGLEAVRSPSFEK (M202) (SEQ ID NO: 199); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0022] In other embodiments, the peptide comprises or consists of:

RD S SPLLQ W GDPIRLRHL YT S GPHGL S S CFLRIRADGVVD C ARGQ S AHSLLEIK A V ALRT VAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEILEDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VT GL EAVRSPSFEK (M203) (SEQ ID NO:200); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0023] In some embodiments, the peptide comprises or consists of: RHPIPDSSPLLQFGDQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M204) (SEQ ID NO:201); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0024] In certain embodiments, the peptide comprises or consists of:

RDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVA LRT VAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEILEDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLESDMF S SPLETD SMDPF GL VT GL EAVRSPSFEK (M205) (SEQ ID NO:202); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0025] In some embodiments, the peptide comprises or consists of: RHPIPDSSPLLQFGGQVRLRHLYTSGPHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHRLPV SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M206) (SEQ ID NO:203); or a subsequence or fragment thereof. In one embodiment, the N-terminal R residue is deleted.

[0026] In other embodiments, the peptide comprises or consists of:

MRD S SPL VHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEILEDGYNVYRSEKHRLPV SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M207) (SEQ ID NO:204); or a subsequence or fragment thereof.

[0027] In some embodiments, the peptide is a variant peptide designated M139. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 193. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 193. In some embodiments, the peptide is a variant peptide designated M140. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 194. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 194. In some embodiments, the peptide is a variant peptide designated M141. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 195. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 195. In some embodiments, the peptide is a variant peptide designated Ml 60. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 196. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 196. In some embodiments, the peptide is a variant peptide designated M200. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 197. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 197. In some embodiments, the peptide is a variant peptide designated M201. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 198. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 198. In other embodiments, the peptide is a variant peptide designated M202. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO: 199. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO: 199. In certain embodiments, the peptide is a variant peptide designated M203. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID N0:200. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO:200. In some embodiments, the peptide is a variant peptide designated M204. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO:201. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO:201. In another embodiment, the peptide is a variant peptide designated M205. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO:202. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO:202. In other embodiments, the peptide is a variant peptide designated M206. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO:203. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO:203. In yet other embodiments, the peptide is a variant peptide designated M207. In some embodiments, the peptide comprises an amino acid sequence set forth in SEQ ID NO:204. In other embodiments, the peptide consists of an amino acid sequence set forth in SEQ ID NO:204.

[0028] In various additional particular aspects, the N-terminus of the peptide sequence comprises or consists of any of:

HPIPD S SPLLQF GGQ VRLRHL YT S G (M5-R) (amino acids 1-25 of SEQ ID NO: 160);

D S SPLLQF GGQ VRLRHL YT S G (M6-R) (amino acids 2-22 of SEQ ID NO:6);

RPL AF SD S SPLLQF GGQ VRLRHL YT S G (M7) (amino acids 1-27 of SEQ ID NO:7);

HPIPD S SPLLQ W GDPIRLRHL YT S G (M8-R) (amino acids 2-26 of SEQ ID NO:8);

HPIPD S SPLLQF GW GDPIRLRHL YT SG (M9-R) (amino acids 2-28 of SEQ ID NO:9);

HPIPD S SPHVH Y GW GDPIRLRHL YT S G (M10-R) (amino acids 2-28 of SEQ ID NO: 10); RPLAFSDAGPLLQWGDPIRLRHLYTSG (Ml 1) (amino acids 1-27 of SEQ ID NO: 11);

RPL AF SD AGPLLQF GW GDPIRLRHL YT S G (M12) (amino acids 1-29 of SEQ ID NO: 12); RPLAF SDAGPLLQF GGQ VRLRHL YTSG (M13) (amino acids 1-27 of SEQ ID NO: 13); HPIPD S SPHVH Y GGQ VRLRHL YT S G (M14-R) (amino acids 2-26 of SEQ ID NO: 14); RPLAF SDAGPHVHYGGQ VRLRHL YTSG (Ml 5) (amino acids 1-27 of SEQ ID NO: 15); RPLAF SDAGPHVHWGDPIRLRHL YTSG (M16) (amino acids 1-27 of SEQ ID NO: 16); RPLAF SDAGPHVGWGDPIRLRHL YTSG (M17) (amino acids 1-27 of SEQ ID NO: 17); RPLAF SDAGPHYGWGDPIRLRHL YTSG (M18) (amino acids 1-27 of SEQ ID NO: 18); RPLAF SD AGP VY GWGDPIRLRHL YTSG (M19) (amino acids 1-27 of SEQ ID NO: 19); RPLAFSDAGPVHGWGDPIRLRHLYTSG (M20) (amino acids 1-27 of SEQ ID NO:20); RPLAF SD AGP VHYWGDPIRLRHL YTSG (M21) (amino acids 1-27 of SEQ ID NO:21); RPL AF SD AGPHVHGW GDPIRLRHL YT S G (M22) (amino acids 1-27 of SEQ ID NO:22); RPLAF SDAGPHHGWGDPIRLRHL YTSG (M23) (amino acids 1-27 of SEQ ID NO:23); RPLAF SDAGPHHYWGDPIRLRHL YTSG (M24) (amino acids 1-27 of SEQ ID NO:24); RPLAF SDAGPHVYWGDPIRLRHL YTSG (M25) (amino acids 1-27 of SEQ ID NO:25); RPLAF SD S SPL VTTW GDPIRLRHL YT S G (M26) (amino acids 1-27 of SEQ ID NO:26); RPLAF SD S SPHVHW GDPIRLRHL YT S G (M27) (amino acids 1-27 of SEQ ID NO:27); RPLAF SDAGPHVWGDPIRLRHL YTSG (M28) (amino acids 1-26 of SEQ ID NO:28); RPLAF SDAGPHVHYWGDPIRLRHL YTSG (M29) (amino acids 1-28 of SEQ ID NO:29); RPLAF SDAGPHVHYAWGDPIRLRHL YTSG (M30) (amino acids 1-29 of SEQ ID NO:30); RHPIPD S SPLLQF GAQ VRLRHL YT S G (M31) (amino acids 1-26 of SEQ ID NO:31); RHPIPD S SPLLQF GDQ VRLRHL YT S G (M32) (amino acids 1-26 of SEQ ID NO:32); RHPIPD S SPLLQF GPQ VRLRHL YT S G (M33) (amino acids 1-26 of SEQ ID NO:33); RHPIPD S SPLLQF GGA VRLRHL YT S G (M34) (amino acids 1-26 of SEQ ID NO:34); RHPIPD S SPLLQF GGEVRLRHL YT SG (M35) (amino acids 1-26 of SEQ ID NO:35); RHPIPD S SPLLQF GGNVRLRHL YT S G (M36) (amino acids 1-26 of SEQ ID NO:36); RHPIPD S SPLLQF GGQ ARLRHL YT S G (M37) (amino acids 1-26 of SEQ ID NO:37); RHPIPD S SPLLQF GGQIRLRHL YT S G (M38) (amino acids 1-26 of SEQ ID NO:38); RHPIPD S SPLLQF GGQTRLRHL YT S G (M39) (amino acids 1-26 of SEQ ID NO:39); RHPIPD S SPLLQF GW GQP VRLRHL YT S G (M40) (amino acids 1-28 of SEQ ID NO:40);

D AGPHVH Y GW GDPIRLRHL YT S G (M74-R) (amino acids 2-24 of SEQ ID NO:74);

VH Y GW GDPIRLRHL YT S G (M75-R) (amino acids 2-19 of SEQ ID NO:75);

RLRHLYTSG (M77-R) (amino acids 2-10 of SEQ ID NO:77);

RHPIPD S SPLLQF GW GDPIRLRHL YT SG (M9) (amino acids 1-28 of SEQ ID NO:9); RHPIPD S SPLLQ W GDPIRLRHL YT S G (M8) (amino acids 1-26 of SEQ ID NO:8);

RPLAF SD AGPLLQF GW GDPIRLRHL YT S G (M12) (amino acids 1-29 of SEQ ID NO: 12); RHPIPD S SPHVH Y GW GDPIRLRHL YT S G (M10) (amino acids 1-28 of SEQ ID NO: 10); RPLAF SDAGPLLQFGGQ VRLRHL YTSG (M13) (amino acids 1-27 of SEQ ID NO: 13); RHPIPDSSPHVHYGGQ VRLRHL YTSG (M14) (amino acids 1-26 of SEQ ID NO: 14); RPL AF SD AGPHVHY GGDIRLRHL YT SG (M43) amino acids 1-27 of SEQ ID NO:43); or RD S SPLLQF GGQ VRLRHL YT SG (M6) (amino acids 1-22 of SEQ ID NO:6); or any of the foregoing peptide sequences where the amino terminal R residue is deleted. [0029] In certain embodiments, the peptide comprises or consists of any of:

HPIPD S SPLLQF GGQ VRLRHL YT S G (M5-R) (amino acids 1-25 of SEQ ID NO: 160); DSSPLLQFGGQ VRLRHL YTSG (M6-R) (amino acids 2-22 of SEQ ID NO:6);

RPL AF SD S SPLLQF GGQ VRLRHL YT S G (M7) (amino acids 1-27 of SEQ ID NO:7); HPIPD S SPLLQ W GDPIRLRHL YT S G (M8-R) (amino acids 2-26 of SEQ ID NO:8);

HPIPD S SPLLQF GW GDPIRLRHL YT SG (M9-R) (amino acids 2-28 of SEQ ID NO:9); HPIPD S SPHVH Y GW GDPIRLRHL YT S G (M10-R) (amino acids 2-28 of SEQ ID NO: 10); RPL AFSDAGPLLQWGDPIRLRHL YTSG (Ml 1) (amino acids 1-27 of SEQ ID NO: 11); RPL AF SD AGPLLQF GW GDPIRLRHL YT S G (M12) (amino acids 1-29 of SEQ ID NO: 12); RPLAFSDAGPLLQFGGQ VRLRHL YTSG (M13) (amino acids 1-27 of SEQ ID NO: 13); HPIPDSSPHVHYGGQ VRLRHL YTSG (M14-R) (amino acids 2-26 of SEQ ID NO: 14); RPLAFSDAGPHVHYGGQ VRLRHL YTSG (Ml 5) (amino acids 1-27 of SEQ ID NO: 15); RPL AF SD AGPHVHW GDPIRLRHL YT S G (M16) (amino acids 1-27 of SEQ ID NO: 16); RPL AF SD AGPH V GW GDPIRLRHL YT S G (M17) (amino acids 1-27 of SEQ ID NO: 17); RPL AF SD AGPH Y GW GDPIRLRHL YT S G (M18) (amino acids 1-27 of SEQ ID NO: 18); RPLAF SD AGP VYGWGDPIRLRHL YTSG (M19) (amino acids 1-27 of SEQ ID NO: 19); RPLAF SD AGP VHGWGDPIRLRHL YTSG (M20) (amino acids 1-27 of SEQ ID NO:20); RPLAF SD AGP VHYWGDPIRLRHL YTSG (M21) (amino acids 1-27 of SEQ ID NO:21); RPLAF SDAGPHVHGWGDPIRLRHL YTSG (M22) (amino acids 1-27 of SEQ ID NO:22); RPLAF SDAGPHHGWGDPIRLRHL YTSG (M23) (amino acids 1-27 of SEQ ID NO:23); RPLAF SDAGPHHYWGDPIRLRHL YTSG (M24) (amino acids 1-27 of SEQ ID NO:24); RPLAF SDAGPHVYWGDPIRLRHL YTSG (M25) (amino acids 1-27 of SEQ ID NO:25); RPLAF SD S SPL VHW GDPIRLRHL YT S G (M26) (amino acids 1-27 of SEQ ID NO:26); RPLAF SD S SPHVHW GDPIRLRHL YT S G (M27) (amino acids 1-27 of SEQ ID NO:27); RPLAF SDAGPHVWGDPIRLRHL YTSG (M28) (amino acids 1-26 of SEQ ID NO:28); RPLAF SDAGPHVHYWGDPIRLRHL YTSG (M29) (amino acids 1-28 of SEQ ID NO:29); RPLAF SDAGPHVHYAWGDPIRLRHL YTSG (M30) (amino acids 1-29 of SEQ ID NO:30); RHPIPDSSPLLQFGAQ VRLRHL YTSG (M31) (amino acids 1-26 of SEQ ID NO:31); RHPIPD S SPLLQF GDQ VRLRHL YT S G (M32) (amino acids 1-26 of SEQ ID NO:32);

RHPIPD S SPLLQF GPQ VRLRHL YT S G (M33) (amino acids 1-26 of SEQ ID NO:33);

RHPIPD S SPLLQF GGA VRLRHL YT S G (M34) (amino acids 1-26 of SEQ ID NO:34);

RHPIPD S SPLLQF GGEVRLRHL YT SG (M35) (amino acids 1-26 of SEQ ID NO:35);

RHPIPD S SPLLQF GGNVRLRHL YT S G (M36) (amino acids 1-26 of SEQ ID NO:36);

RHPIPD S SPLLQF GGQ ARLRHL YT S G (M37) (amino acids 1-26 of SEQ ID NO:37);

RHPIPD S SPLLQF GGQIRLRHL YT S G (M38) (amino acids 1-26 of SEQ ID NO:38);

RHPIPD S SPLLQF GGQTRLRHL YT S G (M39) (amino acids 1-26 of SEQ ID NO:39);

RHPIPD S SPLLQF GW GQP VRLRHL YT S G (M40) (amino acids 1-28 of SEQ ID NO:40);

D AGPHVH Y GW GDPIRLRHL YT S G (M74-R) (amino acids 2-24 of SEQ ID NO:74); VHYGWGDPIRLRHLYTSG (M75-R) (amino acids 2-19 of SEQ ID NO:75);

RLRHLYTSG (M77-R) (amino acids 2-10 of SEQ ID NO:77);

RHPIPD S SPLLQF GW GDPIRLRHL YT SG (M9) (amino acids 1-28 of SEQ ID NO:9);

RHPIPD S SPLLQ W GDPIRLRHL YT S G (M8) (amino acids 1-26 of SEQ ID NO:8);

RPL AF SD AGPLLQF GW GDPIRLRHL YT S G (M12) (amino acids 1-29 of SEQ ID NO: 12); RHPIPD S SPHVH Y GW GDPIRLRHL YT S G (M10) (amino acids 1-28 of SEQ ID NO: 10); RPLAF SD AGPLLQF GGQ VRLRHL YTSG (M13) (amino acids 1-27 of SEQ ID NO: 13); RHPIPD S SPHVHY GGQ VRLRHL YT SG (M14) (amino acids 1-26 of SEQ ID NO: 14);

RPLAF SD AGPHVHY GGDIRLRHL YT SG (M43) amino acids 1-27 of SEQ ID NO:43); or RDSSPLLQFGGQ VRLRHL YTSG (M6) (amino acids 1-22 of SEQ ID NO:6). In some embodiments, the peptide comprise one of the foregoing sequences. In another embodiment, the peptide consists of one of the foregoing sequences. In some embodiments, the peptide comprises a C-terminal region comprising a portion of SEQ ID NO:99 (FGF19), the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises amino acid residues 16-29 of SEQ ID NO:99 (FGF19), WGDPIRLRHLYTSG (SEQ ID NO: 169), wherein the W residue corresponds to the first amino acid position of the C-terminal region.

[0030] In various further particular aspects, a peptide sequence comprises or consists of: HPIPDS SPLLQF GGQVRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ SAHSLLEIKAVA LRTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSP SFEK (SEQ ID NO: 160);

D S SPLLQF GGQ VRLRHL YTSGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AVALRT V AIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S A KQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLE AVRSPSFEK (SEQ ID NO: 138 or 161);

RPL AF SD ASPHVHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ SAHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDP FGLVTGLEAVRSPSFEK (SEQ ID NO: l or 139);

RPL AF SD S SPL VH Y GW GDPIRLRHL YT S GPHGL S S CFLRIRADGVVDC ARGQ S AH SLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDP F GL VT GLEAVRSP SFEK( SEQ ID NO:2 or 140); or

D S SPL VHY GW GDPIRLRHL YTSGPHGL S S CFLRIRADGVVDC ARGQ S AHSLLEIK AVAL RTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSP SFEK (SEQ ID NO: 141); or a subsequence or fragment thereof of any of the foregoing peptide sequences. In certain embodiments of any of the foregoing peptide sequences, the R terminal residue is deleted.

[0031] In further embodiments, a peptide sequence comprises or consists of:

MRD S SPL VHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SLS S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (M70) (SEQ ID NO:70), or a subsequence or fragment thereof.

In certain embodiments, a peptide sequence includes the addition of amino acid residues 30-194 of SEQ ID NO: 99 (FGF19) at the C-terminus, resulting in a chimeric polypeptide.

[0032] In some embodiments, a peptide sequence has at least one amino acid substitution to amino acid residues 125-129 of SEQ ID NO:99 (FGF19), EIRPD. In other embodiments, the peptide sequence has at least one amino acid substitution to amino acid residues 126-128 of SEQ ID NO:99 (FGF19), IRP. In other embodiments, the peptide sequence has at least one amino acid substitution to amino acid residues 127-128 of SEQ ID NO:99 (FGF19), RP. In other embodiments, the peptide sequence has at least one amino acid substitution to amino acid residues 1-124 of SEQ ID NO:99 (FGF19) and/or to amino acid residues 130-194 of SEQ ID NO:99 (FGF19). For example, in certain embodiments, a peptide sequence comprises substitution to one of amino acid residues 127-128 of SEQ ID NO:99 (FGF19), RP, wherein at least one amino acid substitution is R127L or P128E. Said substitutions within a corresponding FGF19 sequence (e.g., EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated. In certain embodiments, the peptide comprises both a R127L and P128E substitution to amino acid residues 127-128 of SEQ ID NO:99 (FGF19), RP, or the corresponding FGF19 sequence thereof in a variant peptide provided herein. In certain embodiments, the amino acid sequence of the peptide comprises at least one amino acid substitution in the Loop-8 region of FGF19, or the corresponding FGF19 sequence thereof in a variant peptide provided herein. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises four amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises five amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution. In other embodiments, the substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is a Pro (P) to Glu (E) substitution. In some embodiments, the substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution and a Pro (P) to Glu (E) substitution. In specific embodiments, the foregoing substitution(s) in the Loop-8 region of FGF19 is in the corresponding FGF19 sequence thereof in a variant peptide provided herein. That is, said substitutions within a corresponding FGF19 sequence (e.g., EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated.

[0033] Peptide or chimeric sequences provided herein can be of any suitable length. In particular embodiments, the N-terminal or C-terminal region of the peptide or chimeric sequence is from about 20 to about 200 amino acid residues in length. In further particular embodiments, a chimeric peptide sequence or peptide sequence has at least one amino acid deletion. In other particular aspects, a peptide or chimeric sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy- terminus or internally. In one embodiment, the amino acid substitution, or deletion is at any of amino acid positions 8-20 of FGF19 (AGPHVHYGWGDPI) (SEQ ID NO: 187). In further particular embodiments, a peptide or chimeric sequence has an N-terminal region, or a C- terminal region that comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids. In additional more particular embodiments, a peptide or chimeric sequence has a FGF19 sequence portion, or a FGF21 sequence portion that comprises or consists of an amino acid sequence of about 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 or more amino acids ofFGF19 orFGF21. [0034] In various further embodiments, a peptide or chimeric sequence has an amino acid substitution, an addition, insertion or is a subsequence that has at least one amino acid deleted. Such amino acid substitutions, additions, insertions and deletions of a peptide sequence can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid residues (10-20, 20-30, 30-40, 40-50, etc.), for example, at the N- or C-terminus, or internal. For example, a subsequence that has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acid deletions from the amino terminus, the carboxy-terminus or internally. In a particular aspect, the amino acid substitution, or deletion is at any of amino acid positions 8-20 of FGF19 (AGPHVHYGWGDPI) (SEQ ID NO: 187).

[0035] In still more particular aspects, a peptide or chimeric sequence includes all or a portion of a FGF19 sequence set forth as:

PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGK M QGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPML PMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLE A VRSP SFEK (SEQ ID NO: 188) positioned at the C-terminus of the peptide, or the amino terminal “R” residue is deleted from the sequence.

