C OMPO SITIONS COMPRISING CO-SELECTED MICROBIOTA AND METHODS

FOR USE THEREOF

Related applications

[0001] This application claims priority of U.S. Provisional Application No. 62/614,151, filed January 5, 2018 and U.S. Provisional Application No. 62/683,850, filed June 12, 2018, the entirety of which are incorporated herein by reference for all purposes.

Sequence Listing

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.

Field of the Invention

[0003] The field of invention relates to compositions and methods for treating disorders associated with dysbiosis (an imbalance of the microbial community inhabiting a subject or inhabiting a particular tissue in a subject). In particular, compositions and methods for treating gastrointestinal disorders associated with dysbiosis are envisioned.

Background of the Invention

[0004] Dysbiosis is associated with a variety of diseases and disorders. Accordingly, there is a need for reagents and methods for using same to restore a healthful balance of microorganisms that comprise a healthy microbiome.

Summary

[0005] Microbial Ecosystem Therapeutic (designated MET-2) is described herein. Exemplary subgroups of MET-2 (e.g., MET-2A and MET-2B) are also set forth herein. Additional exemplary subgroups of MET-2, MET-2A, and MET-2B are set forth in, e.g., Tables 3-5 presented herein. Further exemplary subgroups of MET-2 include: NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13- DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B- AER-MRS-02, and NB2A-10-MRS of Table 1 and also NB2B -20-GAM, NB2B-6-CNA, NB2A- 9-NA, 14 LG, NB2A-8-WC, NB2A-12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU of Table 1. As described herein at least one species of MET-2 and exemplary subgroups thereof and compositions comprising at least one species of MET-2 and exemplary subgroups thereof are encompassed, wherein the total number of species of MET - 2 or a subgroup thereof consists of the total number of species included in MET-2 or the specific subgroup indicated. In certain embodiments, the subset of bacterial species listed in Table 1 consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 species. In certain embodiments, an anhydrous composition comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, or at least 40 of the bacterial species listed in Table 1. Accordingly, at least one species of MET-2 and at least one species of exemplary subgroups of MET-2 and compositions comprising at least one species of MET-2 and at least one species of exemplary subgroups MET-2 are presented as therapeutic agents for use in treating a variety of gastrointestinal diseases (e.g., ulcerative colitis). Methods for treating a variety of gastrointestinal diseases by administering at least one bacterial species of MET-2 and/or at least one bacterial species of exemplary subgroups of MET-2 or compositions comprising at least one bacterial species of MET-2 and/or at least one bacterial species of exemplary subgroups of MET-2 to a subject in need thereof are also described herein. Also encompassed are the use of at least one bacterial species of MET-2 and/or at least one bacterial species of exemplary subgroups of MET-2 for treating a variety of gastrointestinal diseases and the use of at least one bacterial species of MET-2 and/or at least one bacterial species of exemplary subgroups of MET-2 in the preparation of a medicament for treating a variety of gastrointestinal diseases. Such gastrointestinal diseases include diseases or disorders associated with dysbiosis such as, for example, Clostridium difficile ( Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, and/or AIDS enteropathy.

[0006] In an aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises a plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0007] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises at least one of the bacterial species listed in Table 1, wherein the co-selected microbiota consists of bacterial species recited in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0008] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises a plurality of bacterial species, the plurality of bacterial species consisting of at least one bacterial species from each phylum of bacteria listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0009] In another aspect, an anhydrous composition comprising a co-selected microbiota in presented, wherein the co-selected microbiota comprises at least one of the MET-2A bacterial species listed in Table 3, wherein the co-selected microbiota consists of MET-2A bacterial species recited in Table 3, and optionally, at least one additional bacterial species, wherein the MET-2A bacterial species listed in Table 3 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co selected microbiota exhibits resistance to perturbational stress. [0010] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises at least one of the MET-2B bacterial species listed in Table 3, wherein the co-selected microbiota consists of MET-2B bacterial species recited in Table 3, and optionally, at least one additional bacterial species, wherein the MET-2B bacterial species listed in Table 3 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co selected microbiota exhibits resistance to perturbational stress.

[0011] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises at least one of the bacterial species listed in Table 3 that is present in each of MET-2, MET-2A, and MET-2B, wherein the co selected microbiota consists of the total number of bacterial species listed in Table 3 that are present in each of MET-2, MET-2A, and MET-2B, and optionally, at least one additional bacterial species, wherein the bacterial species present in each of MET-2, MET-2A, and MET- 2B are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0012] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises at least one of the bacterial species listed in Table 1, wherein the co-selected microbiota consists of bacterial species NB2B-20- GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A-12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU recited in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species NB2B-20- GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A-12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU recited in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0013] In an embodiment of any one of the aforementioned aspects, the co-selected microbiota comprises at least 25% Gram-negative bacterial species. In an embodiment of any one of the aforementioned aspects, the co-selected microbiota comprises at least 50% Gram-positive bacterial species. In an embodiment of any one of the aforementioned aspects, the co-selected microbiota comprises at least 65% bacterial species within the Firmicutes phylum. In an embodiment of any one of the aforementioned aspects, the co-selected microbiota comprises at least 5% bacterial species within the Bacteroidetes phylum.

[0014] In another aspect, an anhydrous composition comprising a co-selected microbiota is presented, wherein the co-selected microbiota comprises at least one of the bacterial species of any one of the following sub-groups described herein, including: NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13- DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B- AER-MRS-02; a sub-group described in Table 3; a sub-group described in Table 4; or a sub- group described in Table 4, and optionally, at least one additional bacterial species, wherein the sub-group of bacterial species are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

[0015] In a further embodiment of any one of the above aspects or embodiments, the bacterial species are in a state of suspended animation. In a further embodiment of any one of the above aspects or embodiments, the bacterial species exhibit robustness when challenged by perturbational stress in a chemostat model test or an ecosystem output assay.

[0016] In a further embodiment of any one of the above aspects or embodiments, the anhydrous composition further comprises a pharmaceutically acceptable carrier. More particularly, the pharmaceutically acceptable carrier is cellulose. More particularly still, the anhydrous composition is encapsulated in a capsule (e.g., the anhydrous composition may be encapsulated in a double capsule).

[0017] In a further embodiment of any one of the above aspects or embodiments, the at least one additional bacterial species is a species in the Acidaminococcus genus. More particularly, the Acidaminococcus genus is Acidaminococcus intestini or Acidaminococcus fermentans. [0018] In a further embodiment of any one of the above aspects or embodiments, the anhydrous composition further comprises a prebiotic.