[0036] In various embodiments, a peptide or chimeric sequence has a function or activity greater or less than a comparison sequence. In further particular embodiments, chimeric peptide sequences and peptide sequences have particular functions or activities. In one aspect, a chimeric peptide sequence or peptide sequence maintains or increases a fibroblast growth factor receptor 4 (FGFR4) mediated activity. In additional aspects, a chimeric peptide sequence or peptide sequence binds to FGFR4 or activates FGFR4, or does not detectably bind to FGFR4 or activate FGFR4, or binds to FGFR4 with an affinity less than, comparable to or greater than FGF19 binding affinity for FGFR4, or activates FGFR4 to an extent or amount less than, comparable to or greater than FGF19 activates FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein activates FGFR4 to an extent or amount less than the extent or amount that FGF19 activates FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein activates FGFR4 to an extent or amount comparable to the extent or amount that FGF19 activates FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein activates FGFR4 to an extent or amount greater than the extent or amount that FGF19 activates FGFR4. [0037] In one embodiment, a chimeric peptide sequence or peptide sequence provided herein maintains a FGFR4 mediated activity. In one embodiment, a chimeric peptide sequence or peptide sequence provided herein increases a FGFR4 mediated activity. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein binds to FGFR4 with an affinity less than FGF19 binding affinity for FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein binds to FGFR4 with an affinity comparable to FGF19 binding affinity for FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein binds to FGFR4 with an affinity greater than FGF19 binding affinity for FGFR4. In some embodiments, a chimeric peptide sequence or peptide sequence provided herein does not detectably bind to FGFR4.

[0038] In further aspects, a chimeric peptide sequence or peptide sequence has reduced HCC formation compared to FGF19, or a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19; or has greater glucose lowering activity compared to FGF19, or a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19; has less lipid increasing activity compared to FGF19, or a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19; or has less triglyceride, cholesterol, non-HDL or HDL increasing activity compared to FGF19, or a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19; or the peptide sequence has less lean mass reducing activity compared to FGF21. Such functions and activities can be ascertained in vitro or in vivo , for example, in a db/db mouse.

[0039] In one embodiment, a peptide or chimeric sequence has a function or activity greater or less than a comparison sequence. In some embodiments, the comparison sequence is FGF19. In another embodiment, the comparison sequence is FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19. In one embodiment, a peptide or chimeric peptide sequence provided herein has greater glucose lowering activity compared to a comparison sequence. In another embodiment, a peptide or chimeric peptide sequence provided herein has less lipid increasing activity compared to a comparison sequence. In another embodiment, a peptide or chimeric peptide sequence provided herein has lower or reduced lipid ( e.g triglyceride, cholesterol, non- HDL) increasing activity compared to a comparison sequence. In other embodiments, a peptide or chimeric peptide sequence provided herein has more HDL increasing activity as compared to a comparison sequence. In other embodiment, a peptide or chimeric peptide sequence provided herein has less lean mass reducing activity compared to a comparison sequence or FGF21. [0040] In other embodiments, a peptide or chimeric sequence provided herein has greater Veillonella enrichment activity or lactate reducing activity compare to a comparison sequence, FGF19, or FGF21.

[0041] In further additional various embodiments, a peptide or chimeric sequence includes one or more L-amino acids, D-amino acids, non-naturally occurring amino acids, or amino acid mimetic, derivative or analogue. In still further various embodiments, a peptide or chimeric sequence has an N-terminal region, or a C-terminal region, or a FGF19 sequence portion, or a FGF21 sequence portion, joined by a linker or spacer. In some embodiments, the chimeric peptide sequence or peptide sequence is comprised in a pharmaceutical composition. In further embodiments, an additional therapeutic agent is administered. In further embodiments, the additional therapeutic agent is an inflammatory agent.

DESCRIPTION OF DRAWINGS

[0042] FIG. 1 shows that patients with non-alcoholic steatohepatitis (NASH) treated with the FGF19 analogue M70 had stable gut microbial composition by alpha diversity over 12 weeks. [0043] FIGS. 2A and 2B show that patients with non-alcoholic steatohepatitis (NASH) treated with the FGF19 analogue M70 had stable gut microbial composition by beta diversity over 12 weeks with unweighted UniFrac (FIG. 2A) and weighted UniFrac (FIG. 2B). Day 1 shown in light gray, week 12 shown in dark gray.

[0044] FIGS. 3A and 3B show that patients with non-alcoholic steatohepatitis (NASH) treated with the FGF19 analogue M70 had no change in the phyla of the gut microbiome over 12 weeks with Kruskal-Wallis test (FIG. 3A) and Mann-Whitney U-test (FIG. 3B; day 1 (left), week 12 (right)), both with FDR corrections using Benjamini-Hoxhberg. FIG. 3A depicts M70 concentration left to right per phyla as 0.3 mg, 1 mg, 3 mg, 6 mg and placebo. FIGS. 3C and 3D show that patients with NASH treated with the FGF19 analogue M70 had no change in the genera of the gut microbiome over 12 weeks with Kruskal-Wallis test (FIG. 3C) and Mann-Whitney U-test (FIG. 3D; day 1 (left), week 12 (right)), both with FDR corrections using Benjamini-Hoxhberg. FIG. 3C depicts M70 concentration left to right per genera as 0.3 mg, 1 mg, 3 mg, 6 mg and placebo.

[0045] FIG. 4A shows that patients with non-alcoholic steatohepatitis (NASH) treated with the FGF19 analogue M70 had enriched populations of lactate-consuming Veillonella bacteria. FIG. 4B shows that patients with NASH treated with the FGF19 analogue M70 had fecal samples that were positive for Veillonella at baseline and week 12. FIG. 4C shows that patients with NASH treated with the FGF19 analogue M70, did not have any changes in other microbes that are of oral origin, associated with Veillonella , ferment other substrates, or with ethanol producing properties. Day 1 shown in black (left), week 12 shown in gray (right).

[0046] FIG. 5A shows that patients with non-alcoholic steatohepatitis (NASH) treated with FGF19 analogue M70 had enriched populations of lactate-consuming Veillonella , which was inversely correlated with toxic, hydrophobic bile acids compared to baseline. Day 1 shown in light gray (left), week 12 shown in dark gray (right). FIG. 5B shows that patients with NASH treated with the FGF19 analogue M70 had enriched populations of lactate-consuming Veillonella and its operational units were inverselty correlated with concentrations of GCA, GCDCA,

GDCA and DCA.

[0047] FIG. 6A shows that patients with non-alcoholic steatohepatitis (NASH) treated with FGF19 analogue M70 had no change in alpha diversity between low liver fat (Ql) and high liver fat (Q4). FIG. 6B shows that patients with NASH treated with FGF19 analogue M70 showed no separation between Ql and Q4 at baseline. Ql shown in dark gray and Q4 shown in light gray. FIG. 6C and FIG. 6D show that patients with NASH treated with FGF19 analogue M70 showed no significant difference at the phylum and genus level between Ql and Q4 populations. Ql shown in dark gray (left) and Q4 shown in light gray (right). FIG. 6E and FIG. 6F show that patients with NASH treated with FGF19 analogue M70 showed significant differences in Euryarchaeota between M70-treaed subjects who had 70% or greater reduction in liver fat and the placebo group. Lentisphaerae also trended toward significant after FDR correction and no differences in any phyla were observed. Placebo group shown in dark gray (left) and treated group shown in light gray (right).

[0048] FIG. 7A shows that patients with non-alcoholic steatohepatitis (NASH) treated with FGF19 analogue M70 had a gut microbiota composition that was not significantly different between mild fibrosis (FI) and advanced fibrosis (F3) subjects by alpha diversity. FIG. 7B shows that patients with NASH treated with FGF19 analogue M70 had beta diversity that was not significantly different between FI (stage 1) and F3 (stage 3) subjects. Stage 1 shown in dark gray and stage 3 shown in light gray. FIG. 7C and FIG. 7D show that patients with NASH treated with FGF19 analogue M70 had relative abundance of the top bacterial phylotypes at the phylum and genus leels in the FI and F3 groups. Stage 1 shown in dark gray (left) and stage 3 shown in light gray (right).

[0049] FIG. 8A shows that patients with non-alcoholic steatohepatitis (NASH) that had 70% or greater reduction in liver fat content with FGF19 analogue M70 treatment, had a reduction in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). FIG. 8B shows that there is no correlation between the reduction in liver enzymes and Veillonella bacteria. DESCRIPTION

[0050] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for describing particular embodiments only, and is not intended to be limiting.

Definitions

[0051] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering a polypeptide or a pharmaceutical composition comprising a polypeptide) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject. Thus, treatment includes inhibiting (/. ., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0052] The term “in need of treatment” as used herein refers to a judgment made by a physician or other medical professional that a subject requires or will benefit from treatment. [0053] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a polypeptide or a pharmaceutical composition comprising a polypeptide) initiated in a manner ( e.g ., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0054] The term “in need of prevention” as used herein refers to a judgment made by a physician or other medical professional that a subject requires or will benefit from preventative care.

[0055] The term “administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery and/or any other method of physical delivery described herein or known in the art. When a disease, disorder or condition, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of disease, disorder or condition or symptoms thereof. When a disease, disorder or condition, or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease, disorder or condition or symptoms thereof.

[0056] The term “therapeutically effective amount” refers to the administration of an agent to a subject, either alone or as a part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease, disorder or condition when administered to a patient. The therapeutically effective amount can be ascertained by measuring relevant physiological effects.

[0057] The term “metabolic syndrome” refers to an associated cluster of traits that includes, but is not limited to, hyperinsulinemia, abnormal glucose tolerance, obesity, redistribution of fat to the abdominal or upper body compartment, hypertension, dysfibrinolysis, and dyslipidemia characterized by high triglycerides, low high density lipoprotein (HDL)-cholesterol, and high small dense low density lipoprotein (LDL) particles. Subjects having metabolic syndrome are at risk for development of type 2 diabetes and/or other disorders ( e.g ., atherosclerosis).

[0058] The terms “polypeptide,” “peptide,” and “protein”, used interchangeably herein, refer to a polymeric form of amino acids of any length, which can include genetically coded and non- genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with heterologous and homologous leader sequences, with or without N-terminus methionine residues; immunologically tagged proteins; and the like. It will be appreciated that throughout this disclosure reference is made to amino acids according to the single letter or three letter codes. The amino acids forming all or a part of a peptide may be from among the known 21 naturally occurring amino acids, which are referred to by both their single letter abbreviations and their common three-letter abbreviation. In the peptide sequences provided herein, conventional amino acid residues have their conventional meaning. Thus, “Leu” is leucine, “He” is isoleucine, “Me” is norleucine, and so on. To assist the reader, conventional amino acids and their corresponding three letter and single letter abbreviations are as follows: alanine Ala (A) arginine Arg (R) asparagine Asn (N) aspartic acid Asp (D) cysteine Cys (C) glutamic acid Glu (E) glutamine Gin (Q) glycine Gly (G) histidine His (H) isoleucine lie (I) leucine Leu (L) lysine Lys (K) methionine Met (M) phenylalanine Phe (F) proline Pro (P) serine Ser (S) threonine Thr (T) tryptophan Trp (W) tyrosine Tyr (Y) valine Val (V)

[0059] As used herein, the term “variant” encompasses naturally-occurring variants ( e.g ., homologs and allelic variants) and non-naturally-occurring variants (e.g., muteins). Naturally- occurring variants include homologs, i.e., nucleic acids and polypeptides that differ in nucleotide or amino acid sequence, respectively, from one species to another. Naturally-occurring variants include allelic variants, i.e., nucleic acids and polypeptides that differ in nucleotide or amino acid sequence, respectively, from one individual to another within a species. Non-naturally-occurring variants include nucleic acids and polypeptides that comprise a change in nucleotide or amino acid sequence, respectively, where the change in sequence is artificially introduced, e.g, the change is generated in the laboratory or other facility by human intervention (“hand of man”). [0060] The term “native”, in reference to FGF19, refers to biologically active, naturally- occurring FGF19, including biologically active, naturally-occurring FGF19 variants. The term includes the 194 amino acid human FGF19 mature sequence.

[0061] The terms “label”, “labeling” and the like, when use in the context of a polypeptide or nucleic acid (or antibody, as appropriate) of the present disclosure are meant to refer broadly to any means useful in, for example, polypeptide purification, identification, isolation and synthesis. Labels are generally covalently bound to the polypeptide of interest and can be introduced in any manner known in the art, including attachment to a mature polypeptide (generally at the N- or C-terminus), incorporation during solid-phase peptide synthesis, or through recombinant means. Examples include, but are not limited to, fluorescence, biotinylation, and radioactive isotopes. Polypeptide and nucleic acid molecules can be labeled by both in vitro and in vivo methods. Labeling reagents and kits can be obtained from a number of commercial sources (e.g, Thermo Fischer Scientific, Rockford, IL; and Molecular Probes/Life Technologies; Grand Island, NY).

[0062] The term “muteins” as used herein refers broadly to mutated recombinant proteins, i.e., a polypeptide comprising an artificially introduced change in amino acid sequence, e.g, a change in amino acid sequence generated in the laboratory or other facility by human intervention (“hand of man”). These proteins usually carry single or multiple amino acid substitutions and are frequently derived from cloned genes that have been subjected to site- directed or random mutagenesis, or from completely synthetic genes.

[0063] As used herein in reference to native human FGF19 or a FGF19 mutein, the terms “modified”, “modification” and the like refer to one or more changes that enhance a desired property of human FGF19, a naturally-occurring FGF19 variant, or a FGF19 mutein, wherein the change(s) does not alter the primary amino acid sequence of the FGF19. Such desired properties include, for example, enhancing solubility, prolonging the circulation half-life, increasing the stability, reducing the clearance, altering the immunogenicity or allergenicity, improving aspects of manufacturability (e.g., cost and efficiency), and enabling the raising of particular antibodies (e.g, by introduction of unique epitopes) for use in detection assays. Changes to human FGF19, a naturally-occurring FGF19 variant, or a FGF19 mutein that can be carried out include, but are not limited to, pegylation (covalent attachment of one or more molecules of polyethylene glycol (PEG), or derivatives thereof); glycosylation (e.g, N-glycosylation), polysialylation and hesylation; albumin fusion; albumin binding through, for example, a conjugated fatty acid chain (acylation); Fc-fusion; and fusion with a PEG mimetic. Some particular embodiments entail modifications involving polyethylene glycol, other particular embodiments entail modifications involving albumin, and still other particular modifications entail modifications involving glycosylation.

[0064] The terms “DNA”, “nucleic acid”, “nucleic acid molecule”, “polynucleotide” and the like are used interchangeably herein to refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include linear and circular nucleic acids, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers and the like.

[0065] The term “probe” refers to a fragment of DNA or RNA corresponding to a gene or sequence of interest, wherein the fragment has been labeled radioactively (e.g, by incorporating ³² P or ³⁵ S) or with some other detectable molecule, such as biotin, digoxygen or fluorescein. As stretches of DNA or RNA with complementary sequences will hybridize, a probe can be used, for example, to label viral plaques, bacterial colonies or bands on a gel that contain the gene of interest. A probe can be cloned DNA or it can be a synthetic DNA strand; the latter can be used to obtain a cDNA or genomic clone from an isolated protein by, for example, microsequencing a portion of the protein, deducing the nucleic acid sequence encoding the protein, synthesizing an oligonucleotide carrying that sequence, radiolabeling the sequence and using it as a probe to screen a cDNA library or a genomic library.

[0066] The term “heterologous” refers to two components that are defined by structures derived from different sources. For example, in the context of a polypeptide, a “heterologous” polypeptide can include operably linked amino acid sequences that are derived from different polypeptides. Similarly, in the context of a polynucleotide encoding a chimeric polypeptide, a “heterologous” polynucleotide can include operably linked nucleic acid sequences that can be derived from different genes. Exemplary “heterologous” nucleic acids include expression constructs in which a nucleic acid comprising a coding sequence is operably linked to a regulatory element (e.g, a promoter) that is from a genetic origin different from that of the coding sequence ( e.g ., to provide for expression in a host cell of interest, which can be of different genetic origin than the promoter, the coding sequence or both). In the context of recombinant cells, “heterologous” can refer to the presence of a nucleic acid (or gene product, such as a polypeptide) that is of a different genetic origin than the host cell in which it is present. [0067] The term “operably linked” refers to linkage between molecules to provide a desired function. For example, “operably linked” in the context of nucleic acids refers to a functional linkage between nucleic acid sequences. By way of example, a nucleic acid expression control sequence (such as a promoter, signal sequence, or array of transcription factor binding sites) can be operably linked to a second polynucleotide, wherein the expression control sequence affects transcription and/or translation of the second polynucleotide. In the context of a polypeptide, “operably linked” refers to a functional linkage between amino acid sequences (e.g., different domains) to provide for a described activity of the polypeptide.

[0068] As used herein in the context of the structure of a polypeptide, “N-terminus” (or “amino terminus”) and “C-terminus” (or “carboxyl terminus”) refer to the extreme amino and carboxyl ends of the polypeptide, respectively, while the terms “N-terminal” and “C-terminal” refer to relative positions in the amino acid sequence of the polypeptide toward the N-terminus and the C-terminus, respectively, and can include the residues at the N-terminus and C-terminus, respectively. “Immediately N-terminal” or “immediately C-terminal” refers to a position of a first amino acid residue relative to a second amino acid residue where the first and second amino acid residues are covalently bound to provide a contiguous amino acid sequence.

[0069] “Derived from”, in the context of an amino acid sequence or polynucleotide sequence (e.g, an amino acid sequence “derived from” a FGF19 polypeptide), is meant to indicate that the polypeptide or nucleic acid has a sequence that is based on that of a reference polypeptide or nucleic acid (e.g, a naturally occurring FGF19 polypeptide or a FGF 19-encoding nucleic acid), and is not meant to be limiting as to the source or method in which the protein or nucleic acid is made. By way of example, the term “derived from” includes homologues or variants of reference amino acid or DNA sequences.

[0070] In the context of a polypeptide, the term “isolated” refers to a polypeptide of interest that, if naturally occurring, is in an environment different from that in which it can naturally occur. “Isolated” is meant to include polypeptides that are within samples that are substantially enriched for the polypeptide of interest and/or in which the polypeptide of interest is partially or substantially purified. Where the polypeptide is not naturally occurring, “isolated” indicates the polypeptide has been separated from an environment in which it was made by either synthetic or recombinant means.

[0071] “Enriched” means that a sample is non-naturally manipulated (e.g, by a scientist or a clinician) so that a polypeptide of interest is present in a) a greater concentration (e.g, at least 3- fold greater, at least 4-fold greater, at least 8-fold greater, at least 64-fold greater, or more) than the concentration of the polypeptide in the starting sample, such as a biological sample (e.g, a sample in which the polypeptide naturally occurs or in which it is present after administration), or b) a concentration greater than the environment in which the polypeptide was made (e.g., as in a bacterial cell).

Peptides

[0072] Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in the modulation of the gut microbiome. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in promoting enrichment of the gut microbiome. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in promoting enrichment of Veillonella. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in reducing lactate. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in the treatment or prevention of liver disease. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in reducing lactate and thereby ameliorating liver disease. In certain embodiments, the liver disease is NASH. In certain embodiments, the liver disease is cirrhosis. In certain embodiments, the liver disease is PBC. In certain embodiments, the liver disease is acute liver failure. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in the treatment or prevention of a liver-related disease. In certain embodiments, the liver-related disease is hepatic fibrosis. Provided herein, in certain embodiments, are uses of chimeric and peptide sequences in the treatment or prevention of a disease in which lactate is accumulated. The invention is based, in part, on the use of variants of FGF19 peptide sequences, fusions of FGF19 and/or FGF21 peptide sequences and variants of fusions (chimeras) of FGF19 and/or FGF21 peptide sequences having one or more activities associated with modulating the gut microbiome and lactate levels.

[0073] In one embodiment, a chimeric peptide sequence comprises or consists of an N- terminal region having at least seven amino acid residues and the N-terminal region having a first amino acid position and a last amino acid position, where the N-terminal region has a DSSPL (SEQ ID NO: 121) or DASPH (SEQ ID NO: 122) sequence; and a C-terminal region having a portion of FGF19 and the C-terminal region having a first amino acid position and a last amino acid position, where the C-terminal region includes amino acid residues 16-29 of FGF19 (WGDPIRLRHLYTSG; SEQ ID NO: 169) and the W residue corresponds to the first amino acid position of the C-terminal region. In particular embodiments, the variant is M70:

MRD S SPL VHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD S 16MDPF G LVTGLEAVRSPSFEK (SEQ ID NO:70). In other particular embodiments, the variant is M69: RDS SPLVHYGWGDPIRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ S AHSLLEIKAVA LRTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD S 16MDPF GL VTGLEAVRSPSFEK (SEQ ID NO:69). In some embodiments, the N-terminal region has a DSSPL (SEQ ID NO:121). In other embodiments, the N-terminal region has a DASPH (SEQ ID NO: 122) sequence.