[0019] Also encompassed herein is a method for treating a mammalian subject afflicted with a disease or disorder associated with dysbiosis, the method comprising: administering a therapeutically effective amount of an anhydrous composition of any one of the above aspects or embodiments to the mammalian subject, wherein the therapeutically effective amount improves relative ratios of microorganisms in the mammalian subject, thereby treating the mammalian subject. In a particular embodiment thereof, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy.

[0020] Also encompassed herein is an anhydrous composition of any one of the above aspects or embodiments for use in treating a disease or disorder associated with dysbiosis, wherein the anhydrous composition improves relative ratios of microorganisms. In a particular embodiment thereof, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy.

[0021] Also encompassed herein is an anhydrous composition of any one of the above aspects or embodiments for use in the preparation of a medicament for treating a disease or disorder associated with dysbiosis, wherein the anhydrous composition improves relative ratios of microorganisms. In a particular embodiment thereof, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy. [0022] In another aspect, an anhydrous composition comprising a plurality of bacterial species is presented, the plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are (a) in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the anhydrous composition when tested by a chemostat model test is: (b) suspended in a first growth media and cultured to achieve steady state growth of the plurality of bacterial species in the first growth media, wherein a relative abundance of the plurality of bacterial species at steady state growth in the first growth media is established as a first relative abundance, and (c) the plurality of bacterial species at steady state growth in the first growth media is challenged by perturbational stress, wherein the perturbational stress is a change in at least one of substrate type, substrate availability, or xenobiotic challenge, and the plurality of bacterial species exhibits robustness when challenged by the perturbational stress, wherein the robustness is exhibited by maintenance of the first relative abundance of the plurality of bacterial species after challenge by the perturbational stress.

[0023] In another aspect, an anhydrous composition comprising a plurality of bacterial species is presented, the plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are (a) in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the anhydrous composition when tested by an ecosystem output assay is: (b) suspended in a first growth media and cultured to achieve steady state growth of the plurality of bacterial species in the first growth media, wherein a relative abundance of the plurality of bacterial species at steady state growth in the first growth media is established as a first relative abundance, and (c) the plurality of bacterial species at steady state growth in the first growth media is challenged by perturbational stress, wherein the perturbational stress is a change in at least one of substrate type, substrate availability, or xenobiotic challenge, and the plurality of bacterial species exhibits robustness when challenged by the perturbational stress, wherein the robustness is exhibited by maintenance of functional output of types and quantities of selected small molecules generated by the plurality of bacterial species after challenge by the perturbational stress. [0024] In another aspect, an anhydrous composition comprising a plurality of bacterial species is presented, the plurality of bacterial species consisting of at least one bacterial species from each phylum of bacteria listed in Table 1, and optionally, at least one additional bacterial species, wherein the at least one bacterial species from each phylum of bacteria listed in Table 1 are (a) in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the anhydrous composition when tested by a chemostat model test is: (b) suspended in a first growth media and cultured to achieve steady state growth of the plurality of bacterial species in the first growth media, wherein a relative abundance of the plurality of bacterial species at steady state growth in the first growth media is established as a first relative abundance, and (c) the plurality of bacterial species at steady state growth in the first growth media is challenged by perturbational stress, wherein the perturbational stress is a change in at least one of substrate type, substrate availability, or xenobiotic challenge, and the plurality of bacterial species exhibits robustness when challenged by the perturbational stress, wherein the robustness is exhibited by maintenance of the first relative abundance of the plurality of bacterial species after challenge by the perturbational stress.

[0025] In another aspect, an anhydrous composition comprising a plurality of bacterial species is presented, the plurality of bacterial species consisting of at least one bacterial species from each phylum of bacteria listed in Table 1, and optionally, at least one additional bacterial species, wherein the at least one bacterial species from each phylum of bacteria listed in Table 1 are (a) in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the anhydrous composition when tested by an ecosystem output assay is: (b) suspended in a first growth media and cultured to achieve steady state growth of the plurality of bacterial species in the first growth media, wherein a relative abundance of the plurality of bacterial species at steady state growth in the first growth media is established as a first relative abundance, and (c) the plurality of bacterial species at steady state growth in the first growth media is challenged by perturbational stress, wherein the perturbational stress is a change in at least one of substrate type, substrate availability, or xenobiotic challenge, and the plurality of bacterial species exhibits robustness when challenged by the perturbational stress, wherein the robustness is exhibited by maintenance of functional output of types and quantities of selected small molecules generated by the plurality of bacterial species after challenge by the perturbational stress. [0026] In an embodiment of each of the above, the bacterial species are in a state of suspended animation. In a further embodiment, the anhydrous composition further comprises a pharmaceutically acceptable carrier (e.g., cellulose). In a further embodiment, the anhydrous composition is encapsulated in a capsule (e.g., a double capsule). In another embodiment, the at least one additional bacterial species is a species in the Acidaminococcus genus (e.g., Acidaminococcus intestini or Acidaminococcus fermentans). In a further embodiment, the anhydrous composition further comprises a prebiotic.

[0027] Also encompassed herein is a method for treating a mammalian subject afflicted with a disease or disorder associated with dysbiosis, the method comprising: administering a therapeutically effective amount of an anhydrous composition having the aforementioned properties (including exhibiting robustness when challenged by perturbational stress in a chemostat model test or an ecosystem output assay) to the mammalian subject, wherein the therapeutically effective amount improves relative ratios of microorganisms in the mammalian subject, thereby treating the mammalian subject. In an further embodiment, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy.

[0028] Also encompassed herein is an anhydrous composition comprising a co-selected microbiota for use in treating a disease or disorder associated with dysbiosis, wherein the co- selected microbiota comprises a plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress. In another aspect, an anhydrous composition comprising a co-selected microbiota for use in treating a disease or disorder associated with dysbiosis is described, wherein the co-selected microbiota comprises at least one of the bacterial species listed in Table 1, wherein the co-selected microbiota consists of bacterial species recited in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress. In a particular embodiment, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy. More particularly, the bacterial species are in a state of suspended animation. In a more particular embodiment, the anhydrous composition further comprises a pharmaceutically acceptable carrier (e.g., cellulose). In a more particular embodiment, the anhydrous composition is encapsulated in a capsule (e.g., in a double capsule). In another embodiment, the at least one additional bacterial species is a species in the Acidaminococcus genus (e.g., Acidaminococcus intestini or Acidaminococcus fermentans). In another embodiment, the anhydrous composition further comprises a prebiotic.

Also encompassed herein is an anhydrous composition comprising a co-selected microbiota for use in the preparation of a medicament for treating a disease or disorder associated with dysbiosis, wherein the co-selected microbiota comprises a plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress. In another aspect, an anhydrous composition comprising a co-selected microbiota for use in the preparation of a medicament for treating a disease or disorder associated with dysbiosis is presented, wherein the co-selected microbiota comprises at least one of the bacterial species listed in Table 1, wherein the co-selected microbiota consists of bacterial species recited in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder- form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress. [0029] More particularly, the bacterial species are in a state of suspended animation. In a more particular embodiment, the medicament/anhydrous composition further comprises a pharmaceutically acceptable carrier (e.g., cellulose). In a more particular embodiment, the medicament is encapsulated in a capsule (e.g., in a double capsule). In another embodiment, the at least one additional bacterial species is a species in the Acidaminococcus genus (e.g., Acidaminococcus intestini or Acidaminococcus fermentans). In another embodiment, the medicament further comprises a prebiotic. In a particular embodiment, the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn’s disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy.

[0030] Other objects, features and advantages of the present invention will become clear from the following description and examples.

Brief Description of the Figures

[0031] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0032] Figures 1A and 1B show a single-stage chemostat vessel employed in the methods according to some embodiments of the present invention.

[0033] Figure 2 depicts a chemostat model test according to one embodiment of the present invention.

[0034] Figure 3 shows a histogram of relative percent composition of bacterial species within each of the indicated phyla according to one embodiment of the present invention. [0035] Figures 4A and 4B each show a bar graph of relative percent composition of bacterial species within each of the indicated families according to one embodiment of the present invention.

[0036] Figure 5 (Table 2) lists the MET-2 strains with their accompanying 16S rRNA sequence fragments, designated herein SEQ ID NOs: 41-80 in order of appearance in Table 2.

[0037] Figure 6 (Table 4) lists properties of bacterial strains in MET-2.

[0038] Figure 7 (Table 5) lists properties of bacterial strains in MET-2, MET-2A, and MET- 2B.

Detailed Description of the Invention

[0039] Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying figures. Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention which are intended to be illustrative, and not restrictive.

[0040] Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases“in one embodiment” and“in some embodiments” as used herein do not necessarily refer to the same embodiment s), though it may. Furthermore, the phrases“in another embodiment” and“in some other embodiments” as used herein do not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0041] In addition, as used herein, the term“or” is an inclusive“or” operator, and is equivalent to the term“and/or,” unless the context clearly dictates otherwise. The term“based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of“a,”“an,” and“the” include plural references. The meaning of“in” includes“in” and“on.”

[0042] As used herein, the term“OTU” refers to an operational taxonomic unit, defining a species, or a group of species via similarities in nucleic acid sequences, including, but not limited to 16S rRNA gene sequences.

[0043] The term“dysbiosis” as used herein refers to an imbalance of the microbial community inhabiting a subject or inhabiting a particular tissue in a subject. The term typically refers to a decrease in beneficial microbes relative to deleterious microbes or a change in the ratio of microbes such that microbes that are normally only present in small numbers proliferate to a degree whereby they are present at elevated numbers.

[0044] As used herein, the term "state of suspended animation" as used herein with respect to a population of bacteria refers to a population of bacteria that is metabolically quiescent, but capable of resuming normal metabolic activity and proliferating in response to suitable growth promoting conditions.

[0045] The term“prebiotic” as used herein refers to“a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal icroflora that confers benefits upon host well-being and health”. See Roberfroid (2007, J Nutri 137:8305-8375. Particular prebiotics may be chosen for optimal results when used in conjunction with compositions described herein based on the mode of administration to the subject and the target tissue/s needing treatment. Particular prebiotics used in conjunction with compositions described herein may be food grade. Particular prebiotics envisioned for use in combination with compositions described herein include: inulin, fructo-oligosaccharides, or gluco-oligosaccharides and mixtures thereof.

[0046] Solutions of bacterial species are freeze dried/lyophilized to generate anhydrous compositions comprising a plurality of bacterial species having a moisture content of less than 25%, 20%, 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In a particular embodiment, anhydrous compositions described herein are freeze dried to a moisture content of less than 5 %. [0047] As used herein, the term“freeze dried/lyophilized” refers to a laboratory method where live microbes in aqueous suspension are rapidly frozen to <50°C, and then the majority of the frozen water content is forced to sublime under vacuum conditions, allowing this water to be efficiently removed in the gaseous phase.

[0048] As used herein, the term“anhydrous composition comprising a plurality of bacterial species” refers to a manmade, freeze dried/lyophilized population of bacterial species having a moisture content of less than 25%, 20%, 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment, a plurality of bacterial species is isolated from the fecal matter of a single, healthy individual wherein the plurality of bacterial species have been co-selected and co- adapted as an interactive population.

[0049] Technologies typically used for moisture determination include, without limitation: thermogravimetric analysis (oven drying, halogen/IR drying, microwave drying, etc.); chemical analysis (Karl Fischer titration, calcium carbide testing); spectroscopic analysis (IR spectroscopy, microwave spectroscopy, proton nuclear magnetic resonance spectroscopy); and other analyses (e.g. gas chromatography, density determination, refractometry, etc.). With respect to thermogravimetric analysis (TGA), for example, moisture content is derived from the loss of product weight during drying by measuring the change in mass of a sample while being heated at a controlled rate until no more change in weight is observed.

[0050] As used herein, the term“co-selected microbiota” refers to a plurality of bacterial species that has collectively undergone co-selection and co-adaptation in a single subject (e.g., a healthy subject). In a particular embodiment, the co-selected microbiota has collectively undergone co-selection and co-adaptation in the intestines of a single, healthy subject. In contrast, bacterial species isolated or derived from different sources (e.g., different subjects and/or cell depositories) and combined with each other have not undergone co-selection and co- adaptation in a single subject (e.g., a healthy subject). Thus, even when combined in vitro , a plurality of bacterial species that have been isolated from different sources cannot constitute a co-selected microbiota. [0051] As used herein, the term“subject” or“patient” is preferably an animal, including but not limited to animals such as mice, rats, cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, more preferably a primate, and most preferably a human.