[0074] In another embodiment, the treatment peptide, comprises: a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position; and b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises (i) a first C-terminal region sequence comprising WGDPIRLRHLYTSG (amino acids 16 to 29 of SEQ ID NO:99 [FGF19]), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and (ii) a second C-terminal region sequence comprising PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKM QGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPML PMVPEEPEDLRGHLESDMFSSPLETDSMDPFGL VTGLEAVRSPSFEK (amino acid residues 30 to 194 of SEQ ID NO:99 [FGF19]).

[0075] In another embodiment, the treatment peptide, comprises: a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO: 121) or DASPH (SEQ ID NO: 122); and b) a C-terminal region comprising a portion of SEQ ID NO:99 [FGF19], the C-terminal region having a first amino acid position and a last amino acid position, wherein the C-terminal region comprises (i) a first C-terminal region sequence comprising WGDPIRLRHLYTSG (amino acids 16 to 29 of SEQ ID NO:99 [FGF19]), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and (ii) a second C-terminal region sequence comprising

PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGK M QGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPML PMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLE A VRSP SFEK (amino acid residues 30 to 194 of SEQ ID NO:99 [FGF19]). In certain embodiments, the peptide (i) binds to FGFR4 with an affinity equal to or greater than FGF19 binding affinity for FGFR4; (ii) activates FGFR4 to an extent or amount equal to or greater than FGF19 activates FGFR4; (iii) has at least one of reduced HCC formation; greater glucose lowering activity, less lipid increasing activity, less triglyceride activity, less cholesterol activity, less non-HDL activity or less HDL increasing activity; greater lactate reducing activity or greater Veillonella enrichment activity, as compared to FGF19, or as compared to a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV(SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI (SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20 of FGF19 (SEQ ID NO:99); and/or (iv) has less lean mass reducing activity; and/or (v) has greater lactate reducing activity; and/or (vi) has greater Veillonella enrichment activity as compared to FGF21. In some embodiments, the N-terminal region has a DSSPL (SEQ ID NO: 121). In other embodiments, the N-terminal region has a DASPH (SEQ ID NO: 122) sequence.

[0076] In certain embodiments, the second C-terminal region sequence comprises at least one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) sequence. In some embodiments, the at least one amino acid substitution is to the IRP sequence of the EIRPD (amino acids 2-6 of SEQ ID NO: 190) sequence. In some embodiments, the at least one amino acid substitution is to the RP sequence of the EIRPD sequence (amino acids 2-6 of SEQ ID NO: 190). In some embodiments, the at least one amino acid substitution is R to L substitution. In other embodiments, the at least one amino acid substitution is P to E substitution. In yet other embodiments, the at least one amino acid substitution is RP to LE substitution.

[0077] In some embodiments, the second C-terminal region sequence comprises from 2 to 5 amino acid substitutions, deletions or insertions. In other embodiments, the peptide is less than about 250 amino acids in length.

[0078] In one embodiment, the treatment peptide has an amino acid sequence comprising or consisting of

MRD S SPL VHY GW GDPIRLRHL YT SGPHGLS SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL V TGLEAVRSPSFEK (SEQ ID NO:70). In certain embodiments, the treatment peptide has an amino acid sequence comprising SEQ ID NO:70. In other embodiments, the treatment peptide has an amino acid sequence consisting of SEQ ID NO:70. In some embodiments, the treatment peptide is fused with an immunoglobulin Fc region.

[0079] In another embodiment, the treatment peptide has an amino acid sequence comprising or consisting of

RDS SPLVHYGWGDPIRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ S AHSLLEIKAVA LRTVAIKGVHS VRYLCMGADGKMQGLLQ Y SEEDCAFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLEAVRSPSFEK (SEQ ID NO:69). In certain embodiments, the treatment peptide has an amino acid sequence comprising SEQ ID NO:69. In other embodiments, the treatment peptide has an amino acid sequence consisting of SEQ ID NO:69. In some embodiments, the treatment peptide is fused with an immunoglobulin Fc region.

[0080] In another embodiment, the treatment peptide, comprises: a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position,; and b) a C-terminal region comprising a first amino acid position and a last amino acid position, wherein the C-terminal region comprises (i) a first C- terminal region sequence comprising WGDPIRQRHLYTSG (SEQ ID NO: 169 with a L7Q substitution), wherein the W residue corresponds to the first amino acid position of the C- terminal region; and (ii) a second C-terminal region sequence comprising PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKM QGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPML PMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLE A VRSP SFEK (SEQ ID NO: 188). [0081] In another embodiment, the treatment peptide, comprises: a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO: 121), DASPH (SEQ ID NO: 122), or DAGPH (amino acids 7 to 11 of SEQ ID NO: 99 [FGF19]); and b) a C-terminal region comprising a first amino acid position and a last amino acid position, wherein the C-terminal region comprises (i) a first C-terminal region sequence comprising WGDPIRQRHLYTSG (SEQ ID NO: 169 with a L7Q substitution), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and (ii) a second C-terminal region sequence comprising

PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGK M QGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V SLS S AKQRQL YKNRGFLPL SHFLPML PMVPEEPEDLRGHLE SDMF S SPLETD SMDPF GL VT GLE A VRSP SFEK (SEQ ID NO: 188).

In some embodiments, the peptide (i) binds to FGFR4 with an affinity equal to or greater than FGF19 binding affinity for FGFR4; (ii) activates FGFR4 to an extent or amount equal to or greater than FGF19 activates FGFR4; (iii) has at least one of reduced hepatocellular carcinoma (HCC) formation; greater glucose lowering activity, less lipid increasing activity, less triglyceride activity, less cholesterol activity, less non-HDL activity or less HDL increasing activity; greater lactate reducing activity or greater Veillonella enrichment activity as compared to FGF19, or as compared to a FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO: 171), WGDPV (SEQ ID NO: 172), WGDI (SEQ ID NO: 173), GDPI (SEQ ID NO: 174), GPI, WGQPI (SEQ ID NO: 175), WGAPI (SEQ ID NO: 176), AGDPI (SEQ ID NO: 177), WADPI (SEQ ID NO: 178), WGDAI (SEQ ID NO: 179), WGDPA (SEQ ID NO: 180), WDPI (SEQ ID NO: 181), WGDI(SEQ ID NO: 182), WGDP (SEQ ID NO: 183) or FGDPI (SEQ ID NO: 184) substituted for the FGF19 WGDPI (SEQ ID NO: 170) sequence at amino acids 16-20; and/or (iv) has less lean mass reducing activity; and/or (v) has greater lactate reducing activity as compared to FGF21; and/or (vi) has greater Veillonella enrichment activity as compared to FGF21.

[0082] In certain embodiments, the second C-terminal region sequence comprises at least one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) sequence. In some embodiments, the at least one amino acid substitution is to the IRP sequence of the EIRPD (amino acids 2-6 of SEQ ID NO: 190) sequence. In some embodiments, the at least one amino acid substitution is to the RP sequence of the EIRPD sequence (amino acids 2-6 of SEQ ID NO: 190). In some embodiments, the at least one amino acid substitution is R to L substitution.

In other embodiments, the at least one amino acid substitution is P to E substitution. In yet other embodiments, the at least one amino acid substitution is RP to LE substitution.

[0083] In some embodiments, the second C-terminal region sequence comprises from 2 to 5 amino acid substitutions, deletions or insertions. In other embodiments, the peptide is less than about 250 amino acids in length.

[0084] In another embodiment, a chimeric peptide sequence comprises or consists of an N- terminal region having a portion of FGF21 and the N-terminal region having a first amino acid position and a last amino acid position, where the N-terminal region has a GQV sequence and the V residue corresponds to the last amino acid position of the N-terminal region; and a C- terminal region having a portion of FGF19 and the C-terminal region having a first amino acid position and a last amino acid position where the C-terminal region includes amino acid residues 21-29 of FGF19 (RLRHLYTSG; SEQ ID NO: 185) and the R residue corresponds to the first position of the C-terminal region.

[0085] In particular aspects, modifications to the Loop-8 region of FGF19 are disclosed herein that possess favorable metabolic parameters without exhibiting substantial tumorigenicity. Herein, FGF19 residues 127-129 are defined as constituting the Loop-8 region, although in the literature the Loop-8 region is sometimes defined as including or consisting of other residues ( e.g ., residues 125-129). Certain combinations of R127L and P128E substitutions to the FGF19 framework had an unexpectedly positive effect on HCC formation. Even more surprisingly, a combination of R127L and P128E substitutions and a substitution of Gin (Q) for Leu (L) in the FGF19 core region had an even more significant effect on preventing HCC formation. Accordingly, variants of FGF19 Loop-8 region are included since they can reduce or eliminate substantial, measurable or detectable HCC formation. Furthermore, the effect of reducing HCC formation may be enhanced by modifications to amino acid residues outside of the Loop 8 region (e.g., substitutions of amino acid residues in the core region).

[0086] Accordingly, variants of FGF19 Loop-8 region are included since they can reduce or eliminate substantial, measurable or detectable HCC formation. Furthermore, the effect of reducing HCC formation may be enhanced by modifications to amino acid residues outside of the Loop-8 region ( e.g ., substitutions of amino acid residues in the core region, such as the region corresponding to amino acids 21-29 of SEQ ID NO: 99). In some embodiments, the Loop-8 modified variant comprises a substitution in the FGF19 Loop-8 region corresponding to amino acids 127-129 of SEQ ID NO:99. In certain embodiments, the Loop-8 modified variant comprises a substitution in the FGF19 Loop-8 region corresponding to (i) a R127L substitution, (ii) a P128E substitution, or (iii) a R127L substitution and a P128E substitution.

[0087] In certain embodiments, the amino acid sequence of the peptide comprises at least one amino acid substitution in the Loop-8 region of FGF19, or the corresponding FGF19 sequence thereof in a variant peptide provided herein. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO:190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises four amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises five amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO:190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the RP (amino acids 4-5 of SEQ ID NO:190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution. In other embodiments, the substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is a Pro (P) to Glu (E) substitution. In some embodiments, the substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution and a Pro (P) to Glu (E) substitution. In specific embodiments, the foregoing substitution(s) in the Loop-8 region of FGF19 is in the corresponding FGF19 sequence thereof in a variant peptide provided herein. That is, said substitutions within a corresponding FGF19 sequence (e.g., EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated.

[0088] In some embodiments, the FGF19 variant comprises or further comprises a substitution in the core region corresponding to amino acids 21-29 of SEQ ID NO:99. In certain embodiments, the FGF19 variant comprises or further comprises a substitution in the core region corresponding to a L22Q substitution.

[0089] In some embodiments, the Loop-8 modified variant is M70:

MRD S SPL VHY GW GDPIRLRHL YT SGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEIK AV ALRTVAIKGVHSVRYLCMGADGKMOGLLOYSEEDCAFEEEIRPDGYNVYRSEKHRLPV SL S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD S 16MDPF G LVTGLEAVRSPSFEK (SEQ ID NO:70), comprising a substitution in the FGF19 Loop-8 region (underlined). In certain embodiments, the Loop-8 modified M70 variant comprises a substitution in the FGF19 Loop-8 region (RPD; underlined) corresponding to (i) an R to L substitution, (ii) a P to E substitution, or (iii) an R to L substitution and a P to E substitution (SEQ. ID NO:204). In certain embodiments, the Loop-8 modified M70 variant further comprises or further comprises a substitution in the FGF19 core region. In some embodiments, the Loop-8 modified M70 variant comprises a L18Q substitution ( i.e SEQ ID NO:70 with an L18Q substitution).

[0090] In some embodiments, the Loop-8 modified variant is M69:

RDS SPLVHYGWGDPIRLRHLYTSGPHGLS SCFLRIRADGVVDC ARGQ S AHSLLEIKAVA LRTVAIKGVIIS VRYLCMGADGKMQGLLQ Y SEEDC AFEEEIRPDGYNVYRSEKHRLP V S L S S AKQRQL YKNRGFLPL SHFLPMLPMVPEEPEDLRGHLE SDMF S SPLETD S 16MDPF GL VTGLEAVRSPSFEK (SEQ ID NO:69), comprising a substitution in the FGF19 Loop-8 region (underlined). In certain embodiments, the Loop-8 modified M69 variant comprises a substitution in the FGF19 Loop-8 region (RPD; underlined) corresponding to (i) an R to L substitution, (ii) a P to E substitution, or (iii) an R to L substitution and a P to E substitution. In certain embodiments, the Loop-8 modified M69 variant further comprises or further comprises a substitution in the FGF19 core region. In some embodiments, the Loop-8 modified M69 variant comprises a L17Q substitution ( i.e SEQ ID NO:69 with an L17Q substitution).

[0091] Other counterpart modifications in other variants provided herein are also contemplated. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO:190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises four amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises five amino acid substitutions to the EIRPD (amino acids 2-6 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the IRP (amino acids 3-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In other embodiments, the amino acid sequence of the peptide comprises three amino acid substitutions to the IRP (amino acids 3- 5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid sequence of the peptide comprises one amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In some embodiments, the amino acid sequence of the peptide comprises two amino acid substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19. In certain embodiments, the amino acid substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution. In other embodiments, the substitution to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is a Pro (P) to Glu (E) substitution. In some embodiments, the substitutions to the RP (amino acids 4-5 of SEQ ID NO: 190) amino acid sequence in the Loop-8 region of FGF19 is an Arg (R) to Leu (L) substitution and a Pro (P) to Glu (E) substitution. In specific embodiments, the foregoing substitution(s) in the Loop-8 region of FGF19 is in the corresponding FGF19 sequence thereof in a variant peptide provided herein. That is, said substitutions within a corresponding FGF19 sequence ( e.g EIRPD, IRP or RP) of a peptide variant provided herein is also contemplated. [0092] In further embodiments, a peptide sequence includes or consists of a FGF19 variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19. In additional embodiments, a peptide sequence includes or consists of a FGF21 sequence variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF21. In yet additional embodiments, a peptide sequence includes or consists of a portion of a FGF19 sequence fused to a portion of a FGF21 sequence.

In still additional embodiments, a peptide sequence includes or consists of a portion of a FGF19 sequence fused to a portion of a FGF21 sequence, where the FGF19 and/or FGF21 sequence portion(s) have one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19 and/or FGF21. Examples of such sequences are disclosed in PCT Pub. No. WO 2013/006486 and US Pub. No. 2013/0023474, as well as PCT Publ. No. WO 2014/085365, published June 5, 2014. Table 1 and the Sequence Listing also set forth representative sequences that may be used in the methods provided herein.

[0093] In some embodiments, the treatment peptides provided herein include variants and fusions of FGF19 and/or FGF21 peptide sequences. In one embodiment, the treatment peptides include one or more variant or fusion FGF19 and/or FGF21 peptide. In other embodiments, the methods provided herein include contacting or administering to a subject one or more nucleic acid molecules encoding a variant or fusion FGF19 and/or FGF21 peptide sequence (for example, an expression control element in operable linkage with the nucleic acid encoding the peptide sequence, optionally including a vector), in an amount effective for treating a disease associated with elevated lactate.

[0094] A representative reference or wild type FGF19 sequence is set forth as:

RPL AF SD AGPHVHY GW GDPIRLRHL YTSGPHGL S SCFLRIRADGVVDC ARGQ S AHSLLEI KAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNVYRSEKH RLP V SL S S AKQRQL YKNRGFLPL SHFLPMLPM VPEEPEDLRGHLE SDMF S SPLETD SMDP FGLVTGLEAVRSPSFEK (SEQ ID NO:99).

[0095] A representative reference or wild type FGF21 sequence is set forth as:

HPIPD S SPLLQF GGQ VRQRYL YTDD AQQTEAHLEIREDGT VGGAADQ SPESLLQLK ALK PGVIQILGVKT SRFLCQRPDGAL Y GSLHFDPEAC SFRELLLEDGYN VY Q SEAHGLPLHLP GNKSPHRDPAPRGPARFLPLPGLPPALPEPPGILAPQPPDVGSSDPLSMVGPSQGRSPSY A S (SEQ ID NO: 100). FGF21 allelic variants include, e.g., M70, M71 and M72.

[0096] In further embodiments, a peptide sequence comprises or consists of a FGF19 variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19. In additional embodiments, a peptide sequence comprises or consists of a FGF21 sequence variant having one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF21. In yet additional embodiments, a peptide sequence comprises or consists of a portion of a FGF19 sequence fused to a portion of a FGF21 sequence. In still additional embodiments, a peptide sequence comprises or consists of a portion of a FGF19 sequence fused to a portion of a FGF21 sequence, where the FGF19 and/or FGF21 sequence portion(s) have one or more amino acid substitutions, insertions or deletions compared to a reference or wild type FGF19 and/or FGF21. Examples of such sequences are disclosed in PCT Pub. No. WO 2013/006486 and US Pub. No. 2013/0023474, as well as PCT Publ. No. WO 2014/085365, published June 5, 2014. Table 1 and the Sequence Listing also sets forth representative sequences that may be used in the methods provided herein.

[0097] In various particular aspects, a peptide or chimeric sequence provided herein has at the N-terminal region first amino acid position an “M” residue, an “R” residue, a “S” residue, a “H” residue, a “P” residue, a “L” residue or an “D” residue. In various alternative particular aspects, a peptide or chimeric sequence peptide sequence does not have a “M” residue or an “R” residue at the first amino acid position of the N-terminal region.

[0098] Typically, the number of amino acids or residues in a peptide sequence provided herein will total less than about 250 (e.g., amino acids or mimetics thereof). In various particular embodiments, the number of residues comprise from about 20 up to about 200 residues (e.g, amino acids or mimetics thereof). In additional embodiments, the number of residues comprise from about 50 up to about 200 residues (e.g, amino acids or mimetics thereof). In further embodiments, the number of residues comprise from about 100 up to about 195 residues ( e.g ., amino acids or mimetics thereof) in length.

[0099] Amino acids or residues can be linked by amide or by non-natural and non-amide chemical bonds including, for example, those formed with glutaraldehyde, N- hydroxysuccinimide esters, bifunctional maleimides, orN, N’-dicyclohexylcarbodiimide (DCC). Non-amide bonds include, for example, ketomethylene, aminomethylene, olefin, ether, thioether and the like (see, e.g., Spatola in Chemistry and Biochemistry of Amino Acids. Peptides and Proteins. Vol. 7, pp 267-357 (1983), “Peptide and Backbone Modifications,” Marcel Decker, NY). Thus, when a peptide provided herein includes a portion of a FGF19 sequence and a portion of a FGF21 sequence, the two portions need not be joined to each other by an amide bond, but can be joined by any other chemical moiety or conjugated together via a linker moiety. [00100] Also provided herein are subsequences, variants and modified forms of the exemplified peptide sequences (including the FGF19 and FGF21 variants and subsequences listed in the Sequence Listing, or Table 1), so long as the foregoing retains at least a detectable or measureable activity or function. Also, certain exemplified variant peptides, for example, those having all or a portion of FGF21 sequence at the amino-terminus, have an “R” residue positioned at the N-terminus, which can be omitted. Similarly, certain exemplified variant peptides, include an “M” residue positioned at the N-terminus, which can be appended to or further substituted for an omitted residue, such as an “R” residue. More particularly, in various embodiments peptide sequences at the N-terminus include any of: RDSS (SEQ ID NO: 115), DSS, MDSS (SEQ ID NO: 116) or MRDSS (SEQ ID NO: 117). Furthermore, when a “M” residue is adjacent to a “S” residue, the “M” residue may be cleaved such that the “M” residue is deleted from the peptide sequence, whereas when the “M” residue is adjacent to a “D” residue, the “M” residue may not be cleaved. Thus, by way of example, in various embodiments peptide sequences include those with the following residues at the N-terminus: MDSSPL (SEQ ID NO: 119), MSDSSPL (SEQ ID NO: 120) (cleaved to SDSSPL (SEQ ID NO: 112)) and MSSPL (SEQ ID NO: 113) (cleaved to SSPL (SEQ ID NO: 114)).