[0052] As used herein, the term "treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0053] As used herein, the term "preventing" or "prevention" refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset).

[0054] As used herein, the term "prophylaxis" is related to "prevention" and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0055] As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.

[0056] As used herein, the phrase "therapeutically effective amount" is used to refer to an amount of an agent (e.g., a therapeutic agent) sufficient to reduce a pathological feature of a disease or condition by at least about 30 percent, by at least 50 percent, or by at least 90 percent. A "therapeutically effective amount" of an agent results in a clinically significant reduction in at least one pathological feature (e.g., a clinical symptom) of a disease or condition.

[0057] As used herein, the term "complementary" refers to two DNA strands that exhibit substantial normal base pairing characteristics. Complementary DNA may, however, contain one or more mismatches.

[0058] As used herein, the term "hybridization" refers to the hydrogen bonding that occurs between two complementary DNA strands.

[0059] As used herein, the term "nucleic acid" or a "nucleic acid molecule" refers to any DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule may be described herein according to the normal convention of providing the sequence in the 5' to 3' direction. With reference to nucleic acids of the invention, the term "isolated nucleic acid" is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous in the naturally occurring genome of the organism in which it originated. For example, an "isolated nucleic acid" may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryotic or eukaryotic cell or host organism.

[0060] When applied to RNA, the term "isolated nucleic acid" refers primarily to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from other nucleic acids with which it is generally associated in its natural state (i.e., in cells or tissues). An isolated nucleic acid (either DNA or RNA) may further represent a molecule produced directly by biological or synthetic means and separated from other components present during its production.

[0061] As used herein, the terms“natural allelic variants", "mutants", and "derivatives" of particular sequences of nucleic acids refer to nucleic acid sequences that are closely related to a particular sequence but which may possess, either naturally or by design, changes in sequence or structure. By closely related, it is meant that at least about 60%, but often, more than 85%, of the nucleotides of the sequence match over the defined length of the nucleic acid sequence referred to using a specific SEQ ID NO. Changes or differences in nucleotide sequence between closely related nucleic acid sequences may represent nucleotide changes in the sequence that arise during the course of normal replication or duplication in nature of the particular nucleic acid sequence. Other changes may be specifically designed and introduced into the sequence for specific purposes, such as to change an amino acid codon or sequence in a regulatory region of the nucleic acid. Such specific changes may be made in vitro using a variety of mutagenesis techniques or produced in a host organism placed under particular selection conditions that induce or select for the changes. Such sequence variants generated specifically may be referred to as "mutants" or "derivatives" of the original sequence.

[0062] As used herein, the terms "percent similarity", "percent identity" and "percent homology" when referring to a particular sequence are used as set forth in the University of Wisconsin GCG software program and are known in the art.

[0063] As used herein, the phrase "consisting essentially of' when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO:. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the basic and novel characteristics of the sequence.

[0064] A "replicon" is any genetic element, for example, a plasmid, cosmid, bacmid, phage or virus, that is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded.

[0065] A "vector" is a replicon, such as a plasmid, cosmid, bacmid, phage or virus, to which another genetic sequence or element (either DNA or RNA) may be attached so as to bring about the replication of the attached sequence or element.

[0066] An "expression vector" or "expression operon" refers to a nucleic acid segment that may possess transcriptional and translational control sequences, such as promoters, enhancers, translational start signals (e.g., ATG or AUG codons), polyadenylation signals, terminators, and the like, and which facilitate the expression of a polypeptide coding sequence in a host cell or organism.

[0067] As used herein, the term "operably linked" refers to a regulatory sequence capable of mediating the expression of a coding sequence and which are placed in a DNA molecule (e.g., an expression vector) in an appropriate position relative to the coding sequence so as to effect expression of the coding sequence. This same definition is sometimes applied to the arrangement of coding sequences and transcription control elements (e.g. promoters, enhancers, and termination elements) in an expression vector. This definition is also sometimes applied to the arrangement of nucleic acid sequences of a first and a second nucleic acid molecule wherein a hybrid nucleic acid molecule is generated.

[0068] As used herein, the term "oligonucleotide" refers to primers and probes described herein, which are defined as a nucleic acid molecule comprised of two or more ribo- or deoxyribonucleotides, preferably more than three. The exact size of the oligonucleotide will depend on various factors and on the particular application and use of the oligonucleotide.

[0069] As used herein, the term "probe" refers to an oligonucleotide, polynucleotide or nucleic acid, either RNA or DNA, whether occurring naturally as in a purified restriction enzyme digest or produced synthetically, which is capable of annealing with or specifically hybridizing to a nucleic acid with sequences complementary to the probe. A probe may be either single-stranded or double-stranded. The exact length of the probe will depend upon many factors, including temperature, source of probe and use of the method. For example, for diagnostic applications, depending on the complexity of the target sequence, the oligonucleotide probe typically contains 15-25 or more nucleotides, although it may contain fewer nucleotides. The probes herein are selected to be "substantially" complementary to different strands of a particular target nucleic acid sequence. This means that the probes must be sufficiently complementary so as to be able to "specifically hybridize" or anneal with their respective target strands under a set of pre- determined conditions. Therefore, the probe sequence need not reflect the exact complementary sequence of the target. For example, a non-complementary nucleotide fragment may be attached to the 5' or 3' end of the probe, with the remainder of the probe sequence being complementary to the target strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the probe, provided that the probe sequence has sufficient complementarity with the sequence of the target nucleic acid to anneal therewith specifically.

[0070] As used herein, the term "specifically hybridize" refers to the association between two single-stranded nucleic acid molecules of sufficiently complementary sequence to permit such hybridization under pre-determined conditions generally used in the art (sometimes termed "substantially complementary"). In particular, the term refers to hybridization of an oligonucleotide with a substantially complementary sequence contained within a single-stranded DNA or RNA molecule of the invention, to the substantial exclusion of hybridization of the oligonucleotide with single-stranded nucleic acids of non-complementary sequence.

[0071] As used herein, the term "primer" refers to an oligonucleotide, either RNA or DNA, either single-stranded or double-stranded, either derived from a biological system, generated by restriction enzyme digestion, or produced synthetically which, when placed in the proper environment, is able to functionally act as an initiator of template-dependent nucleic acid synthesis. When presented with an appropriate nucleic acid template, suitable nucleoside triphosphate precursors of nucleic acids, a polymerase enzyme, suitable cofactors and conditions such as a suitable temperature and pH, the primer may be extended at its 3' terminus by the addition of nucleotides by the action of a polymerase or similar activity to yield a primer extension product. The primer may vary in length depending on the particular conditions and requirement of the application. For example, in diagnostic applications, the oligonucleotide primer is typically 15-25 or more nucleotides in length. The primer must be of sufficient complementarity to the desired template to prime the synthesis of the desired extension product, that is, to be able anneal to the desired template strand in a manner sufficient to provide the 3' hydroxyl moiety of the primer in appropriate juxtaposition for use in the initiation of synthesis by a polymerase or similar enzyme. It is not required that the primer sequence represent an exact complement of the desired template. For example, a non-complementary nucleotide sequence may be attached to the 5' end of an otherwise complementary primer. Alternatively, non- complementary bases may be interspersed within the oligonucleotide primer sequence, provided that the primer sequence has sufficient complementarity with the sequence of the desired template strand to functionally provide a template-primer complex for the synthesis of the extension product. [0072] Primers and/or probes may be labeled fluorescently with 6-carboxyfluorescein (6- FAM). Alternatively primers may be labeled with 4, 7, 2', 7'-Tetrachloro-6-carboxyfluorescein (TET). Other alternative DNA labeling methods are known in the art and are contemplated to be within the scope of the invention.

[0073] In a particular embodiment, oligonucleotides according to the present invention that hybridize to nucleic acid sequences identified as specific for one of the bacterial species and/or strains described herein, are at least about 10 nucleotides in length, more particularly at least 15 nucleotides in length, more particularly at least about 20 nucleotides in length. Further to the above, fragments of nucleic acid sequences identified as specific for one of the bacterial species and/or strains described herein represent aspects of the present invention. Such fragments and oligonucleotides specific for same may be used as primers or probes for determining the amount of the particular bacterial species and/or strain in a bacterial sample generated in vitro or in a biological sample obtained from a subject, wherein the particular species or strain may be identified by the presence of any one of SEQ ID NOs: 1-40. Primers such as those described herein (e.g., SEQ ID NOs: 81 and 82) may, moreover, be used in polymerase chain reaction (PCR) assays in methods directed to determining the amount of a particular bacterial species and/or strain in a bacterial sample generated in vitro or in a biological sample obtained from a subject, wherein the particular bacterial species and/or strain comprises any one of, for example, SEQ ID NOs: 1-40.

[0074] Further to the above, a given strain’s 16S rRNA sequence is species specific and in many cases, depending on the species, strain specific as well. Further to this point, some bacterial species are highly conserved and thus, different strains may have extremely similar or even identical sequences. Most species, however, include strains wherein sequence differences are detected.

[0075] Preparation of Bacterial Samples (for 16S rRNA Sanger Sequencing)

[0076] Master Mix contents (per reaction or sample):

HPLC grade ddH20 (Caledon Laboratory Chemicals) - 38.5 pL

dNTPs, working stock (Invitrogen) - 3 pL

10X Therm oPol Reaction Buffer (NEB) - 5 pL V3kl/V6r primers (IDT) - 1 pL of each

Taq DNA Polymerase High Purity (BioBasic) - 0.5 pL

DNA Template - 1 pL or 1 colony

[0077] PCR. Sequencing of Products and Analysis of PCR Products

1) Determine how much of each Master Mix component is required by multiplying each by the number of samples. Add three additional reactions to account for pipetting error.

2) Bring the required amounts of ddH20, dNTPs (stored at -20°C), buffer (stored at -20°C), primers (stored at -20°C), 2 mL flip-cap tubes (sterile, from Axygen) and a V-bottom 96-well plate (sterile, from Fisher) into the Labconco Purifier Biological Safety Cabinet (Labconco, 08018496A). UV the hood and supplies for 15 minutes.

3) Turn the UV light off. Bring Taq (stored at -20°C) and DNA template samples (if they are in liquid form) into the safety cabinet.

4) Prepare Master Mix in a 2 mL flip-cap tube, aliquoting all of the required reagents into the same tube. Mix it by gently inverting the tube several times.

5) Aliquot Master Mix into the 96-well plate, 48 pL per reaction (or sample).

6) If your DNA is in liquid or broth form, skip Steps 9) and 10). If your DNA is taken directly from colonies on media plates skip Step 7).

7) Add 1 pL of your DNA template per aliquoted reaction (i.e. one PCR reaction for each of your DNA template samples). For example, 27 DNA template samples (or 27 strains to be tested) = 27 PCR reactions.

8) Remove the aliquoted Master Mix in the 96-well plate from the biological safety cabinet.

9) Transfer the aliquoted Master Mix in the 96-well plate into the Whitley anaerobic chamber workstation.

10) Use a sterile wooden applicator (Puritan) to touch a colony of interest and, using a twisting motion, deposit the colony into one well of the 96-well plate that contains an aliquot of Master Mix. Repeat for all bacterial strains of interest.

11) Run PCR reactions in the 96-well plate in the Eppendorf Mastercycler epgradient (Eppendorf, 5340 014805):

12) Using, for example, a Eppendorf Mastercycler (a.k.a. thermocycler) run the following: -Cycle parameters are 94°C for (the initial) 10 minutes, (94°C for 30s, 60°C for 30s, 72°C for 30s) for 30 cycles, then 72°C for 5 minutes, and 4°C for indefinite time.

13) Sequencing is performed via Sanger sequencing methods, which are a matter of routine practice in research-based laboratories.

14) Sequences (16S rRNA full-length rRNA sequences associated with each bacterial strain) generated are compared to databases of known sequences such as, for example, those maintained by U.S. government agencies, which can be accessed via the web (e.g., blast.ncbi.nlm.nih.gov/Blast.cgi) using known programs (e.g., BLAST).

15) When using, for example, a BLAST program and an alignment application thereof, a value of 99% or higher indicates that the template sequence and the query sequence are identical. If the template sequence and the query sequence are identical this indicates that the query sequence (which was obtained from a bacterial strain of interest) is the same identity as that which is associated with the template sequence.

[0078] Table 1 presents a list of MET 2 strains, which is an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein if the bacterial species are derived from a co-selected microbiota. In a particular embodiment, an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1, but does not exceed including each and every one of the species recited in the exemplary list of Table 1. In a more particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of each of the strains listed in Table 1.