[00101] As used herein, the term “modify” and grammatical variations thereof, means that the composition deviates relative to a reference composition, such as a peptide sequence. Such modified peptide sequences, nucleic acids and other compositions may have greater or less activity or function, or have a distinct function or activity compared with a reference unmodified peptide sequence, nucleic acid, or other composition, or may have a property desirable in a protein formulated for therapy ( e.g . serum half-life), to elicit antibody for use in a detection assay, and/or for protein purification. For example, a peptide sequence provided herein can be modified to increase serum half-life, to increase in vitro and/or in vivo stability of the protein, etc.

[00102] Particular examples of such subsequences, variants and modified forms of the peptide sequences exemplified herein (e.g., a peptide sequence listed in the Sequence Listing or Table 1) include substitutions, deletions and/or insertions/additions of one or more amino acids, to or from the amino-terminus, the carboxy-terminus or internally. One example is a substitution of an amino acid residue for another amino acid residue within the peptide sequence. Another is a deletion of one or more amino acid residues from the peptide sequence, or an insertion or addition of one or more amino acid residues into the peptide sequence.

[00103] The number of residues substituted, deleted or inserted/added are one or more amino acids (e.g, 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100- 110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200- 225, 225-250, or more) of a peptide sequence. Thus, a FGF19 or FGF21 sequence can have few or many amino acids substituted, deleted or inserted/added (e.g, 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140- 150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250, or more). In addition, a FGF19 amino acid sequence can include or consist of an amino acid sequence of about 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120- 130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250, or more amino acids from FGF21; or a FGF21 amino acid or sequence can include or consist of an amino acid sequence of about 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180- 190, 190-200, 200-225, 225-250, or more amino acids from FGF19.

[00104] Specific examples of substitutions include substituting a D residue for an L-residue. Accordingly, although residues are listed in the L-isomer configuration, D-amino acids at any particular or all positions of the peptide sequences provided herein are included, unless a D- isomer leads to a sequence that has no detectable or measurable function. [00105] Additional specific examples are non-conservative and conservative substitutions. A “conservative substitution” is a replacement of one amino acid by a biologically, chemically or structurally similar residue. Biologically similar means that the substitution is compatible with a biological activity, e.g ., activity that ameliorate disease associated with elevated lactate and/or the manifestations thereof. Structurally similar means that the amino acids have side chains with similar length, such as alanine, glycine and serine, or having similar size, or the structure of a first, second or additional peptide sequence is maintained. Chemical similarity means that the residues have the same charge or are both hydrophilic and hydrophobic. Particular examples include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine or methionine, for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, serine for threonine, etc. Routine assays can be used to determine whether a subsequence, variant or modified form has activity, e.g. , activity that ameliorate disease associated with elevated lactate and/or the manifestations thereof.

[00106] Particular examples of subsequences, variants and modified forms of the peptide sequences exemplified herein have 50%-60%, 60%-70%, 70%-75%, 75%-80%, 80%-85%, 85%- 90%, 90%-95%, or 96%, 97%, 98%, or 99% identity to a reference peptide sequence. The term “identity” and “homology” and grammatical variations thereof mean that two or more referenced entities are the same. Thus, where two amino acid sequences are identical, they have the identical amino acid sequence. “Areas, regions or domains of identity” mean that a portion of two or more referenced entities are the same. Thus, where two amino acid sequences are identical or homologous over one or more sequence regions, they share identity in those regions. [00107] The extent of identity between two sequences can be ascertained using a computer program and mathematical algorithm known in the art. Such algorithms that calculate percent sequence identity (homology) generally account for sequence gaps and mismatches over the comparison region. For example, a BLAST (e.g, BLAST 2.0) search algorithm (see, e.g, Altschul etal, J. Mol. Biol. 215:403 (1990), publicly available through NCBI) has exemplary search parameters as follows: Mismatch -2; gap open 5; gap extension 2. For peptide sequence comparisons, a BLASTP algorithm is typically used in combination with a scoring matrix, such as PAMIOO, PAM 250, BLOSUM 62 or BLOSUM 50. FASTA (e.g, FASTA2 and FASTA3) and SSEARCH sequence comparison programs are also used to quantitate the extent of identity (Pearson et al, Proc. Natl. Acad. Sci. USA 85:2444 (1988); Pearson, Methods Mol Biol. 132:185 (2000); and Smith et al. , J. Mol. Biol. 147:195 (1981)). Programs for quantitating protein structural similarity using Delaunay-based topological mapping have also been developed (Bostick et al. , Biochem Biophys Res Commun. 304:320 (2003)).

[00108] In the peptide sequences, including subsequences, variants and modified forms of the peptide sequences exemplified herein, an “amino acid” or “residue” includes conventional alpha- amino acids as well as beta-amino acids; alpha, alpha disubstituted amino acids; and N- substituted amino acids, wherein at least one side chain is an amino acid side chain moiety as defined herein. An “amino acid” further includes N-alkyl alpha-amino acids, wherein the N- terminus amino group has a Ci to G linear or branched alkyl substituent. The term “amino acid” therefore includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids (e.g, by glycosylation, phosphorylation, ester or amide cleavage, etc.), enzymatically modified or synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, amino acids with a side chain moiety modified, derivatized from naturally occurring moieties, or synthetic, or not naturally occurring, etc. Modified and unusual amino acids are included in the peptide sequences provided herein (see, for example, in Synthetic Peptides: A User’s Guide: Hruby et al, Biochem. J. 268:249 (1990); and Toniolo C., Int. J. Peptide Protein Res. 35:287 (1990)).

[00109] In addition, protecting and modifying groups of amino acids are included. The term “amino acid side chain moiety” as used herein includes any side chain of any amino acid, as the term “amino acid” is defined herein. This therefore includes the side chain moiety in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids as set forth herein and known to one of skill in the art, such as side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified or synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, etc. For example, the side chain moiety of any amino acid disclosed herein or known to one of skill in the art is included within the definition.

[00110] A “derivative of an amino acid side chain moiety” is included within the definition of an amino acid side chain moiety. Non-limiting examples of derivatized amino acid side chain moieties include, for example: (a) adding one or more saturated or unsaturated carbon atoms to an existing alkyl, aryl, or aralkyl chain; (b) substituting a carbon in the side chain with another atom, such as oxygen or nitrogen; (c) adding a terminal group to a carbon atom of the side chain, including methyl (— CH3), methoxy (— OCH3), nitro (— NO2), hydroxyl (—OH), or cyano (— C=N); (d) for side chain moieties including a hydroxy, thiol or amino groups, adding a suitable hydroxy, thiol or amino protecting group; or (e) for side chain moieties including a ring structure, adding one or more ring substituents, including hydroxyl, halogen, alkyl, or aryl groups attached directly or through, e.g ., an ether linkage. For amino groups, suitable protecting groups are known to the skilled artisan. Provided such derivatization provides a desired activity in the final peptide sequence (e.g, activity that ameliorate disease associated with elevated lactate and/or the manifestations thereof).

[00111] An “amino acid side chain moiety” includes all such derivatization, and particular non-limiting examples include: gamma-amino butyric acid, 12-amino dodecanoic acid, alpha- aminoisobutyric acid, 6-amino hexanoic acid, 4-(aminomethyl)-cyclohexane carboxylic acid, 8- amino octanoic acid, biphenylalanine, Boc— t-butoxycarbonyl, benzyl, benzoyl, citrulline, diaminobutyric acid, pyrrollysine, diaminopropionic acid, 3,3-diphenylalanine, orthonine, citrulline, l,3-dihydro-2H-isoindolecarboxylic acid, ethyl, Fmoc — fluorenylmethoxycarbonyl, heptanoyl (CH3— (CH2)s— C(=0)~ ), hexanoyl (CH3— (CH2)4— C(=0)~ ), homoarginine, homocysteine, homolysine, homophenylalanine, homoserine, methyl, methionine sulfoxide, methionine sulfone, norvaline (NVA), phenylglycine, propyl, isopropyl, sarcosine (SAR), tert- butylalanine, and benzyloxy carbonyl.

[00112] A single amino acid, including stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically-synthesized amino acids, non-naturally occurring amino acids including derivatized amino acids, an alpha, alpha disubstituted amino acid derived from any of the foregoing (i.e., an alpha, alpha disubstituted amino acid, wherein at least one side chain is the same as that of the residue from which it is derived), a beta-amino acid derived from any of the foregoing (i.e., a beta-amino acid which, other than for the presence of a beta-carbon, is the same as the residue from which it is derived) etc., including all of the foregoing can be referred to herein as a “residue.” Suitable substituents, in addition to the side chain moiety of the alpha- amino acid, include Ci to Ce linear or branched alkyl. Aib is an example of an alpha, alpha disubstituted amino acid. While alpha, alpha disubstituted amino acids can be referred to using conventional L- and D-isomeric references, it is to be understood that such references are for convenience, and that where the substituents at the alpha-position are different, such amino acid can interchangeably be referred to as an alpha, alpha disubstituted amino acid derived from the L- or D-isomer, as appropriate, of a residue with the designated amino acid side chain moiety. Thus (S)-2-Amino-2-methyl-hexanoic acid can be referred to as either an alpha, alpha disubstituted amino acid derived from L-Nle (norleucine) or as an alpha, alpha disubstituted amino acid derived from D-Ala. Similarly, Aib can be referred to as an alpha, alpha disubstituted amino acid derived from Ala. Whenever an alpha, alpha disubstituted amino acid is provided, it is to be understood as including all (R) and (S) configurations thereof.

[00113] An “N- substituted amino acid” includes any amino acid wherein an amino acid side chain moiety is covalently bonded to the backbone amino group, optionally where there are no substituents other than H in the alpha-carbon position. Sarcosine is an example of an N- substituted amino acid. By way of example, sarcosine can be referred to as an N-substituted amino acid derivative of Ala, in that the amino acid side chain moiety of sarcosine and Ala is the same, i.e., methyl.

[00114] In certain embodiments, covalent modifications of the peptide sequences, including subsequences, variants and modified forms of the peptide sequences exemplified herein are provided. An exemplary type of covalent modification includes reacting targeted amino acid residues with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues of the peptide. Derivatization with bifunctional agents is useful, for instance, for cross-linking peptide to a water-insoluble support matrix or surface for use in the method for purifying anti-peptide antibodies, and vice-versa. Commonly used cross linking agents include, e.g ., l,l-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3’-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1, 8-octane and agents such as methyl-3-[(p- azi dopheny l)dithi o]propi oimi date .

[00115] Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties. W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)), acetylation of the N-terminal amine, amidation of any C-terminal carboxyl group, etc.

[00116] Exemplified peptide sequences, and subsequences, variants and modified forms of the peptide sequences exemplified herein can also include alterations of the backbone for stability, derivatives, and peptidomimetics. The term “peptidomimetic” includes a molecule that is a mimic of a residue (referred to as a “mimetic”), including but not limited to piperazine core molecules, keto-piperazine core molecules and diazepine core molecules. Unless otherwise specified, an amino acid mimetic of a peptide sequence provided herein includes both a carboxyl group and amino group, and a group corresponding to an amino acid side chain, or in the case of a mimetic of Glycine, no side chain other than hydrogen.

[00117] By way of example, these would include compounds that mimic the sterics, surface charge distribution, polarity, etc. of a naturally occurring amino acid, but need not be an amino acid, which would impart stability in the biological system. For example, Proline may be substituted by other lactams or lactones of suitable size and substitution; Leucine may be substituted by an alkyl ketone, N-substituted amide, as well as variations in amino acid side chain length using alkyl, alkenyl or other substituents, others may be apparent to the skilled artisan. The essential element of making such substitutions is to provide a molecule of roughly the same size and charge and configuration as the residue used to design the molecule. Refinement of these modifications will be made by analyzing the compounds in a functional ( e.g ., glucose lowering) or other assay, and comparing the structure-activity relationship. Such methods are within the scope of the skilled artisan working in medicinal chemistry and drug development.

[00118] The term “bind,” or “binding,” when used in reference to a peptide sequence, means that the peptide sequence interacts at the molecular level. Specific and selective binding can be distinguished from non-specific binding using assays known in the art (e.g., competition binding, immunoprecipitation, ELISA, flow cytometry, Western blotting).

[00119] Peptides and peptidomimetics can be produced and isolated using methods known in the art. Peptides can be synthesized, in whole or in part, using chemical methods (see, e.g, Caruthers (1980). Nucleic Acids Res. Symp. Ser. 215; Horn (1980); and Banga, A.K., Therapeutic Peptides and Proteins. Formulation. Processing and Delivery Systems (1995) Technomic Publishing Co., Lancaster, PA). Peptide synthesis can be performed using various solid-phase techniques (see, e.g ., Roberge Science 269:202 (1995); Merrifield, Methods Enzymol. 289:3 (1997)) and automated synthesis may be achieved, e.g. , using the ABI 431 A Peptide Synthesizer (Perkin Elmer) in accordance with the manufacturer’s instructions. Peptides and peptide mimetics can also be synthesized using combinatorial methodologies. Synthetic residues and polypeptides incorporating mimetics can be synthesized using a variety of procedures and methodologies known in the art (see, e.g. , Organic Syntheses Collective Volumes, Gilman, etal. (Eds) John Wiley & Sons, Inc., NY). Modified peptides can be produced by chemical modification methods (see, for example, Belousov, Nucleic Acids Res. 25:3440 (1997); Frenkel, Free Radic. Biol. Med. 19:373 (1995); and Blommers, Biochemistry 33:7886 (1994)). Peptide sequence variations, derivatives, substitutions and modifications can also be made using methods such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR-based mutagenesis. Site-directed mutagenesis (Carter et al ., Nucl. Acids Res., 13:4331 (1986); Zoller etal, Nucl. Acids Res. 10:6487 (1987)), cassette mutagenesis (Wells etal. , Gene 34:315 (1985)), restriction selection mutagenesis (Wells et al. , Philos. Trans. R. Soc. London SerA 317:415 (1986)) and other techniques can be performed on cloned DNA to produce peptide sequences, variants, fusions and chimeras provided herein, and variations, derivatives, substitutions and modifications thereof.

[00120] A “synthesized” or “manufactured” peptide sequence is a peptide made by any method involving manipulation by the hand of man. Such methods include, but are not limited to, the aforementioned, such as chemical synthesis, recombinant DNA technology, biochemical or enzymatic fragmentation of larger molecules, and combinations of the foregoing.

[00121] Peptide sequences provided herein including subsequences, sequence variants and modified forms of the exemplified peptide sequences (e.g., sequences listed in the Sequence Listing or Table 1), can also be modified to form a chimeric molecule. In certain embodiments, provided herein are peptide sequences that include a heterologous domain. Such domains can be added to the amino-terminus or at the carboxyl-terminus of the peptide sequence. Heterologous domains can also be positioned within the peptide sequence, and/or alternatively flanked by FGF19 and/or FGF21 derived amino acid sequences.

[00122] The term “peptide” also includes dimers or multimers (oligomers) of peptides. In certain embodiments, dimers or multimers (oligomers) of the exemplified peptide sequences are provided herein, as well as subsequences, variants and modified forms of the exemplified peptide sequences, including sequences listed in the Sequence Listing or Table 1.

[00123] In certain embodiments, a peptide sequence provided herein comprises an amino acid sequence set forth in Table 1. In other embodiments, a peptide sequence provided herein consists of an amino acid sequence set forth in Table 1.

Table 1

[00124] In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:l. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:2. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:3. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:4. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:5. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:6. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:7. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:8. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:9. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 10. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 11. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 12. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 13. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 14. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 15. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 16. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 17. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 18. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 19. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:20. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:21. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:22. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:23. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:24. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:25. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:26. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:27. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:28. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:29. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:30. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:31. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:32. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:33. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:34. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:35. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:36. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:37. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:38. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:39. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:40. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:41. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:42. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:43. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:44. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:45. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:46. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:47. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:48. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:49. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:50. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:51. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:52. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:53. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:54. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:55. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:56. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:57. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:58. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:59. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:60. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:61. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:62. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:63. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:64. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:65. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:66. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:67. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:68. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:69. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:70. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:71. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:72. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:73. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:74. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:75. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:76. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:77. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:78. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:79. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:80. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:81. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:82. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:83. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:84. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:85. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:86. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:87. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:88. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:89. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:90. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:91. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:92. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:93. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:94. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:95. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:96. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:97. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:98. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 138. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 139. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 140. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 141. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 142. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 143. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 144. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 145. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 146. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 147. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 148. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 149. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 150. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 151. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 152. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 153. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 154. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 155. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 156. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 157. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 158. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 159. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 160. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 161. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 162. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 163. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 164. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 165. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 166. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 167. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 168. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 192. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 193. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 194. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 195. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 196. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 197. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 198. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO: 199. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:200. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:201. In other embodiments, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:202. In one embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:203. In another embodiment, the peptide sequence comprises an amino acid sequence set forth in SEQ ID NO:204. In certain embodiments of the various peptide sequences provided herein, the R residue at the N-terminus is deleted.

[00125] In yet other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 1. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:2. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:3. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:4. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:5. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:6. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:7. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:8. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:9. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 10. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 11. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 12. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 13. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 14. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 15. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 16. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 17. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 18. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 19. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:20. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:21. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:22. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:23. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:24. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:25. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:26. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:27. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:28. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:29. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:30. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:31. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:32. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:33. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:34. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:35. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:36. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:37. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:38. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:39. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:40. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:41. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:42. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:43. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:44. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:45. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:46. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:47. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:48. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:49. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:50. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:51. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:52. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:53. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:54. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:55. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:56. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:57. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 58. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:59. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:60. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:61. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:62. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:63. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:64. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:65. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:66. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:67. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:68. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:69. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:70. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:71. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:72. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:73. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:74. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:75. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:76. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:77. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:78. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:79. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:80. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:81. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:82. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:83. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:84. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:85. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:86. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:87. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:88. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:89. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:90. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:91. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:92. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:93. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:94. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:95. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:96. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:97. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:98. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 138. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 139. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 140. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 141. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 142. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:143. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 144. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 145. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 146. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 147. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 148. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 149. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 150. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 151. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 152. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 153. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 154. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:155. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 156. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 157. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 158. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 159. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 160. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 161. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 162. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 163. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 164. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 165. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 166. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 167. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 168. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 192. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 193. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 194. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 195. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 196. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 197. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 198. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO: 199. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:200. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:201. In other embodiments, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:202. In one embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:203. In another embodiment, the peptide sequence consists of an amino acid sequence set forth in SEQ ID NO:204. In certain embodiments of the various peptide sequences provided herein, the R residue at the N-terminus is deleted.

Nucleic Acid Molecules

[00126] Also provided are nucleic acid molecules encoding peptide sequences provided herein, including subsequences, sequence variants and modified forms of the sequences listed in the Sequence Listing or Table 1, and in PCT Pub. No. WO 2013/006486 and US Pub. No. 2013/0023474, as well as PCT Publ. No. WO 2014/085365, and vectors that include nucleic acid encoding the peptides used in the methods described herein. Accordingly, “nucleic acids” include those that encode the exemplified peptide sequences disclosed herein, as well as those encoding functional subsequences, sequence variants and modified forms of the exemplified peptide sequences, so long as the foregoing retain at least detectable or measureable activity or function useful in the modulation of lactate homeostasis, or in the treatment or prevention of disease associated with elevated lactate.

[00127] Nucleic acid, which can also be referred to herein as a gene, polynucleotide, nucleotide sequence, primer, oligonucleotide or probe, refers to natural or modified purine- and pyrimidine-containing polymers of any length, either polyribonucleotides or polydeoxyribonucleotides or mixed polyribo-polydeoxyribo nucleotides and a-anomeric forms thereof. The two or more purine- and pyrimidine-containing polymers are typically linked by a phosphoester bond or analog thereof. The terms can be used interchangeably to refer to all forms of nucleic acid, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The nucleic acids can be single strand, double, or triplex, linear or circular. Nucleic acids include genomic DNA and cDNA. RNA nucleic acid can be spliced or unspliced mRNA, rRNA, tRNA or antisense. Nucleic acids include naturally occurring, synthetic, as well as nucleotide analogs and derivatives.

[00128] The terms “SNP” or “single nucleotide polymorphism” refer to a variation in a single nucleotide that occurs at a specific position in the genome. Single-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. [00129] As a result of the degeneracy of the genetic code, the nucleic acid molecules provided herein include sequences degenerate with respect to nucleic acid molecules encoding the peptide sequences useful in the methods provided herein. Thus, degenerate nucleic acid sequences encoding peptide sequences, including subsequences, variants and modified forms of the peptide sequences exemplified herein ( e.g ., in the Sequence Listing or Table 1), are provided. The term “complementary,” when used in reference to a nucleic acid sequence, means the referenced regions are 100% complementary, /. e. , exhibit 100% base pairing with no mismatches.

[00130] Nucleic acid can be produced using any of a variety of known standard cloning and chemical synthesis methods, and can be altered intentionally by site-directed mutagenesis or other recombinant techniques known to one skilled in the art. Purity of polynucleotides can be determined through, for example, sequencing, gel electrophoresis, and UV spectrometry.

[00131] Nucleic acids may be inserted into a nucleic acid construct in which expression of the nucleic acid is influenced or regulated by an “expression control element,” referred to herein as an “expression cassette.” The term “expression control element” refers to one or more nucleic acid sequence elements that regulate or influence expression of a nucleic acid sequence to which it is operatively linked. An expression control element can include, as appropriate, promoters, enhancers, transcription terminators, gene silencers, a start codon (e.g., ATG) in front of a protein-encoding gene, etc.

[00132] An expression control element operatively linked to a nucleic acid sequence controls transcription and, as appropriate, translation of the nucleic acid sequence. The term “operatively linked” refers to a juxtaposition wherein the referenced components are in a relationship permitting them to function in their intended manner. Typically, expression control elements are juxtaposed at the 5’ or the 3’ ends of the genes but can also be intronic.

[00133] Expression control elements include elements that activate transcription constitutively, that are inducible (i.e., require an external signal or stimuli for activation), or derepressible (i.e., require a signal to turn transcription off; when the signal is no longer present, transcription is activated or “derepressed”). Also included in the expression cassettes provided herein are control elements sufficient to render gene expression controllable for specific cell types or tissues (i.e., tissue-specific control elements). Typically, such elements are located up stream or downstream (i.e., 5’ or 3’) of the coding sequence. Promoters are generally positioned 5’ of the coding sequence. Promoters, produced by recombinant DNA or synthetic techniques, can be used to provide for transcription of the polynucleotides provided herein. A “promoter” typically means a minimal sequence element sufficient to direct transcription.

[00134] Nucleic acids may be inserted into a plasmid for transformation into a host cell and for subsequent expression and/or genetic manipulation. A plasmid is a nucleic acid that can be stably propagated in a host cell; plasmids may optionally contain expression control elements in order to drive expression of the nucleic acid. For purposes of this invention, a vector is synonymous with a plasmid. Plasmids and vectors generally contain at least an origin of replication for propagation in a cell and a promoter. Plasmids and vectors may also include an expression control element for expression in a host cell, and are therefore useful for expression and/or genetic manipulation of nucleic acids encoding peptide sequences, expressing peptide sequences in host cells and organisms, or producing peptide sequences, for example.

[00135] As used herein, the term “transgene” means a polynucleotide that has been introduced into a cell or organism by artifice. For example, in a cell having a transgene, the transgene has been introduced by genetic manipulation or “transformation” of the cell. A cell or progeny thereof into which the transgene has been introduced is referred to as a “transformed cell” or “transformant.” Typically, the transgene is included in progeny of the transformant or becomes a part of the organism that develops from the cell. Transgenes may be inserted into the chromosomal DNA or maintained as a self-replicating plasmid, YAC, minichromosome, or the like.

[00136] Bacterial system promoters include T7 and inducible promoters such as pL of bacteriophage l, plac, ptrp, ptac (ptrp-lac hybrid promoter) and tetracycline-responsive promoters. Insect cell system promoters include constitutive or inducible promoters ( e.g ., ecdysone). Mammalian cell constitutive promoters include SV40, RSV, bovine papilloma virus (BPV) and other virus promoters, or inducible promoters derived from the genome of mammalian cells (e.g., metallothionein IIA promoter; heat shock promoter) or from mammalian viruses (e.g, the adenovirus late promoter; the inducible mouse mammary tumor virus long terminal repeat). Alternatively, a retroviral genome can be genetically modified for introducing and directing expression of a peptide sequence in appropriate host cells. [00137] As methods and uses provided herein include in vivo delivery, expression systems further include vectors designed for in vivo use. Particular non-limiting examples include adenoviral vectors (U.S. Patent Nos. 5,700,470 and 5,731,172), adeno-associated vectors (U.S. Patent No. 5,604,090), herpes simplex virus vectors (U.S. Patent No. 5,501,979), retroviral vectors (U.S. Patent Nos. 5,624,820, 5,693,508 and 5,674,703), BPV vectors (U.S. Patent No. 5,719,054), CMV vectors (U.S. Patent No. 5,561,063) and parvovirus, rotavirus, Norwalk virus and lentiviral vectors (see, e.g ., U.S. Patent No. 6,013,516). Vectors include those that deliver genes to cells of the intestinal tract, including the stem cells (Croyle etal. , Gene Ther. 5:645 (1998); S.J. Henning, Adv. Drug Deliv. Rev. 17:341 (1997), U.S. Patent Nos. 5,821,235 and 6,110,456). Many of these vectors have been approved for human studies.

[00138] Yeast vectors include constitutive and inducible promoters (see, e.g. , Ausubel et al ., In: Current Protocols in Molecular Biology Vol. 2, Ch. 13, ed., Greene Publish. Assoc. & Wiley Interscience, 1988; Grant etal. Methods in Enzymology, 153:516 (1987), eds. Wu & Grossman; Bitter Methods in Enzymology, 152:673 (1987), eds. Berger & Kimmel, Acad. Press, N.Y.; and, Strathem etal. , The Molecular Biology of the Yeast Saccharomyces (1982) eds. Cold Spring Harbor Press, Vols. I and II). A constitutive yeast promoter such as ADH or LEU2 or an inducible promoter such as GAL may be used (R. Rothstein In: DNA Cloning. A Practical Approach. Vol.11, Ch. 3, ed. D.M. Glover, IRL Press, Wash., D.C., 1986). Vectors that facilitate integration of foreign nucleic acid sequences into a yeast chromosome, via homologous recombination for example, are known in the art. Yeast artificial chromosomes (YAC) are typically used when the inserted polynucleotides are too large for more conventional vectors (e.g, greater than about 12 Kb).

[00139] Expression vectors also can contain a selectable marker conferring resistance to a selective pressure or identifiable marker (e.g, beta-galactosidase), thereby allowing cells having the vector to be selected for, grown and expanded. Alternatively, a selectable marker can be on a second vector that is co-transfected into a host cell with a first vector containing a nucleic acid encoding a peptide sequence. Selection systems include, but are not limited to, herpes simplex virus thymidine kinase gene (Wigler et al, Cell 11 :223 (1977)), hypoxanthine-guanine phosphoribosyltransferase gene (Szybalska etal, Proc. Natl. Acad. Sci. USA 48:2026 (1962)), and adenine phosphoribosyltransferase (Lowy et al, Cell 22:817 (1980)) genes that can be employed in tk-, hgprt or aprt cells, respectively. Additionally, antimetabolite resistance can be used as the basis of selection for dhfr, which confers resistance to methotrexate (O’Hare et al. , Proc. Natl. Acad. Sci. USA 78:1527 (1981)); the gpt gene, which confers resistance to mycophenolic acid (Mulligan et al, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neomycin gene, which confers resistance to aminoglycoside G-418 (Colberre-Garapin etal. , J. Mol. Biol. 150:1(1981)); puromycin; and hygromycin gene, which confers resistance to hygromycin (Santerre etal. , Gene 30:147 (1984)). Additional selectable genes include trpB, which allows cells to utilize indole in place of tryptophan; hisD, which allows cells to utilize histinol in place of histidine (Hartman etal. , Proc. Natl. Acad. Sci. USA 85:8047 (1988)); and ODC (ornithine decarboxylase), which confers resistance to the ornithine decarboxylase inhibitor, 2- (difluoromethyl)-DL-ornithine, DFMO (McConlogue (1987) In: Current Communications in Molecular Biology Cold Spring Harbor Laboratory).

Cell Lines and Animal Models

[00140] In certain embodiments, also provided is a transformed cell(s) (in vitro , ex vivo and in vivo ) and host cells that produce a variant or fusion of FGF19 and/or FGF21 as set forth herein, where expression of the variant or fusion of FGF19 and/or FGF21 is conferred by a nucleic acid encoding the variant or fusion of FGF19 and/or FGF21. As used herein, a “transformed” or “host” cell is a cell into which a nucleic acid is introduced that can be propagated and/or transcribed for expression of an encoded peptide sequence. The term also includes any progeny or subclones of the host cell. Transformed and host cells that express peptide sequences provided herein typically include a nucleic acid that encodes the peptide sequence. In one embodiment, a transformed or host cell is a prokaryotic cell. In another embodiment, a transformed or host cell is a eukaryotic cell. In various aspects, the eukaryotic cell is a yeast or mammalian ( e.g ., human, primate, etc.) cell.

[00141] Transformed and host cells include but are not limited to microorganisms such as bacteria and yeast; and plant, insect and mammalian cells. For example, bacteria transformed with recombinant bacteriophage nucleic acid, plasmid nucleic acid or cosmid nucleic acid expression vectors; yeast transformed with recombinant yeast expression vectors; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g, Ti plasmid); insect cell systems infected with recombinant virus expression vectors (e.g, baculovirus); and animal cell systems infected with recombinant virus expression vectors (e.g., retroviruses, adenovirus, vaccinia virus), or transformed animal cell systems engineered for transient or stable propagation or expression.

[00142] For gene therapy uses and methods, a transformed cell can be in a subject. A cell in a subject can be transformed with a nucleic acid that encodes a peptide sequence as set forth herein in vivo. Alternatively, a cell can be transformed in vitro with a transgene or polynucleotide, and then transplanted into a tissue of subject in order to effect treatment. Alternatively, a primary cell isolate or an established cell line can be transformed with a transgene or polynucleotide that encodes a variant of FGF19 and/or FGF21 or a fusion/chimeric sequence (or variant) thereof, such as a chimeric peptide sequence including all or a portion of FGF19, or including all or a portion of FGF21, and then optionally transplanted into a tissue of a subject.

[00143] Non-limiting target cells for expression of peptide sequences, particularly for expression in vivo , include pancreas cells (islet cells), muscle cells, mucosal cells and endocrine cells. Such endocrine cells can provide inducible production (secretion) of a variant of FGF19 and/or FGF21, or a fusion/chimeric sequence (or variant) thereof, such as a chimeric peptide sequence including all or a portion of FGF19, or including all or a portion of FGF21. Additional cells to transform include stem cells or other multipotent or pluripotent cells, for example, progenitor cells that differentiate into the various pancreas cells (islet cells), muscle cells, mucosal cells and endocrine cells. Targeting stem cells provides longer term expression of peptide sequences provided herein.

[00144] As used herein, the term “cultured,” when used in reference to a cell, means that the cell is grown in vitro. A particular example of such a cell is a cell isolated from a subject, and grown or adapted for growth in tissue culture. Another example is a cell genetically manipulated in vitro , and transplanted back into the same or a different subject.

[00145] The term “isolated,” when used in reference to a cell, means a cell that is separated from its naturally occurring in vivo environment. “Cultured” and “isolated” cells may be manipulated by the hand of man, such as genetically transformed. These terms include any progeny of the cells, including progeny cells that may not be identical to the parental cell due to mutations that occur during cell division. The terms do not include an entire human being. [00146] Nucleic acids encoding peptide sequences provided herein can be introduced for stable expression into cells of a whole organism. Such organisms, including non-human transgenic animals, are useful for studying the effect of peptide expression in a whole animal and therapeutic benefit. For example, as disclosed herein, production of a variant of FGF19 and/or FGF21 or a fusion/chimeric sequence (or variant) thereof, such as a chimeric peptide sequence including all or a portion of FGF19, or including all or a portion of FGF21 as set forth herein, in mice.

[00147] Mice strains that develop or are susceptible to developing a particular disease ( e.g ., diabetes, degenerative disorders, cancer, etc.) are also useful for introducing therapeutic proteins as described herein in order to study the effect of therapeutic protein expression in the disease- susceptible mouse. Transgenic and genetic animal models that are susceptible to particular disease or physiological conditions, such as streptozotocin (STZ)-induced diabetic (STZ) mice, are appropriate targets for expressing variants of FGF19 and/or FGF21, fusions/chimeric sequences (or variant) thereof, such as a chimeric peptide sequence including all or a portion of FGF19, or including all or a portion of FGF21, as set forth herein. Thus, in certain embodiments, there are provided non-human transgenic animals that produce a variant of FGF19 and/or FGF21, or a fusion/chimeric sequence (or variant) thereof, such as a chimeric peptide sequence including all or a portion of FGF19, or including all or a portion of FGF21, the production of which is not naturally occurring in the animal which is conferred by a transgene present in somatic or germ cells of the animal.

[00148] The term “transgenic animal” refers to an animal whose somatic or germ line cells bear genetic information received, directly or indirectly, by deliberate genetic manipulation at the subcellular level, such as by microinjection or infection with recombinant virus. The term “transgenic” further includes cells or tissues (i.e., “transgenic cell,” “transgenic tissue”) obtained from a transgenic animal genetically manipulated as described herein. In the present context, a “transgenic animal” does not encompass animals produced by classical crossbreeding or in vitro fertilization, but rather denotes animals in which one or more cells receive a nucleic acid molecule. Transgenic animals provided herein can be either heterozygous or homozygous with respect to the transgene. Methods for producing transgenic animals, including mice, sheep, pigs and frogs, are well known in the art (see, e.g., U.S. Patent Nos. 5,721,367, 5,695,977, 5,650,298, and 5,614,396) and, as such, are additionally included.

[00149] Peptide sequences, nucleic acids encoding peptide sequences, vectors and transformed host cells expressing peptide sequences include isolated and purified forms. The term “isolated,” when used as a modifier of a composition provided herein, means that the composition is separated, substantially, completely, or at least in part, from one or more components in an environment. Generally, compositions that exist in nature, when isolated, are substantially free of one or more materials with which they normally associate with in nature, for example, one or more protein, nucleic acid, lipid, carbohydrate or cell membrane. The term “isolated” does not exclude alternative physical forms of the composition, such as variants, modifications or derivatized forms, fusions and chimeras, multimers/oligomers, etc ., or forms expressed in host cells. The term “isolated” also does not exclude forms ( e.g ., pharmaceutical compositions, combination compositions, etc.) in which there are combinations therein, any one of which is produced by the hand of man. An “isolated” composition can also be “purified” when free of some, a substantial number of, or most or all of one or more other materials, such as a contaminant or an undesired substance or material.

[00150] As used herein, the term “recombinant,” when used as a modifier of peptide sequences, nucleic acids encoding peptide sequences, etc ., means that the compositions have been manipulated (i.e., engineered) in a fashion that generally does not occur in nature (e.g., in vitro). A particular example of a recombinant peptide would be where a peptide sequence provided herein is expressed by a cell transfected with a nucleic acid encoding the peptide sequence. A particular example of a recombinant nucleic acid would be a nucleic acid (e.g, genomic or cDNA) encoding a peptide sequence cloned into a plasmid, with or without 5’, 3’ or intron regions that the gene is normally contiguous within the genome of the organism. Another example of a recombinant peptide or nucleic acid is a hybrid or fusion sequence, such as a chimeric peptide sequence comprising a portion of FGF19 and a portion of FGF21.

Particular Modifications to Enhance Peptide Function

[00151] It is frequently beneficial, and sometimes imperative, to improve one of more physical properties of the treatment modalities disclosed herein and/or the manner in which they are administered. Improvements of physical properties include, for example, modulating immunogenicity; methods of increasing solubility, bioavailability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Certain modifications may also be useful to, for example, raise of antibodies for use in detection assays (e.g, epitope tags) and to provide for ease of protein purification. Such improvements must generally be imparted without adversely impacting the bioactivity of the treatment modality and/or increasing its immunogenicity. [00152] Pegylation of is one particular modification contemplated herein, while other modifications include, but are not limited to, glycosylation (N- and O-linked); polysialylation; albumin fusion molecules comprising serum albumin ( e.g ., human serum albumin (HSA), cyno serum albumin, or bovine serum albumin (BSA)); albumin binding through, for example a conjugated fatty acid chain (acylation); and Fc-fusion proteins.

[00153] Pegylation: The clinical effectiveness of protein therapeutics is often limited by short plasma half-life and susceptibility to protease degradation. Studies of various therapeutic proteins (e.g., filgrastim) have shown that such difficulties may be overcome by, for example, conjugating or linking the protein to any of a variety of nonproteinaceous polymers, e.g, polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes. This is frequently effected by a linking moiety covalently bound to both the protein and the nonproteinaceous polymer, e.g, a PEG. Such PEG-conjugated biomolecules have been shown to possess clinically useful properties, including better physical and thermal stability, protection against susceptibility to enzymatic degradation, increased solubility, longer in vivo circulating half-life and decreased clearance, reduced immunogenicity and antigenicity, and reduced toxicity. In addition to the beneficial effects of pegylation on pharmacokinetic parameters, pegylation itself may enhance activity.

[00154] PEGs suitable for conjugation to a polypeptide sequence are generally soluble in water at room temperature, and have the general formula R(0-CH2-CH2)n0-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. When R is a protective group, it generally has from 1 to 8 carbons. The PEG conjugated to the polypeptide sequence can be linear or branched. Branched PEG derivatives, “star-PEGs” and multi-armed PEGs are contemplated by the present disclosure. A molecular weight of the PEG used in embodiments provided herein is not restricted to any particular range, and examples are set forth elsewhere herein; by way of example, certain embodiments have molecular weights between 5kDa and 20kDa, while other embodiments have molecular weights between 4kDa and lOkDa.

[00155] In other embodiments, provided herein are compositions of conjugates wherein the PEGs have different n values, and thus the various different PEGs are present in specific ratios. For example, some compositions comprise a mixture of conjugates where n=l, 2, 3 and 4. In some compositions, the percentage of conjugates where n=l is 18-25%, the percentage of conjugates where n=2 is 50-66%, the percentage of conjugates where n=3 is 12-16%, and the percentage of conjugates where n=4 is up to 5%. Such compositions can be produced by reaction conditions and purification methods know in the art. Cation exchange chromatography may be used to separate conjugates, and a fraction is then identified which contains the conjugate having, for example, the desired number of PEGs attached, purified free from unmodified protein sequences and from conjugates having other numbers of PEGs attached.

[00156] Pegylation most frequently occurs at the alpha amino group at the N-terminus of the polypeptide, the epsilon amino group on the side chain of lysine residues, and the imidazole group on the side chain of histidine residues. Since most recombinant polypeptides possess a single alpha and a number of epsilon amino and imidazole groups, numerous positional isomers can be generated depending on the linker chemistry.

[00157] General pegylation strategies known in the art can be applied herein. PEG may be bound to a polypeptide provided herein via a terminal reactive group (a “spacer” or “linker”) which mediates a bond between the free amino or carboxyl groups of one or more of the polypeptide sequences and polyethylene glycol. The PEG having the spacer which may be bound to the free amino group includes N-hydroxysuccinylimide polyethylene glycol which may be prepared by activating succinic acid ester of polyethylene glycol with N- hydroxysuccinylimide. Another activated polyethylene glycol which may be bound to a free amino group is 2,4-bis(0-methoxypolyethyleneglycol)-6-chloro-s-triazine, which may be prepared by reacting polyethylene glycol monomethyl ether with cyanuric chloride. The activated polyethylene glycol which is bound to the free carboxyl group includes polyoxyethylenediamine.

[00158] Conjugation of one or more of the polypeptide sequences provided herein to PEG having a spacer may be carried out by various conventional methods. For example, the conjugation reaction can be carried out in solution at a pH of from 5 to 10, at temperature from 4°C to room temperature, for 30 minutes to 20 hours, utilizing a molar ratio of reagent to protein of from 4:1 to 30: 1. Reaction conditions may be selected to direct the reaction towards producing predominantly a desired degree of substitution. In general, low temperature, low pH ( e.g ., pH=5), and short reaction time tend to decrease the number of PEGs attached, whereas high temperature, neutral to high pH (e.g., pH>7), and longer reaction time tend to increase the number of PEGs attached. Various means known in the art may be used to terminate the reaction. In some embodiments, the reaction is terminated by acidifying the reaction mixture and freezing at, e.g ., -20°C. Pegylation of various molecules is discussed in, for example, U.S. Pat. Nos. 5,252,714; 5,643,575; 5,919,455; 5,932,462; and 5,985,263.