[0079] In a particular embodiment, an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1 : NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3- NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, or NB2A-10-MRS, but does not exceed further including each and every one of the species recited in this exemplary list. In a particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises the following strains listed in Table 1 : NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, and NB2A-10-MRS, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In a more particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the following strains listed in Table 1 : NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, and NB2A-10-MRS.

[0080] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1 : NB2B-20-GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A- 12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU, but does not exceed further including each and every one of the species recited in this exemplary list. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1 : NB2B-20-GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A- 12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1.

[0081] Table 3 sets forth additional exemplary microbiotic communities comprising the indicated bacterial strains. These exemplary microbiotic communities are designated herein MET-2A and MET-2B.

[0082] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the MET-2A strains listed in Table 3, but does not exceed further including each and every one of the MET-2A species recited in Table 3. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following MET-2A strains listed in Table 3, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the MET-2A strains listed in Table 3.

[0083] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the MET-2B strains listed in Table 3, but does not exceed further including each and every one of the MET-2B species recited in Table 3. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following MET-2B strains listed in Table 3, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the MET-2B strains listed in Table 3.

[0084] As used herein, the term“ecosystem output assay” refers to a method whereby the composition of a microbial ecosystem may be determined from its functional output in terms of types and quantities of selected small molecule metabolites. Small molecule metabolites are known in the art and include, without limitation: organic acids (e.g., carboxylic acids and derivatives thereof), amino acids, alcohols (e.g., polyols), phenols, and fatty acids and conjugates thereof. Metabolites are typically measured in the range of millimolar concentrations. The MET-2 community, for example, exhibits a metabolic profile that comprises tartrate and urea and significantly elevated levels of glutamate, pyroglutamate, asparagine, glycolate, choline, thymine, and formate when compared to the metabolic profiles of bacterial communities isolated from different donors. See Yen et al. (2015, J Proteome Res 14: 1472-1482).

[0085] As used herein, the term“microbial ecosystem” refers to a plurality of different bacterial species that have been grown together either in an in vitro assay or in a biological setting such as, for example, a subject’s gut. In a particular embodiment, the subject may be a human.

[0086] As used herein, the term“chemostat model assay” refers to an assay wherein a plurality of bacterial species is seeded into a vessel compatible with bacterial proliferation, wherein the vessel is maintained under growth promoting conditions and comprises culture medium comprising growth factors suitable for promoting proliferation of the plurality of bacterial species. In an embodiment thereof, the proliferation of each of the bacterial species seeded into the vessel may be determined after a defined time period of incubation in the chemostat model assay. Such a determination may be made using techniques known in the art such as cell counting via automated or manual means and may be facilitated by cell staining using various dyes that are taken up by cells. Such dyes may be taken up differentially by live versus dead cells and thus, provide for distinguishing viable cells from dead or dying cells. The relative proliferation of each of the bacterial species seeded into the vessel may also be determined and total numbers of each bacterial species determined after a defined time period of incubation in the chemostat model assay. Accordingly, the chemostat model assay may be used to determine proliferation and/or proliferation rate of different bacterial species in the plurality of bacterial species seeded into the vessel and thus, provide an assay for comparing proliferation and/or proliferation rate among the different bacterial species seeded into the vessel under various growth promoting conditions. [0087] In a particular embodiment, the number of bacterial cells may be determined using a LIVE/DEAD™ BacLigM™ Bacterial Viability Kit in accordance with the manufacturer’s protocol . Live versus dead cells are distinguished using the LIVE/DEAD™ &icLight™ Bacterial Viability Kit, which differentially stains dead and dying cells with compromised membranes red and live cells having intact membranes green. The differential staining facilitates an accurate assessment of viable cells in a given sample.

[0088] in a more particular embodiment, the number of cells is determined via flow cytometry used in conjunction with a LIVE/DEAD™ &cLight™ Bacterial Viability Kit, which combination facilitates measuring the different colors of the differentially stained cells via fluorescence detection in a plate reader. Such an approach reveals information as to relative values of live and dead cells in a sample and generally improves accuracy of cell counting.

[0089] The chemostat model assay, therefore, provides an assay wherein the growth of the plurality of bacterial species initially seeded into a vessel (bacterial seed population) may be determined at different defined time periods of incubation in the chemostat model assay. Using the chemostat model assay, multiple vessels can be seeded with different bacterial seed populations and the growth of the different bacterial seed populations and particular species in the different bacterial seed populations can be determined at different defined time periods of incubation. Results determined from multiple vessels run in the chemostat model assay can, in turn, be compared to determine if different bacterial seed populations respond differentially to different growth conditions and perturbational stress.

[0090] As used herein, the term“robustness” as it relates to a microbial community refers to the resistance and resilience of the community towards external perturbation/s relative to the state of the microbial community absent or prior to exposure to the external perturbation/s. Robustness may, for example, be reflected in the ability of the microbial community to maintain relative ratios of representation (numbers) of each of the different species or phylums wherein the species are classified post-perturbation as compared to pre-perturbation. Robustness may also, for example, be reflected in the ability of the microbial community to maintain metabolic output post-perturbation relative to pre-perturbation. [0091] As used herein, the term“perturbational stress” refers to a change in at least one of substrate type, substrate availability, and xenobiotic challenge in the culturing conditions in which a population of bacterial cells is grown.

[0092] As used herein, the term“substrate” refers to a substance or compound present in the culture medium in which a population of bacterial cells is grown that is utilized metabolically by the bacterial cells.

[0093] As used herein, the term“xenobiotic challenge” refers to the introduction of a chemical substance into an ecosystem, wherein the chemical substance is not naturally produced or expected to be present within the ecosystem, or is present at a much higher concentration than in the natural situation.

[0094] Compositions described herein may be formulated for oral administration as capsules, powders, tablets, granulates, chewable foods, liquids, and beverages. In a particular embodiment, the compositions are formulated into a capsule (e.g., an enteric-coated microcapsule). In another particular embodiment, the compositions are formulated into a tablet. In yet another particular embodiment, the compositions are formulated into granulated or water soluble powders. Further particular compositions may be formulated into liquids, creams, lotions, gels dispersions or ointments for topical administration.