[00159] In some embodiments, also provided herein are uses of PEG mimetics. Recombinant PEG mimetics have been developed that retain the attributes of PEG (e.g, enhanced serum half- life) while conferring several additional advantageous properties. By way of example, simple polypeptide chains (comprising, for example, Ala, Glu, Gly, Pro, Ser and Thr) capable of forming an extended conformation similar to PEG can be produced recombinantly already fused to the peptide or protein drug of interest (e.g, XTEN technology; Amunix; Mountain View, CA). This obviates the need for an additional conjugation step during the manufacturing process. Moreover, established molecular biology techniques enable control of the side chain composition of the polypeptide chains, allowing optimization of immunogenicity and manufacturing properties.

[00160] Glvcosylation: As used herein, “glycosylation” is meant to broadly refer to the enzymatic process by which glycans are attached to proteins, lipids or other organic molecules. The use of the term “glycosylation” herein is generally intended to mean adding or deleting one or more carbohydrate moieties (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that may or may not be present in the native sequence. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins involving a change in the nature and proportions of the various carbohydrate moieties present.

[00161] Glycosylation can dramatically affect the physical properties (e.g, solubility) of polypeptides and can also be important in protein stability, secretion, and subcellular localization. Glycosylated polypeptides may also exhibit enhanced stability or may improve one or more pharmacokinetic properties, such as half-life. In addition, solubility improvements can, for example, enable the generation of formulations more suitable for pharmaceutical administration than formulations comprising the non-glycosylated polypeptide.

[00162] Addition of glycosylation sites can be accomplished by altering the amino acid sequence. The alteration to the polypeptide may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues (for O-linked glycosylation sites) or asparagine residues (for N-linked glycosylation sites). The structures of N-linked and O-linked oligosaccharides and the sugar residues found in each type may be different. One type of sugar that is commonly found on both is N-acetylneuraminic acid (hereafter referred to as sialic acid). Sialic acid is usually the terminal residue of both N-linked and O-linked oligosaccharides and, by virtue of its negative charge, may confer acidic properties to the glycoprotein. A particular embodiment comprises the generation and use of N-glycosylation variants.

[00163] The polypeptide sequences provided herein may optionally be altered through changes at the nucleic acid level, particularly by mutating the nucleic acid encoding the polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids. Various cell lines can be used to produce proteins that are glycosylated. One non limiting example is Dihydrofolate reductase (DHFR)-deficient Chinese Hamster Ovary (CHO) cells, which are a commonly used host cell for the production of recombinant glycoproteins. These cells do not express the enzyme beta-galactoside alpha-2, 6-sialyltransferase and therefore do not add sialic acid in the alpha-2,6 linkage to N-linked oligosaccharides of glycoproteins produced in these cells.

[00164] Polysialylation: In certain embodiments, also provided herein is the use of polysialylation, the conjugation of polypeptides to the naturally occurring, biodegradable a- (2 8) linked polysialic acid (“PSA”) in order to improve the polypeptides’ stability and in vivo pharmacokinetics.

[00165] Albumin Fusion: Additional suitable components and molecules for conjugation include albumins such as human serum albumin (HSA), cyno serum albumin, and bovine serum albumin (BSA).

[00166] In some embodiments, albumin is conjugated to a drug molecule ( e.g ., a polypeptide described herein) at the carboxyl terminus, the amino terminus, both the carboxyl and amino termini, and internally (see, e.g., US Pat Nos. 5,876,969 and 7,056,701).

[00167] In the HSA-drug molecule conjugates embodiments provided herein, various forms of albumin may be used, such as albumin secretion pre-sequences and variants thereof, fragments and variants thereof, and HSA variants. Such forms generally possess one or more desired albumin activities. In additional embodiments, fusion proteins are provided herein comprising a polypeptide drug molecule fused directly or indirectly to albumin, an albumin fragment, an albumin variant, etc., wherein the fusion protein has a higher plasma stability than the unfused drug molecule and/or the fusion protein retains the therapeutic activity of the unfused drug molecule. In some embodiments, the indirect fusion is effected by a linker, such as a peptide linker or modified version thereof.

[00168] As alluded to above, fusion of albumin to one or more polypeptides provided herein can, for example, be achieved by genetic manipulation, such that the nucleic acid coding for HSA, or a fragment thereof, is joined to the nucleic acid coding for the one or more polypeptide sequences.

[00169] Alternative Albumin Binding Strategies: Several albumin - binding strategies have been developed as alternatives to direct fusion and may be used with the agents described herein. By way of example, in certain embodiments, provided herein is albumin binding through a conjugated fatty acid chain (acylation) and fusion proteins which comprise an albumin binding domain (ABD) polypeptide sequence and the sequence of one or more of the polypeptides described herein.

[00170] Fusion of albumin to a peptide sequence can, for example, be achieved by genetic manipulation, such that the DNA coding for HSA (human serum albumin), or a fragment thereof, is joined to the DNA coding for a peptide sequence. Thereafter, a suitable host can be transformed or transfected with the fused nucleotide sequence in the form of, for example, a suitable plasmid, so as to express a fusion polypeptide. The expression may be effected in vitro from, for example, prokaryotic or eukaryotic cells, or in vivo from, for example, a transgenic organism. In some embodiments, the expression of the fusion protein is performed in mammalian cell lines, for example, CHO cell lines.

[00171] Further means for genetically fusing target proteins or peptides to albumin include a technology known as Albufuse® (Novozymes Biopharma A/S; Denmark), and the conjugated therapeutic peptide sequences frequently become much more effective with better uptake in the body. The technology has been utilized commercially to produce Albuferon® (Human Genome Sciences), a combination of albumin and interferon a-2B used to treat hepatitis C infection. [00172] Another embodiment entails the use of one or more human domain antibodies (dAb). dAbs are the smallest functional binding units of human antibodies (IgGs) and have favorable stability and solubility characteristics. The technology entails a dAb(s) conjugated to HSA (thereby forming a “AlbudAb”; see, e.g., EP1517921B, W02005/118642 and W02006/051288) and a molecule of interest (e.g., a peptide sequence provided herein). AlbudAbs are often smaller and easier to manufacture in microbial expression systems, such as bacteria or yeast, than current technologies used for extending the serum half-life of peptides. As HSA has a half-life of about three weeks, the resulting conjugated molecule improves the half-life. Use of the dAb technology may also enhance the efficacy of the molecule of interest.

[00173] Conjugation with Other Molecules: Additional suitable components and molecules for conjugation include, for example, thyroglobulin; tetanus toxoid; Diphtheria toxoid; polyamino acids such as poly(D-lysine:D-glutamic acid); VP6 polypeptides of rotaviruses; influenza virus hemagglutinin, influenza virus nucleoprotein; Keyhole Limpet Hemocyanin (KLH); and hepatitis B virus core protein and surface antigen; or any combination of the foregoing.

[00174] Thus, in certain embodiments, conjugation of one or more additional components or molecules at the N- and/or C-terminus of a polypeptide sequence, such as another polypeptide e.g ., a polypeptide having an amino acid sequence heterologous to the subject polypeptide), or a carrier molecule is also contemplated. Thus, an exemplary polypeptide sequence can be provided as a conjugate with another component or molecule.

[00175] A polypeptide may also be conjugated to large, slowly metabolized macromolecules such as proteins; polysaccharides, such as sepharose, agarose, cellulose, or cellulose beads; polymeric amino acids such as polyglutamic acid, or polylysine; amino acid copolymers; inactivated virus particles; inactivated bacterial toxins such as toxoid from diphtheria, tetanus, cholera, or leukotoxin molecules; inactivated bacteria; and dendritic cells. Such conjugated forms, if desired, can be used to produce antibodies against a polypeptide provided herein. [00176] Fc-fusion Molecules: In certain embodiments, the amino- or carboxyl- terminus of a polypeptide sequence provided herein is fused with an immunoglobulin Fc region to form a fusion conjugate (or fusion molecule). In a specific embodiment, the immunoglobulin Fc region is a human Fc region. Fusion conjugates have been shown to increase the systemic half-life of biopharmaceuticals, and thus the biopharmaceutical product may require less frequent administration. In certain embodiments, the half-life is increased as compared to the same polypeptide that is not fused to an immunoglobulin Fc region.

[00177] Fc binds to the neonatal Fc receptor (FcRn) in endothelial cells that line the blood vessels, and, upon binding, the Fc fusion molecule is protected from degradation and re-released into the circulation, keeping the molecule in circulation longer. This Fc binding is believed to be the mechanism by which endogenous IgG retains its long plasma half-life. More recent Fc- fusion technology links a single copy of a biopharmaceutical to the Fc region of an antibody to optimize the pharmacokinetic and pharmacodynamic properties of the biopharmaceutical as compared to traditional Fc-fusion conjugates.

[00178] Well-known and validated Fc-fusion drugs consist of two copies of a biopharmaceutical linked to the Fc region of an antibody to improve pharmacokinetics, solubility, and production efficiency. More recent Fc-fusion technology links a single copy of a biopharmaceutical to the Fc region of an antibody to optimize the pharmacokinetic and pharmacodynamic properties of the biopharmaceutical as compared to traditional Fc-fusion conjugates.

[00179] In some embodiments, provided herein is a fusion of M70 to a human antibody Fc fragment. In some embodiments, provided herein is a fusion of M69 to a human antibody Fc fragment. Such fusions can be useful in the treatment of bile acid related disorders and other metabolic disorders provided herein. In some embodiments, the Fc-fusion of M70 has a longer half-life. In specific embodiments, the longer half-life of the Fc-fusion of M70 is as compared to M70 that is not an Fc-fusion. In some embodiments, the Fc-fusion of M69 has a longer half-life. In specific embodiments, the longer half life of the Fc-fusion of M69 is as compared to M69 that is not an Fc-fusion. Such a long half-life makes these fusions suitable for once weekly, or less frequent dosing.

[00180] In some embodiments, the Fc-fusion comprises a linker. Exemplary flexible linkers include glycine polymers (G _)n , glycine-serine polymers, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers. In certain embodiments, the linker is (G)4S. In some embodiments, the linker is ((G)4S)n, where n is an integer of at least one. In some embodiments, the linker is ((G)4S)2. Glycine and glycine-serine polymers are relatively unstructured, and therefore may serve as a neutral tether between components. In some embodiments, the glycine- serine polymer is (GS)n, where n is an integer of at least one. In some embodiments, the glycine- serine polymer is GSGGSn(SEQ ID NO: 129), where n is an integer of at least one. In some embodiments, the glycine-serine polymer is GGGSn (SEQ ID NO: 130), where n is an integer of at least one. In certain embodiments, the linker comprises an additional G residue at the N’ terminus of SEQ ID NO: 130. In one embodiment, the linker is GGSG (SEQ ID NO: 131). In one embodiment, the linker is GGSGG (SEQ ID NO: 132). In one embodiment, the linker is GSGSG (SEQ ID NO: 133). In one embodiment, the linker is GSGGG (SEQ ID NO: 134). In one embodiment, the linker is GGGSG (SEQ ID NO: 189). In one embodiment, the linker is GSSSG (SEQ ID NO: 135).

[00181] Purification: Additional suitable components and molecules for conjugation include those suitable for isolation or purification. Particular non-limiting examples include binding molecules, such as biotin (biotin-avidin specific binding pair), an antibody, a receptor, a ligand, a lectin, or molecules that comprise a solid support, including, for example, plastic or polystyrene beads, plates or beads, magnetic beads, test strips, and membranes.

[00182] Purification methods such as cation exchange chromatography may be used to separate conjugates by charge difference, which effectively separates conjugates into their various molecular weights. For example, the cation exchange column can be loaded and then washed with ~20 mM sodium acetate, pH ~4, and then eluted with a linear (0 M to 0.5 M) NaCl gradient buffered at a pH from 3 to 5.5, such as at pH ~4.5. The content of the fractions obtained by cation exchange chromatography may be identified by molecular weight using conventional methods, for example, mass spectroscopy, SDS-PAGE, or other known methods for separating molecular entities by molecular weight. A fraction is then identified which contains the conjugate having the desired number of PEGs attached, purified free from unmodified protein sequences and from conjugates having other numbers of PEGs attached.

[00183] Other Modifications: In certain embodiments, also provided herein is the use of other modifications, currently known or developed in the future, to improve one or more properties. Examples include hesylation, various aspects of which are described in, for example, U.S. Patent Appln. Nos. 2007/0134197 and 2006/0258607, and fusion molecules comprising SUMO as a fusion tag (LifeSensors, Inc.; Malvern, PA).

[00184] In still other embodiments, a peptide sequence provided herein is linked to a chemical agent ( e.g ., an immunotoxin or chemotherapeutic agent), including, but are not limited to, a cytotoxic agent, including taxol, cytochalasin B, gramicidin D, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, and analogs or homologs thereof. Other chemical agents include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6- thioguanine, cytarabine, 5-fluorouracil decarbazine); alkylating agents (e.g, mechlorethamine, carmustine and lomustine, cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cisplatin); antibiotics (e.g, bleomycin); and anti-mitotic agents (e.g, vincristine and vinblastine). Cytotoxins can be conjugated to a peptide provided herein using linker technology known in the art and described herein.

[00185] Further suitable components and molecules for conjugation include those suitable for detection in an assay. Particular non-limiting examples include detectable labels, such as a radioisotope ( e.g ., ¹²⁵ I; ³⁵ S, ³² P; ³³ P), an enzyme which generates a detectable product (e.g, luciferase, b-galactosidase, horse radish peroxidase and alkaline phosphatase), a fluorescent protein, a chromogenic protein, dye (e.g., fluorescein isothiocyanate); fluorescence emitting metals (e.g, ¹⁵² Eu); chemiluminescent compounds (e.g, luminol and acridinium salts); bioluminescent compounds (e.g, luciferin); and fluorescent proteins. Indirect labels include labeled or detectable antibodies that bind to a peptide sequence, where the antibody may be detected.

[00186] In certain embodiments, a peptide sequence provided herein is conjugated to a radioactive isotope to generate a cytotoxic radiopharmaceutical (radioimmunoconjugates) useful as a diagnostic or therapeutic agent. Examples of such radioactive isotopes include, but are not limited to, iodine ¹³¹ , indium ¹¹¹ , yttrium ⁹⁰ and lutetium ¹⁷⁷ . Methods for preparing radioimmunoconjugates are known to the skilled artisan. Examples of radioimmunoconjugates that are commercially available include ibritumomab, tiuxetan, and tositumomab.

[00187] Linkers: Linkers and their use have been described above. Any of the foregoing components and molecules used to modify the polypeptide sequences provided herein may optionally be conjugated via a linker. Suitable linkers include “flexible linkers” which are generally of sufficient length to permit some movement between the modified polypeptide sequences and the linked components and molecules. The linker molecules are generally about 6-50 atoms long. The linker molecules may also be, for example, aryl acetylene, ethylene glycol oligomers containing 2-10 monomer units, diamines, diacids, amino acids, or combinations thereof. Suitable linkers can be readily selected and can be of any suitable length, such as 1 amino acid (e.g., Gly), 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-50 or more than 50 amino acids. [00188] Exemplary flexible linkers include glycine polymers (G)n, glycine-serine polymers (for example, (GS)n, GSGGSn (SEQ ID NO: 129) and GGGSn (SEQ ID NO: 130), where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers. Glycine and glycine-serine polymers are relatively unstructured, and therefore may serve as a neutral tether between components. Exemplary flexible linkers include, but are not limited to GGSG (SEQ ID NO: 131), GGSGG (SEQ ID NO: 132), GSGSG (SEQ ID NO: 133), GSGGG (SEQ ID NO: 134), GGGSG (SEQ ID NO: 189), and GSSSG (SEQ ID NO: 135). In certain embodiments, the linker is (G)4S. In some embodiments, the linker is ((G)4S)n), where n is an integer of at least one. In some embodiments, the linker is ((G)4S)2). In some embodiments, the glycine-serine polymer is (GS)n, where n is an integer of at least one. In some embodiments, the glycine-serine polymer is GSGGSn (SEQ ID NO: 129), where n is an integer of at least one. In some embodiments, the glycine-serine polymer is GGGSn (SEQ ID NO: 130), where n is an integer of at least one. In certain embodiments, the linker comprises an additional G residue at the N’ terminus of SEQ ID NO: 130. In one embodiment, the linker is GGSG (SEQ ID NO:131). In one embodiment, the linker is GGSGG (SEQ ID NO:132). In one embodiment, the linker is GSGSG (SEQ ID NO: 133). In one embodiment, the linker is GSGGG (SEQ ID NO: 134). In one embodiment, the linker is GGGSG (SEQ ID NO: 189). In one embodiment, the linker is GSSSG (SEQ ID NO: 135).

Gut Microbiome and Liver Diseases and the Modulation, Treatment or Prevention Thereof [00189] The peptide sequences set forth herein can be used in methods for, for example, modulating the gut microbiome. The peptide sequences set forth herein can be used for, for example, enriching Veillonella. The peptide sequences set forth herein can be used for, for example, reducing lactate. The peptide sequences set forth herein can be used for, for example, negatively regulating bile acids. The peptide sequences set forth herein can be used for, for example, enriching Veillonella by negatively regulating bile acids. The peptide sequences set forth herein can be used for, for example, ameliorating hepatic fibrosis. The peptide sequences set forth herein can be used for, for example, ameliorating hepatic steatosis. The peptide sequences set forth herein can be used for, for example, ameliorating inflammation. The peptide sequences set forth herein can be used for, for example, treating or preventing liver disease. The peptide sequences set forth herein can be used for, for example, treating or preventing disease associated with an increase in lactate. The methods include administering an effective amount of a peptide sequence, such as a FGF19 or FGF21 variant, fusion or chimera disclosed herein ( e.g ., in the Sequence Listing, Table 1, or Examples I and II), or a subsequence, a variant or modified form of a FGF19 or FGF21 variant, fusion or chimera disclosed herein (e.g., the Sequence Listing or Table 1), to a subject in need thereof for modulating bile acid homeostasis, treating or preventing liver disease, or treating or preventing disease associated with an increase in lactate. In some embodiments, the peptide sequences used in methods as provided herein are fused with an immunoglobulin Fc region.

[00190] In some embodiments, provided herein are methods for enriching Veillonella in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein. In some embodiments, provided herein are methods for reducing lactate in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein. In some embodiments, provided herein are methods for treating or preventing disease associated with elevated lactate in a subject in need thereof that include administering an effective amount of a peptide sequence disclosed herein.

[00191] As used herein, a “disease associated with elevated lactate” refers to a condition in which lactate levels increase, e.g ., systemically or in the blood. An increase in the level of lactate is an indication that organ systems are not functioning appropriately and coincides with more severe disease. As an example, lactate accumulates in various liver diseases. Specifically, lactate accumulates in cirrhosis patients, which is associated with a worsening of the disease. Lactate also accumulates in patients with NASH, PBC and acute liver failure. Non-liver diseases associated with elevated lactate include diabetes, renal failure, infectious disease and heart disease.

[00192] Subjects: As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal that would benefit from treatment with a peptide sequence provided herein. Particular examples include primates (e.g, humans), dogs, cats, horses, cows, pigs, and sheep. [00193] In some embodiments, the subject is a human.

[00194] Subjects that can be treated with methods described herein can have a disease associated with elevated lactate. In particular embodiments, the subject has or is at risk of having a disease associated with elevated lactate. In particular, embodiments, the subject is a patient having a disease associated with elevated lactate. In particular embodiments, the subject is a patient having elevated lactate. In some embodiments, the subject can be a heathy individual. Subjects at risk of developing a disease associated with elevated lactate include, for example, those who may have a family history or genetic predisposition toward a disease associated with elevated lactate, as well those whose diet or habits may contribute to development of such disorders. [00195] In some embodiments, the subject that has or is at risk for a disease associated with elevated lactate has a liver disease. In some embodiments, the subject has cirrhosis. In some embodiments, the subject has NASH. In some embodiments, the subject has primary biliary cirrhosis. In some embodiments, the subject has acute liver failure. In some embodiments, the subject is overweight. In some embodiments, the subject is obese. In some embodiments, the subject has a Body Mass Index (BMI) that is at least 25 0 In some embodiments, the subject has a BMI that is at least 30 0

[00196] In some embodiments, the subject that has or is at risk for a disease associated with elevated lactate has an infection. In some embodiments, the subject that has or is at risk for a disease associated with elevated lactate has an autoimmune disorder. In some embodiments, the subject that has or is at risk for a disease associated with elevated lactate has a cancer.

[00197] Subjects that can be treated with methods described herein can have a liver disease. Subjects that can be treated with methods described herein can have a disease associated with elevated lactate. Subjects that can be treated with the methods described herein can have a bile acid-related disorder. In some embodiments, a bile acid-related disorder comprises a liver disease. In other embodiments, a liver disease comprises a bile acid-related disorder. The term “bile acid-related disorder,” or the like, when used in reference to a condition of a subject, means a disruption of bile acid homeostasis, which may manifest itself as, for example, an acute, transient or chronic abnormal level of a bile acid or one or more bile acids. The condition can be caused by inhibition, reduction or a delay in bile acid synthesis, metabolism or absorption such that the subject exhibits a bile acid level not typically found in normal subjects. Accordingly, subjects that can be treated with methods described herein can have a bile acid-related disorder, such as cholestasis, including, for example diseases of intrahepatic cholestasis ( e.g ., biliary cirrhosis (PBC), primary familial intrahepatic cholestasis (PFIC), primary sclerosing choangitis (PSC), pregnancy intrahepatic cholestasis (PIC), neonatal cholestasis, and drug induced cholestasis (e.g., estrogen)), and diseases of extrahepatic cholestasis (e.g, bile cut compression from tumor, bile duct blockade by gall stones); bile acid malabsorption and other disorders involving the distal small intestine, including ileal resection, inflammatory bowel diseases (e.g, Crohn’s disease and ulcerative colitis), short bowel syndrome, and GI, liver, and/or biliary cancers (e.g, colon cancer and hepatocellular cancer); and/or bile acid synthesis abnormalities, such as those contributing to non-alcoholic steatohepatitis (“NASH”), nonalcoholic fatty liver disease (NAFLD), cirrhosis and portal hypertension; or subjects that do not have a disorder but may be at risk of developing the disorder. In some embodiments, the subject has cholestasis. In some embodiments, the subject has PBC. In some embodiments, the subject has PFIC. In some embodiments, the subject has PSC. In some embodiments, the subject has neonatal cholestasis. In some embodiments, the subject has PIC. In some embodiments, the subject has bile acid malabsorption. In some embodiments, the subject has NASH. In some embodiments, the subject has NAFLD. Additional bile acid-related disorders include metabolic syndrome, a lipid or glucose disorder, cholesterol or triglyceride metabolism, diabetes ( e.g ., type 2 diabetes), other hyperglycemic-related disorders, including kidney damage (e.g., tubule damage or nephropathy), liver degeneration, eye damage (e.g, diabetic retinopathy or cataracts), and diabetic foot disorders, and dyslipidemias and their sequelae such as, for example, atherosclerosis, coronary artery disease, cerebrovascular disorders and the like.

[00198] Other conditions associated with metabolic syndrome can also include such as obesity and elevated body mass (including the co-morbid conditions thereof such as, but not limited to, nonalcoholic fatty liver di. suave (NAFLD), nonalcoholic steatohepatitis (NASH), and polycystic ovarian syndrome (PCOS)), and also include thromboses, hypercoagulable and prothrombotic states (arterial and venous), hypertension (including portal hypertension (defined as a hepatic venous pressure gradient (HVPG) greater than 5 mm Hg), cardiovascular disease, stroke and heart failure; Disorders or conditions in which inflammatory reactions are involved, including atherosclerosis, chronic inflammatory bowel diseases (e.g, Crohn’s disease and ulcerative colitis), asthma, lupus erythematosus, arthritis, or other inflammatory rheumatic disorders; Disorders of cell cycle or cell differentiation processes such as adipose cell tumors, lipomatous carcinomas including, for example, liposarcomas, solid tumors, and neoplasms; Neurodegenerative diseases and/or demyelinating disorders of the central and peripheral nervous systems and/or neurological diseases involving neuroinflammatory processes and/or other peripheral neuropathies, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, progressive multifocal leukoencephalopathy and Guillian-Barre syndrome; Skin and dermatological disorders and/or disorders of wound healing processes, including erythemato- squamous dermatoses; and Other Disorders such as syndrome X, osteoarthritis, and acute respiratory distress syndrome.

Dosing and Administration [00199] As disclosed herein, treatment methods include administering a peptide as set forth herein ( e.g ., a variant or fusion of FGF19 and/or FGF21 as set forth in the Sequence Listing or Table 1) in an amount effective to achieve a desired outcome or result in a subject. A treatment that results in a desired outcome or result includes decreasing, reducing or preventing the severity or frequency of one or more symptoms of the condition in the subject, e.g., an improvement in the subject’s condition or a “beneficial effect” or “therapeutic effect.”

Therefore, treatment can decrease or reduce or prevent the severity or frequency of one or more symptoms of the disorder, stabilize or inhibit progression or worsening of the disorder, and in some instances, reverse the disorder, transiently (e.g, for 1-6, 6-12, or 12-24 hours), for medium term (e.g., 1-6, 6-12, 12-24 or 24-48 days) or long term (e.g., for 1-6, 6-12, 12-24, 24-48 weeks, or greater than 24-48 weeks). Thus, in the case of a disease associated with elevated lactate, treatment can lower or reduce one or more symptoms or effects of same.

[00200] An “effective amount” or a “sufficient amount” for use and/or for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, treatments, protocols, or therapeutic regimens, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g, for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disorder, or one, multiple or all adverse symptoms, consequences or complications of the disorder, to a measurable extent, although reducing or inhibiting a progression or worsening of the disorder, is considered a satisfactory outcome.

[00201] As used herein, the term “ameliorate” means an improvement in the subject’s disorder, a reduction in the severity of the disorder, or an inhibition of progression or worsening of the disorder (e.g, stabilizing the disorder). In the case of a disease associated with elevated lactate, an improvement can be a lowering or a reduction in one or more symptoms or effects of the disorder, including lactate.

[00202] A therapeutic benefit or improvement therefore need not be complete ablation of any one, most or all symptoms, complications, consequences or underlying causes associated with the disorder or disease. Thus, a satisfactory endpoint is achieved when there is a transient, medium or long term, incremental improvement in a subject’s condition, or a partial reduction in the occurrence, frequency, severity, progression, or duration, or inhibition or reversal, of one or more associated adverse symptoms or complications or consequences or underlying causes, worsening or progression ( e.g ., stabilizing one or more symptoms or complications of the condition, disorder or disease), of the disorder or disease, over a duration of time (hours, days, weeks, months, etc.).

[00203] Thus, in the case of a disorder treatable by a peptide sequence provided herein, the amount of the peptide and the additional agent sufficient to ameliorate a disorder will depend on the type, severity and extent, or duration of the disorder, the therapeutic effect or outcome desired, and can be readily ascertained by the skilled artisan. Appropriate amounts will also depend upon the individual subject (e.g., the bioavailability within the subject, gender, age, etc.). For example, a transient, or partial, reduction of lactate in a subject can reduce the dosage amount or frequency of the peptides described herein in order to treat a disease associated with elevated lactate even though complete freedom from treatment has not resulted. A therapeutically effective amount can be ascertained, for example, by measuring one or more relevant physiological effects.

[00204] Peptide sequences provided herein including subsequences, sequence variants and modified forms of the exemplified peptide sequences (e.g., sequences listed in the Sequence Listing or Table 1), may be formulated in a unit dose or unit dosage form. In a particular embodiment, a peptide sequence is in an amount effective to treat a subject in need of treatment. Exemplary unit doses range from about 25-250, 250-500, 500-1000, 1000-2500, 2500-5000, 5000-25,000, or 25,000-50,000 ng; from about 25-250, 250-500, 500-1000, 1000-2500, 2500- 5000, 5000-25,000, or 25,000-50,000 pg; and from about 25-250, 250-500, 500-1000, or 1000- 2500 mg.

[00205] Peptide sequences provided herein including subsequences, sequence variants and modified forms of the exemplified peptide sequences (e.g., sequences listed in the Sequence Listing or Table 1) can be administered to provide the intended effect as a single dose or multiple dosages, for example, in an effective or sufficient amount. Exemplary doses range from about 25-250, 250-500, 500-1000, 1000-2500, 2500-5000, 5000-25,000, or 25,000-50,000 pg/kg; from about 50-500, 500-5000, 5000-25,000 or 25,000-50,000 ng/kg; and from about 25-250, 250-500, 500-1000, or 1000-2500 pg/kg. Single or multiple doses can be administered, for example, multiple times per day, on consecutive days, alternating days, weekly or intermittently (e.g, twice per week, once every 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or once every 2, 3, 4, 5 or 6 months). [00206] In some embodiments, the peptide sequences provided herein can be administered to provide the intended effect as short-term therapies (e.g. daily administration for multiple days). For example, the peptide sequences provided herein can be administered daily for a period of 7 to 336 days, including any number of days in between. In some embodiments, the peptide sequences provided herein can be administered daily for a period of 7 to 280 days, 7 to 224 days, 7 to 168 days, 7 to 112 days, or 7 to 56 days. In some embodiments, the peptide sequences provided herein can be administered daily for a period of 14 to 336 days, 14 to 280 days, 14 to 224 days, 14 to 168 days, 14 to 112 days, or 14 to 56 days. In some embodiments, the peptide sequences provided herein can be administered daily for a period of 21 to 336 days, 21 to 280 days, 21 to 224 days, 21 to 168 days, 21 to 112 days, or 21 to 56 days. In some embodiments, the peptide sequences provided herein can be administered daily for a period of 28 to 336 days, 28 to 280 days, 28 to 224 days, 28 to 168 days, 28 to 112 days, or 28 to 56 days. In some embodiments, the peptide sequences provided herein can be administered daily for 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84 days,

91 days, 98 days, 105 days, 112 days, 119 days, 126 days, 133 days, 140 days, 147 days, 154 days, 161 days, 168 days, 175 days, 182 days, 189 days, 196 days, 203 days, 210 days, 217 days,

224 days, 231 days, 238 days, 245 days, 252 days, 259 days, 266 days, 273 days, 280 days, 287 days, 294 days, 301 days, 308 days, 315 days, 322 days, 329 days, or 336 days. In some embodiments, the peptide sequences provided herein can be administered daily for 21 days. In some embodiments, the peptide sequences provided herein can be administered daily for 42 days. In some embodiments, the peptide sequences provided herein can be administered daily for 63 days. In some embodiments, the peptide sequences provided herein can be administered daily for 84 days. In some embodiments, the peptide sequences provided herein can be administered daily for 105 days. In some embodiments, the peptide sequences provided herein can be administered daily for 126 days. In some embodiments, the peptide sequences provided herein can be administered daily for 147 days. In some embodiments, the peptide sequences provided herein can be administered daily for 168 days.

[00207] In some embodiments, the peptide sequences provided herein can be administered to provide the intended effect as longer-term therapies (e.g. weekly administration for multiple weeks). For example, the peptide sequences provided herein can be administered weekly for a period of 8 to 156 weeks, including any number of weeks in between. In some embodiments, the peptide sequences provided herein can be administered for a period of 2 to 36 months, 2 to 30 months, 2 to 24 months, 2 to 18 months, 2 to 12 months, or 2 to 6 months. In some embodiments, the peptide sequences provided herein can be administered for a period of 3 to 36 months, 3 to 30 months, 3 to 24 months, 3 to 18 months, 3 to 12 months, or 3 to 6 months. In some embodiments, the peptide sequences provided herein can be administered for a period of 4 to 36 months, 4 to 30 months, 4 to 24 months, 4 to 18 months, 4 to 12 months, or 4 to 6 months. In some embodiments, the peptide sequences provided herein can be administered for a period of 5 to 36 months, 5 to 30 months, 5 to 24 months, 5 to 18 months, 5 to 12 months, or 5 to 6 months. In some embodiments, the peptide sequences provided herein can be administered weekly for 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months,

10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months or 36 months. In some embodiments, the peptide sequences provided herein can be administered weekly for 12 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 24 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 36 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 48 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 60 weeks.

In some embodiments, the peptide sequences provided herein can be administered weekly for 72 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 84 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 96 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 108 weeks. In some embodiments, the peptide sequences provided herein can be administered weekly for 120 weeks.

[00208] In some embodiments, the peptide sequences provided herein can be administered to provide the intended effect as a combination of short-term therapies and long-term multiple therapies. For example, the peptide sequences provided herein can be administered daily for for a period of 7 to 336 days, followed by weekly administration for a period of 8 to 156 weeks. In some embodiments, the peptide sequences provided herein can be administered daily for 7 to 280 days, 7 to 224 days, 7 to 168 days, 7 to 112 days, 7 to 56 days, 14 to 336 days, 14 to 280 days, 14 to 224 days, 14 to 168 days, 14 to 112 days, 14 to 56 days, 21 to 336 days, 21 to 280 days, 21 to 224 days, 21 to 168 days, 21 to 112 days, 21 to 56 days, 28 to 336 days, 28 to 280 days, 28 to 224 days, 28 to 168 days, 28 to 112 days, or 28 to 56 days followed by weekly administration for 2 to 36 months, 2 to 30 months, 2 to 24 months, 2 to 18 months, 2 to 12 months, 2 to 6 months, 3 to 36 months, 3 to 30 months, 3 to 24 months, 3 to 18 months, 3 to 12 months, 3 to 6 months, 4 to 36 months, 4 to 30 months, 4 to 24 months, 4 to 18 months, 4 to 12 months, 4 to 6 months, 5 to 36 months, 5 to 30 months, 5 to 24 months, 5 to 18 months, 5 to 12 months, or 5 to 6 months.

In some embodiments, the peptide sequences provided herein can be administered daily for 21 to 168 days followed by weekly administration for 2 to 36 months, 2 to 30 months, 2 to 24 months, 2 to 18 months, 2 to 12 months, 2 to 6 months, 3 to 36 months, 3 to 30 months, 3 to 24 months, 3 to 18 months, 3 to 12 months, 3 to 6 months, 4 to 36 months, 4 to 30 months, 4 to 24 months, 4 to 18 months, 4 to 12 months, 4 to 6 months, 5 to 36 months, 5 to 30 months, 5 to 24 months, 5 to 18 months, 5 to 12 months, or 5 to 6 months. In some embodiments, the peptide sequences provided herein can be administered daily for 7 to 280 days, 7 to 224 days, 7 to 168 days, 7 to 112 days, 7 to 56 days, 14 to 336 days, 14 to 280 days, 14 to 224 days, 14 to 168 days, 14 to 112 days, 14 to 56 days, 21 to 336 days, 21 to 280 days, 21 to 224 days, 21 to 168 days, 21 to 112 days, 21 to 56 days, 28 to 336 days, 28 to 280 days, 28 to 224 days, 28 to 168 days, 28 to 112 days, or 28 to 56 days followed by weekly administration for 12 to 104 weeks. In some embodiments, the peptide sequences provided herein can be administered daily for 21 to 168 days followed by weekly administration for 12 to 104 weeks.

[00209] Peptide sequences provided herein including subsequences, variants and modified forms of the exemplified peptide sequences ( e.g ., sequences listed in the Sequence Listing or Table 1) can be administered and methods may be practiced via systemic, regional or local administration, by any route. For example, a peptide sequence can be administered parenterally (e.g., subcutaneously, intravenously, intramuscularly, or intraperitoneally), orally (e.g, ingestion, buccal, or sublingual), inhalation, intradermally, intracavity, intracranially, transdermally (topical), transmucosally or rectally. Peptide sequences provided herein including subsequences, variants and modified forms of the exemplified peptide sequences (e.g, sequences listed in the Sequence Listing or Table 1) and methods provided herein including pharmaceutical compositions can be administered via a (micro)encapsulated delivery system or packaged into an implant for administration. [00210] A particular non-limiting example of parenteral ( e.g ., subcutaneous) administration entails the use of Intarcia’s subcutaneous delivery system (Intarcia Therapeutics, Inc.; Hayward, CA). The system comprises a miniature osmotic pump that delivers a consistent amount of a therapeutic agent over a desired period of time. In addition to maintaining drug levels within an appropriate therapeutic range, the system can be used with formulations that maintain the stability of proteinaceous therapeutic agents at human body temperature for extended periods of time.

[00211] Another non-limiting example of parenteral administration entails the use of DUROS®-type implantable osmotic pumps (from, e.g., DURECT Corp.). The DUROS® system can be used for therapies requiring systemic or site-specific administration of a drug. To deliver drugs systemically, the DUROS® system is placed just under the skin, for example in the upper arm, in an outpatient procedure that is completed in just a few minutes using local anesthetic. To deliver a drug to a specific site, miniaturized catheter technology can be used.

The catheter can be attached to the DUROS® system to direct the flow of a drug to the target organ, tissue or synthetic medical structure, such as a graft. Site-specific delivery enables a therapeutic concentration of a drug to be administered to the desired target without exposing the entire body to a similar concentration. The precision, size and performance of the DUROS® system will allow for continuous site-specific delivery to a variety of precise locations within the body.

[00212] Yet another non-limiting example of parenteral administration entails the use of an on-body delivery system (e.g, the NEULASTA® Delivery Kit by Amgen). This on-body delivery system includes an on-body injector, which is a small, lightweight, injection system applied on the same day as a doctor visit (such as the day of chemotherapy). It is designed to deliver a dose of the therapeutic agent the next day, or in the near future of the doctor visit, so that the patient does not need to return to the doctor’s office to receive the injection.

[00213] Various methods of controlled release is also contemplated herein. Encapsulation of therapeutic molecules within polymer particles is a well-established method for achieving controlled release and can be used in methods provided herein. Also, by taking advantage of the adsorption of protein therapeutics to poly(lactic-co-glycolic acid) (PLGA) nanoparticles, controlled release can also be achieved without encapsulation. In particular, extended-release for protein therapeutics can be applied with and without encapsulation in PLGA nanoparticles embedded within a hydrogel. The release profile tunable by modifying nanoparticle concentration, nanoparticle size, or environmental pH. Pakulska et al., Science Advances 2(5): el600519 (2016).

Combination Therapy

[00214] Provided herein is the use of variants of FGF19 peptide sequences, fusions of FGF19 and/or FGF21 peptide sequences and variants of fusions (chimeras) of FGF19 and/or FGF21 peptide sequences having one or more activities associated with the modulation of lactate homeostasis in combination with other therapeutic agents and/or treatment modalities. Provided herein is the use of variants of FGF19 peptide sequences, fusions of FGF19 and/or FGF21 peptide sequences and variants of fusions (chimeras) of FGF19 and/or FGF21 peptide sequences having one or more activities associated with the enrichment of Veillonella in combination with other therapeutic agents and/or treatment modalities. Provided herein is the use of variants of FGF19 peptide sequences, fusions of FGF19 and/or FGF21 peptide sequences and variants of fusions (chimeras) of FGF19 and/or FGF21 peptide sequences having one or more activities associated with the treatment and/or prevention of a disease associated with elevated lactate in combination with other therapeutic agents and/or treatment modalities.

[00215] By way of example, additional therapeutic agents (and classes thereof) that can be used in combination with peptide sequences described herein in the methods of treating or preventing a disease associated with elevated lactate include, but are not limited to a lactate lowering agent, or a probiotic.

[00216] In some embodiments, the additional therapeutic agent is a lactate-lowering agent. In some embodiments, the lactate-lowering agent is a lactate-lowering drug. In some embodiments, the lactate-lowering drug can be alkalinizing agents. In some embodiments, the alkalinizing agent can be sodium bicarbonate. In some embodiments, the alkalinizing agent can be tromethamine.

[00217] In some embodiments, the additional therapeutic agent is a probiotic. In some embodiments, the probiotic can be a probiotic that enriches Veillonella. In some embodiments, the probiotic can contain Veillonella.