[0095] In a particular embodiment, a composition described herein is a powder. A powder may be administered as such or may be dissolved in a fluid, for example, for oral consumption (e.g., via capsule or double capsule) or for rectal administration via an enema. With respect to oral consumption, a powder composition may be provided in a palatable form for reconstitution as a drink or for reconstitution as a food additive. A powder composition may also be dissolved in a fluid for rectal administration via an enema (colonoscopic infusion). The powder may also be reconstituted to be infused via naso-duodenal infusion. Exemplary fluids for such purposes include physiological saline solutions.

[0096] Methods described herein are applicable to animals in general (e.g., mammals), and more particularly to humans and economically significant domestic animals, such as dogs, cats, cows, pigs, horses, sheep, mice, rats, and monkeys. [0097] When formulated, the composition may contain further ingredients, including ingredients that confer properties relating to healthfulness, flavor, formulating, or tableting. Non-limiting examples of additional ingredients that may be incorporated in compositions described herein include: prebiotics, vitamins, minerals, nutritional supplements (e.g., fiber), sweeteners, flow aids, and fillers. When formulated for oral administration, the compositions comprise at least 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or more w/w % of a composition of an anhydrous composition comprising a plurality of bacterial species described herein.

[0098] Compositions of the invention are useful in methods for treating various diseases and disorders characterized by dysbiosis. Compositions described herein may be used to promote digestive health, metabolism (nutritional heath), and weight management when administered orally or rectally. Compositions described herein may be used to treat or alleviate a positive indicator or symptom of a digestive disorder including: irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, and AIDS enteropathy.

[0099] Compositions described herein are also envisioned for use in treating or alleviating a positive indicator or symptom of a digestive disorder including: irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, and AIDS enteropathy.

[00100] Treatment regimens may be comprise administration of compositions described herein to a subject in need thereof on a daily basis (typically once or twice per day), twice or thrice weekly, bi-weekly, or once per month. Treatment regimens may also be altered as the subject’s condition changes and may, furthermore, be intermittent. A suitable treatment regimen may be determined by a medical practitioner and/or may be established based on empirical results as evaluated by a medical practitioner and/or the subject being treated.

[00101] Unless stated otherwise, all percentages referred to herein are by weight based on the total weight of the composition. Fecal-Derived Bacterial Populations and Anhydrous Compositions Thereof

[00102] In a particular embodiment, a fecal-derived bacterial population is isolated or derived from a healthy subject.

[00103] In a particular embodiment, a fecal-derived bacterial population is derived from a subject (e.g., a healthy subject) by a method comprising: a. obtaining a freshly voided stool sample, and placing the sample in an anaerobic chamber (in an atmosphere of 90% N2, 5% CO2 and 5% H2); b. generating a fecal slurry by macerating the stool sample in a buffer; and c. removing food particles by centrifugation, and retaining the supernatant, which comprises the bacteria isolated from fecal matter and food particles. Accordingly, the supernatant comprises a purified population of intestinal bacteria that is free of fecal matter and food particles. Given that, the purified population of intestinal bacteria is a manmade product that is fecal matter-free and food particle-free.

[00104] In a further embodiment, a fecal sample (either fresh or frozen) is diluted in saline and plated onto a series of 13-20 different media types, each tailored to the isolation of particular types of species. The fecal sample may also be used undiluted as inoculum to seed a chemostat, which is grown to steady state, and then an aliquot of the steady state culture is diluted in saline and subsequently plated onto a series of 13-20 different media types, each tailored to the isolation of particular types of species. A diluted sample of bacteria may, for example, be treated with ethanol to select for sporulating bacteria. In another embodiment, antibiotics are added that exclude certain types of bacterial cells. In another embodiment, filter-sterile spent chemostat medium is added to provide growth substrates that promote proliferative or provide a selective advantage for certain types of bacterial cells. Following transfer into the 13-20 different media types, bacterial cell cultures are incubated for 3-10 days and individual colonies are picked, re streaked to purity, and then frozen down. Frozen stocks are grown in culture to curate/characterize the strain by conducting a 16S rRNA gene sequencing read using Sanger chemistry and the obtained trace compared to the RDP database. [00105] Once the strains have been curated/characterized, each bacterial species listed in Table 1 or a subset thereof is cultured individually to expand the population of each bacterial species to reach a threshold of biomass for each bacterial species. For bacterial species that grow poorly relative to other species listed in Table 1, a larger volume of bacterial culture is grown so as to achieve a biomass equivalent to that of faster growing species. The strains are all grown separately in Wilkins-Chalgren broth under anaerobic conditions at 37°C. The cultured bacterial population of each species is then concentrated by centrifugation, resuspended in medium optionally containing a cryoprotectant/lyoprotectant (inulin and riboflavin), and then rapidly frozen at -80°C. Frozen material is placed into a lyophilizer instrument and the cycle run to sublimate and remove the water content, leaving a fine powder representing a matrix of preserved bacterial cells and optionally cryo-lyoprotectant. The individual powders from each individual isolate are tested for purity and if pure, may be combined into desired combinations as powders via thorough mixing to generate an anhydrous composition comprising a desired plurality of bacterial species.

[00106] In certain embodiments, an anhydrous composition comprising a population of bacterial species may be derived from fecal matter in accordance with methods disclosed in U.S. Patent Nos. 8,906,668 and 9,511,099 and in U.S. Patent Application Publication No. 20140342438, the entire content of each of which is incorporated herein by reference.

Culture Methods According to Certain Embodiments

[00107] In certain embodiments, an anhydrous composition comprising a plurality of bacterial species is cultured in a chemostat vessel. In certain embodiments, the chemostat vessel is the vessel disclosed in U.S. Patent Application Publication No. 20140342438. In some embodiments, the chemostat vessel is the vessel described in Figures 1 A and 1B.

[00108] In certain embodiments, the chemostat vessel is converted from a fermentation system to a chemostat by blocking off the condenser and bubbling nitrogen gas through the culture. In certain embodiments, the pressure forces the waste out of a metal tube (formerly a sampling tube) at a set height and allows for the maintenance of given working volume of the chemostat culture. [00109] In certain embodiments, the chemostat vessel is kept anaerobic by bubbling filtered nitrogen gas through the chemostat vessel. In certain embodiments, temperature and pressure are automatically controlled and maintained

[00110] In certain embodiments, the culture pH of the chemostat culture is maintained using 5% (v/v) HC1 (Sigma) and 5% (w/v) NaOH (Sigma).