[00218] Accordingly, treatment methods can include administering one or more additional therapeutic agents or therapeutic modalities useful in reducing lactate or in the treatment or prevention of disease associated with elevated lactate, such as those agents or therapeutic modalities described herein, in an amount effective to achieve a desired outcome or result in a subject. Treatment methods can include administering one or more additional therapeutic agents of therapeutic modalities useful in enriching Veillonella. A treatment that results in a desired outcome or result includes decreasing, reducing or preventing the severity or frequency of one or more symptoms of the condition in the subject, e.g ., an improvement in the subject’s condition or a “beneficial effect” or “therapeutic effect.” Therefore, treatment can decrease or reduce or prevent the severity or frequency of one or more symptoms of the disorder, stabilize or inhibit progression or worsening of the disorder, and in some instances, reverse the disorder, transiently (e.g., for 1-6, 6-12, or 12-24 hours), for medium term (e.g., 1-6, 6-12, 12-24 or 24-48 days) or long term (e.g, for 1-6, 6-12, 12-24, 24-48 weeks, or greater than 24-48 weeks). Thus, in the case of a disease associated with lactate elevation, treatment with a peptide provided herein in combination with another therapeutic agent can prevent the formation, cause regression of or stabilize atherosclerotic plaques in a subject. In the case of a disease associated with lactate elevation, treatment with a peptide provided herein in combination with another therapeutic agent can lower or reduce one or more symptoms or effects of the disease. In the case of modulating lactate homeostasis, treatment with a peptide provided herein in combination with another therapeutic agent can reduce serum level of lactate.

[00219] Accordingly, methods and uses provided herein for treating a subject having, or at risk of developing, a disease associated with lactate elevation can be practiced prior to, substantially contemporaneously with, or following administration or application of another agent useful for the treatment or prevention of a disease associated with lactate elevation, and/or can be supplemented with other forms of therapy. Methods and uses provided herein for treating a subject having, or at risk of developing, a disease associated with lactate elevation can be practiced prior to, substantially contemporaneously with, or following administration or application of another agent useful for the treatment or prevention of a disease associated with lactate elevation, and/or can be supplemented with other forms of therapy.

[00220] Supplementary therapies can be administered prior to, contemporaneously with or following methods and uses provided herein.

Compositions

[00221] Also provided herein are “pharmaceutical compositions,” which include a peptide sequence (or sequences) provided herein, including subsequences, variants and modified forms of the exemplified peptide sequences ( e.g ., sequences listed in the Sequence Listing or Table 1), and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients; in combination with, or separate from, one or more additional agents for the modulation of lactate homeostasis, for enrichment of Veillonella , for the treatment or prevention of a disease associated with lactate elevation, or a composition comprising such one or more additional agents and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In particular embodiments, a peptide sequence or sequences and an additional agent(s) are present in a therapeutically acceptable amount. The pharmaceutical compositions can be used in accordance with the methods and uses provided herein. Thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice treatment methods and uses provided herein. Pharmaceutical compositions provided herein can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.

[00222] In some aspects, the pharmaceutical compositions may further comprise an additional therapeutically active agents or compounds disclosed or known to the skilled artisan which can be used in the treatment or prevention of a disease associated with lactate elevation as set forth herein. In some aspects, the pharmaceutical compositions can further comprise an additional therapeutically active agents or compounds disclosed or known to the skilled artisan which can be used in the treatment or prevention of an a disease associated with lactate elevation as set forth herein. For example, the additional agent can be a lactate lowering agent or a probiotic. As set forth above, the additional therapeutically active agents or compounds can be present in a separate pharmaceutical composition(s). Exemplary dosing parameters and regimens are described herein.

[00223] Pharmaceutical compositions typically comprise a therapeutically effective amount of at least one of the peptide sequences provided herein, including subsequences, variants and modified forms of the exemplified peptide sequences (e.g., sequences listed in the Sequence Listing or Table 1) and/or one or more additional agents described herein, and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g, ascorbic acid and sodium bisulfate), preservatives (e.g, benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that could be used in the pharmaceutical compositions and dosage forms used herein. Typical buffers include, but are not limited to pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. Buffer components also include water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.

[00224] A primary solvent in a vehicle may be either aqueous or non-aqueous in nature. In addition, the vehicle may contain other pharmaceutically acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, sterility or stability of the pharmaceutical composition. In certain embodiments, the pharmaceutically acceptable vehicle is an aqueous buffer. In other embodiments, a vehicle comprises, for example, sodium chloride and/or sodium citrate.

[00225] Pharmaceutical compositions provided herein may contain still other pharmaceutically-acceptable formulation agents for modifying or maintaining the rate of release of a peptide and/or an additional agent, as described herein. Such formulation agents include those substances known to artisans skilled in preparing sustained-release formulations. For further reference pertaining to pharmaceutically and physiologically acceptable formulation agents, see, for example, Remington’s Pharmaceutical Sciences. 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712, The Merck Index. 12th Ed. (1996, Merck Publishing Group, Whitehouse, NJ); and Pharmaceutical Principles of Solid Dosage Forms (1993, Technonic Publishing Co., Inc., Lancaster, Pa.). Additional pharmaceutical compositions appropriate for administration are known in the art and are applicable in the methods and compositions provided herein.

[00226] A pharmaceutical composition may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such compositions may be stored either in a ready to use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, a pharmaceutical composition is provided in a single-use container ( e.g ., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas a multi-use container (e.g, a multi-use vial) is provided in other embodiments. Any drug delivery apparatus may be used to deliver peptides and the other agents described herein, including implants (e.g, implantable pumps) and catheter systems, both of which are known to the skilled artisan. Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release peptides and/or other agents described herein over a defined period of time. Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. The skilled artisan is familiar with possible formulations and uses of depot injections.

[00227] A pharmaceutical composition can be formulated to be compatible with its intended route of administration. Thus, pharmaceutical compositions include carriers, diluents, or excipients suitable for administration by routes including parenteral (e.g, subcutaneous (s.c.), intravenous, intramuscular, or intraperitoneal), intradermal, oral (e.g, ingestion), inhalation, intracavity, intracranial, and transdermal (topical).

[00228] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated using suitable dispersing or wetting agents and suspending agents disclosed herein or known to the skilled artisan. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butane did. Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer’s solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids such as oleic acid find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g, aluminum monostearate or gelatin).

[00229] Pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents such as sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets containing a peptide provided herein may be in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[00230] Tablets, capsules and the like suitable for oral administration may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, carbohydrates, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, polyanhydrides, polyglycolic acid, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethyl enevinyl acetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly (methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, non encapsulated nanoparticles, microspheres, microbeads, and lipid-based systems ( e.g N-fatty acyl groups such as N-lauroyl, N-oleoyl, fatty amines such as dodecyl amine, oleoyl amine, etc., see US Patent No. 6,638,513), including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods of preparing liposomes are described in, for example, U.S. Patent Nos. 4,235,871, 4,501,728, and 4,837,028. Methods for the preparation of encapsulated-free controlled release using nanoparticles are described, for example, in Pakulska etal, Science Advances 2(5): el600519 (2016). Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.

[00231] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[00232] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives.

[00233] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.

[00234] Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[00235] Pharmaceutical compositions provided herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

[00236] Pharmaceutical compositions can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including implants, liposomes, hydrogels, prodrugs and microencapsulated delivery systems.

For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed. Prolonged absorption of injectable pharmaceutical compositions can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.

[00237] Also provided herein are peptides and/or one or more additional agents described herein in the form of suppositories for rectal administration. The suppositories can be prepared by mixing a peptide and/or one or more additional agents described herein with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.

[00238] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described herein.

[00239] All applications, publications, patents and other references, GenBank citations and ATCC citations cited herein are incorporated by reference in their entirety. In case of conflict, the specification, including definitions, will control. As used herein, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “a peptide sequence” or a “treatment,” includes a plurality of such sequences, treatments, and so forth. [00240] As used herein, numerical values are often presented in a range format throughout this document. The use of a range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention unless the context clearly indicates otherwise. Accordingly, the use of a range expressly includes all possible subranges, all individual numerical values within that range, and all numerical values or numerical ranges including integers within such ranges and fractions of the values or the integers within ranges, unless the context clearly indicates otherwise. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91- 94%, 91-93%, and so forth. Reference to a range of 90-100% also includes 91%, 92%, 93%, 94%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.

[00241] In addition, reference to a range of 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc. In a further example, reference to a range of 25-250, 250-500, 500- 1000, 1000-2500, 2500-5000, 5000-25,000, or 5000-50,000 includes any numerical value or range within or encompassing such values, e.g, 25, 26, 27, 28, 29...250, 251, 252, 253,

254....500, 501, 502, 503, 504..., etc.

[00242] A series of ranges are disclosed throughout this document. The use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document. Thus, for example, reference to a series of ranges such as 5-10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, 100-150, includes ranges such as 5-20, 5-30, 5-40, 5-50, 5-75, 5- 100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth.

[00243] The invention is generally disclosed herein using affirmative language to describe the numerous embodiments. The invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, procedures, assays or analysis. Thus, even though the invention is generally not expressed herein in terms of what the invention does not include, aspects that are not expressly included in the invention are nevertheless disclosed herein.

[00244] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the descriptions in the Experimental section are intended to illustrate but not limit the scope of invention described in the claims.

EXAMPLES

[00245] In the study described herein, it was discovered that M70, an analogue of FGF19, promotes Veillonella enrichment in the gut microbiome of patients with NASH. It was further identified that Veillonella was negatively correlated with bile acid levels, specifically the more hydrophobic and toxic bile acids. These findings demonstrate a surprising role for M70 in the composition and diversity of the gut microbiome and suggest that M70 may be useful in stabilizing the gut microbiome and increasing Veillonella.

Example I

Stable Gut Microbiome Composition and Diversity with M70 Therapy in Patients with

Non-alcoholic Steatohepatitis

[00246] The in vivo role of M70 on gut microbiome composition and diversity was explored in the context of NASH in pooled phase 2 studies of double-blind, placebo-controlled as well as open-label dose expansion cohorts. Briefly, 144 NASH patients, with NAS > 4 (at least 1 point in each component), stage 1-3 fibrosis and absolute liver content by MRI-PDFF > 8%, received 0.3 mg, 1 mg, 3 mg or 6 mg of M70 or placebo daily for 12 weeks. Baseline and week 12 stool samples were collected.

[00247] In order to study the effect of M70 on gut microbiome composition and diversity, samples were analyzed by 16Sv4 PCR/Illumina MiSeq sequencing using the Diversigen 16S rRNA pipeline. The groups were compared pre- and post-treatment in alpha diversity, beta diversity, and taxonomy at the phylum and genus level. P values were calculated using Kruskal- Wallis (among multiple groups) or Mann Whitney (baseline v. week 12) with false discovery rate corrections by Benjamini-Hochberg method. A general linear model (GLM) was run in R Statistics to incorporate additional covariates.

[00248] 85% of reads produced were mapped to the SILVA database. There were no differences in alpha diversity for each treatment group at baseline or week 12 (FIG. 1). UniFrac- based principal coordinates analysis did not reveal any clustering in treatment groups by time (FIG. 2). No changes were seen in phylum ( Bacteroidetes , Firmicutes, Proteobacteria, Verrucomicrobia, Fusobacteria, Actinobacteria, Tenericutes, Cyanobacteria, Lentisphaerae, Synergistetes, Euryarchaeota, Spirochaetae ) or the top 30 most abundant genera over time or between M70 and placebo treatment (FIG. 3A). No changes were seen in genus (FIG. 3B). [00249] The results indicate that M70 therapy maintains stable gut microbial composition and diversity.

[00250] Weighted UniFrac-based principal coordinates analysis also did not reveal any clustering between placebo and M70 groups, indicating stable phylogenetic composition of the samples (FIG. 2B). No changes were seen in genera ( Bacteroides , Prevote llaceae, Alistipes, Lachnospiraceae, Faecalibacterium, Parabacteroides, Escherichia, Lachnoclostridium , Akkermansia, Fusobacterium, and Parasutterelld) between M70 and placebo treatment (FIG. 3C) or the 30 most abundant genera over time (FIG. 3D).

Example II

Veillonella as a Bile Acid-sensitive Bacteria in the Gut Microbiome: Analysis from M70 Trials in Patients with Non-alcoholic Steatohepatitis [00251] The in vivo role of M70 on minor genera Veillonella was explored in the context of NASH, using the methods described in Example I.

[00252] In order to study the effect of M70 on Veillonella in the gut microbiome, stool samples were analyzed using 16S rRNA method (Diversigen). Serum bile acid was measured with LC/MS (Mayo Clinic). A linear mixed-effect model was performed to account for non independence of the data set with the following model: Veillonella abundancQ ~ treatment type + visit + (1 (subject). Correlation between pre- and post-treatment in the relative abundance of Veillonella and bile acid species was determined by Spearman’s rank correlation coefficient. [00253] Subjects treated with M70 had stable gut microbial composition and diversity. No taxonomic changes were observed among 12 phyla or the top 30 most abundant genera over time or between M70 and placebo, except for an increase in the low abundance genus Veillonella in subjects who received M70 compared to the placebo group (FIG. 4A). At week 12, the relative abundance of Veillonella was negatively correlated with concentrations of bile acids, and the more hydrophobic, toxic bile acids in particular (GDCA: r=-0.45, pO.OOOl; GCDCA: r=-0.38, pO.OOOl; DCA: r=-0.38, pO.OOOl; GCA: r=-0.37, pO.OOOl).

-Ill- [00254] The results indicate that M70 promotes the enrichment of Veillonella , a gram negative bacterium that ferments lactate. Therefore, M70 may reduce lactate levels.

Furthermore, these results indicate that Veillonella is sensitive to bile acids. Thus, M70 may enrich Veillonella and reduce lactate through its negative regulation of bile acids. Because lactate is elevated in patients with advanced liver disease, which is associated with organ failure and mortality, M70 may be a useful treatment option for liver diseases or other related diseases that have elevated levels of lactate (see, e.g., Drolz et al., J. Hepatol. 69:258 (2019)).

[00255] At week 12, 82%, 83%, 75% and 86% of patients receiving 0.3 mg, 1 mg, 3 mg and 6 mg M70, respectively, had Veillonella present in their fecal samples, compared with 33% in the placebo group (FIG. 4B). The effect of M70 on Veillonella enrichment was not due to its effects on other microbes that are associated with Veillonella, or microbes that ferment other substrates, or that produce ethanol. For example, no enrichment was seen in taxonomically unrelated bacteria which tend to be associated with Veillonella, such as Campylobacter and Fusobacterium (FIG. 4C). Microbial genera that can ferment xylan and cellulose to produce short-chain fatty acids (SCFAs), such as Prevotella, were also not affected by M70 (FIG. 4C). There were no changes in Bacteroides, Bifidobacterium, and Escherichia, which are capable of producing alcohol (FIG. 4C), even though elevated representation of ethanol-producing bacteria was reported in NASH microbiome. (see, e.g., Zhu et al., J. Hepatol. 57(2):601-609 (2013)).

[00256] In order to determine the correlation between Veillonella and bile acid species, targeted metabolomics profiling of serum bile acids using gas chromatography-mass spectrometry was performed. There were marked reductions in the levels of bile acid species — especially the more toxic, glycine-conjugated, hydrophobic bile acids, among them GCA, GCDCA and GDCA — in patients treated with M70 (FIG. 5A). At week 12, 27%, 52%, 73% and 51% decrease in GCA, 21%, 33%, 56% and 26% decrease in GCDCA, 18%, 67%, 80% and 75% decrease in GDCA, were seen in patients receiving 0.3 mg, 1 mg, 3 mg or 6 mg M70, respectively. In contrast, no significant changes were seen in placebo treated patients. The hydrophobic, secondary bile acid DCA that was previously implicated in bile acid-associated carcinogenesis (see, e.g., Yoshimoto et al., Nature. 499(7456):97-101 (2013)), was significantly and dose-dependently reduced with M70 treatment (47%, 66%, 84% and 92% decrease in DCA, were seen in patients receiving 0.3 mg, 1 mg, 3 mg or 6 mg M70, respectively, compared with a 22% increase in patients receiving placebo) (FIG. 5A). [00257] A correlation analysis was conducted between Veillonella and the bile acid metabolome, including GCA, TCA, GCDCA, TCDCA, GDCA, TDCA, GLCA, TLCA, GUDCA, TUDCA, GHDCA, THDCA, CA, CDCA, DCA, LCA and UDCA (Table 1). At week 12, abundance of Veillonella significantly and inversely correlated with concentrations of the more toxic, hydrophobic bile acids. The Spearman’s correlation coefficients were: r=-0.45, pO.OOOl for GDCA; r=-0.38, pO.OOOl for GCDCA; r=-0.38, pO.OOOl for DCA; r=-0.37, p<0.0001 for GCA; and r=-0.36, p<0.0001 for TDCA (Table 2 and FIG. 5B).

Table 2 Example III

Correlation between gut microbiome and liver steatosis

[00258] Previous studies have shown that several phyla were significantly associated with liver steatosis (see, Hoyles et al., Nat. Med., 24(7):1070-80 (2018)), including Proteobacteria, Actinobacteria, and Verrucomicrobia that were positively correlated with liver steatosis, and Firmicutes and Euryarchaeota that were negatively correlated with liver steatosis. Thus, the relationship between fecal microbiota and liver fat content using data from the pooled cohort of patients was evaluated by 16S rRNA gene sequencing as described in Example II above. To assess liver fat content, patients underwent MRI-PDFF at baseline and at 12 weeks. Steatosis in hepatocytes was scored as 0, 1, 2 or 3 if there were less than 5%, 5-33%, 33-66%, or greater than 66% hepatocytes with fat, respectively.

[00259] Microbiome composition in patients with the top quartile versus the bottom quartile of liver fat content at baseline were compared. No differences were observed between quartile 1 (Ql) and quartile 4 (Q4) subjects in alpha diversity, a measurement of microbial richness and evenness (FIG. 6A). No clustering was seen between Ql and Q4 in beta diversity by either weighted or unweighted UniFrac analysis (FIG. 6B). Comparison of Ql and Q4 subjects revealed no significant differences at the phylum and genus levels by Mann-Whitney test with FDR corrections (FIG.

6C and 6D).

[00260] Next, the microbiome of patients who achieved > 70% reduction in liver fat on M70 versus placebo-treated patients were compared. 30 patients (out of 176 patients) were identified to have achieved a 70% or greater reduction in liver fat after 12 weeks of treatment with M70, versus none in the placebo group. Euryarchaeota were significantly differentially abundant between treated group with 70% or greater reduction in liver fat compared to the placebo group (P < 0.05 by Mann-Whitney test with FDR corrections using Benjamin-Hochberg method) (FIG. 6E). Lentisphaerae also trended toward significance. At the genus level, Haemophilus was significantly enriched in subjects with > 70% liver fat reduction after FDR correction (FIG. 6F). [00261] These results indicate that several microbial taxa in the gut microbiome are correlated with reduced liver fat content in patients with NASH.

Example IV

Correlation between gut microbiome and liver fibrosis [00262] Non-invasive detecting of liver fibrosis among patients with NASH is an important clinical need. Previous studies comparing the bacterial taxonomic composition between patients with mild/moderate fibrosis and patients with advanced fibrosis have yielded variable and often contradictory findings. To investigate the relationship between gut microbiota and liver fibrosis, baseline data from the pooled cohort of NASH patients was used. Differences in the composition of microbiota taxa in patients with mild (FI) or advanced fibrosis (F3) was assessed. No differences were observed between FI and F3 subjects in alpha diversity (FIG. 7A). No clustering was detected between FI and F3 in beta diversity by either weighted or unweighted UniFrac analysis (FIG. 7B). [00263] A differential analysis was also conducted to evaluate taxa whose abundances were different between FI and F3. There were no statistically significant differential abundances identified across fibrosis stage after FDR correction. Comparison of FI and F3 subjects revealed no significant differences at the phylum level by Mann-Whitney test with FDR corrections (FIG. 7C).

At the genus level, Ruminococcaceae (UncOlfpj) and Prevotellaceae (Unc99918) were enriched in F3, while Lachnospiraceae (Unc021zj) was enriched in FI, though the differential abundance was not statistically significant (FIG. 7D).

Example V

Liver Enzyme Content in Patients with Non-alcoholic Steatohepatitis Treated with M70 [00264] The role of the microbiome of patients who achieved >70% reduction in liver fat on M70 (“super-responders”) was explored in the context of NASH, using the methods described in Example I.

[00265] The “super-responders” had significant reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (FIG. 8A); however, these changes did not appear to correlate with microbiome (FIG. 8B).