[00111] In certain embodiments, the culture medium of the chemostat vessel is continually replaced. In certain embodiments, the replacement occurs over a period of time equal to the retention time of the distal gut. Consequently, in certain embodiments, the culture medium is continuously fed into the chemostat vessel at a rate of 400 mL/day (16.7 mL/hour) to give a retention time of 24 hours, a value set to mimic the retention time of the distal gut. An alternate retention time can be 65 hours (approximately 148 mL/day, 6.2 mL/hour). In certain embodiments, the retention time can be as short as 12 hours.

[00112] In certain embodiments, the culture medium is a culture medium disclosed in U.S. Patent Application Publication No. 20140342438.

[00113] While a number of embodiments of the present invention have been described, it is understood that these embodiments are illustrative only, and not restrictive, and that many modifications may become apparent to those of ordinary skill in the art. Further still, the various steps may be carried out in any desired order (and any desired steps may be added and/or any desired steps may be eliminated).

[00114] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

Examples

Example 1 : Comparison of microbial ecosystems derived from a single donor versus those derived from multiple donors

[00115] The present inventors investigated whether microbes derived from a single individual have co-adapted to the host and demonstrate‘cohesiveness’ or an ability to work efficiently together. The present inventors hypothesized that such cohesiveness may be critical to the ability of the ecosystem to best respond to commonly encountered environmental perturbations

[00116] To test this, the present inventors created 2 defined microbial communities of 27 bacterial species each, representing 6 bacterial phyla commonly found in the human gut. The first community (CC) represented a group of bacterial isolates, each representative of a different species, which had been isolated from a single donor. Accordingly, CC is a co-selected microbiota. The second community (FC) represented a group of isolates which matched the CC community in species identity (>97% identity across the full length 16S rRNA gene sequences), but wherein each community member had been sourced from a different individual (i.e., 27 different individuals in total). The communities were verified for purity by individual deep sequencing of 16S rRNA genes on the Illumina Miseq platform.

[00117] Each community was separately seeded into a bioreactor vessel fed with a high fibre diet and allowed to achieve steady state (14 days), and then samples were removed for analysis. See Figure 2.

[00118] After sample removal at steady state, the bioreactors were switched abruptly to a high protein diet to simulate a perturbational stress. Steady state was allowed to develop over a further 14 days and the ecosystems were resampled. See Figure 2. 16S rRNA sequence profiling was carried out on the samples using the Illumina MiSeq platform.

[00119] 16S rRNA primers were used to generate 16S rRNA sequence fragments Figure 5

(Table 2) and full length 16S rRNA sequences (Appendix A) corresponding to each bacterial strain presented in Table 1. Exemplary 16S rRNA primers with T3 and T7 tails, respectively are as follows:

ATTAACCCTCACTAAAGTACGG[AG]AGGCAGCAG (SEQ ID NO: 81) V3kl primer AATACGACTCACTATAGGGAC[AG]ACACGAGCTGACGAC (SEQ ID NO: 82) V6r primer. [00120] Full length 16S rRNA sequences for each of the MET-2 strains are presented in Appendix A (attached hereto) and designated SEQ ID NOs: 1-40.

[00121] Figure 5 (Table 2) lists the MET-2 strains with their accompanying 16S rRNA sequence fragments. The 16S rRNA sequence fragments are designated SEQ ID NOs: 41-80 in order of their appearance in Table 2.

[00122] In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook et al, "Molecular Cloning: A Laboratory Manual" (1989); "Current Protocols in Molecular Biology" Volumes T-TTT [Ausubel, R. M., ed. (1994)]; "Cell Biology: A Laboratory Handbook" Volumes I-III [J. E. Celis, ed. (1994))]; "Current Protocols in Immunology" Volumes I-III [Coligan, J. E., ed. (1994)]; "Oligonucleotide Synthesis" (M. J. Gait ed. 1984); "Nucleic Acid Hybridization" [B. D. Hames & S. J. Higgins eds. (1985)]; "Transcription And Translation" [B. D. Hames & S. J. Higgins, eds. (1984)]; "Animal Cell Culture" [R. I. Freshney, ed. (1986)]; "Immobilized Cells And Enzymes" [IRL Press, (1986)]; B. Perbal, "A Practical Guide To Molecular Cloning" (1984).

[00123] Results

[00124] A switch from high fibre to high protein diet resulted in little appreciable change in the relative abundance profiles of the CC community, suggesting that the community could efficiently adapt to the perturbation. Conversely, the FC community showed a dramatic change in relative abundance with a marked increase in Proteobacteria - a common sign of dysbiosis. Proteobacteria include many microbial species that tend to be metabolically versatile and thus opportunistic feeders. See Figures 3 and 4.

[00125] Based on the results presented herein, the present inventors conclude that microbial communities that have been co-selected and co-adapted within a host (co-selected microbiota) demonstrate robustness during perturbational stress. This provides justification for creating MET products derived from a single selected donor rather than an amalgamation of many donors. Protocol for treating humans afflicted with diseases or disorders associated with dysbiosis

As described herein, MET-2 and exemplary subgroups thereof (e.g., MET-2A and MET-2B) are described as therapeutic agents for treating gastrointestinal diseases in subjects afflicted with such diseases, including ulcerative colitis. The bacterial isolates found in MET-2 are pure live bacterial cultures of intestinal bacteria that were isolated from a stool sample of a healthy 25- year-old male donor. The microbial ecosystem therapeutic product is comprised of 40 lyophilized pure bacterial cultures mixed in predefined ratios. The product is delivered to the patients orally, in capsule form.

MET-2 comprises 40 strains of lyophilized bacteria, originally purified from a healthy 25-year- old stool donor and further selected based on their favorable safety profile. The donor used to derive MET-2 was also successfully used as a donor for FMT in the treatment of multiple patients with Clostridium difficile. A phase la clinical trial with MET-2 in patients with rCDI is currently in progress. Preliminary evidence suggests MET-2 is well tolerated with no serious adverse events related to treatment with this therapeutic to date. Furthermore, there have been no reported cases of bacteremia, sepsis or invasive infections in rCDI patients undergoing MET-2 treatment to date.

MET-2 has modifications that reflect and incorporate novel information that has emerged from the rapidly evolving field of gut microbiota research in the context of ulcerative colitis.

The donor from which MET-2 was derived was screened extensively for viral, bacterial and medical disease. Briefly, MET-2 excludes pathogenic organisms including extended spectrum beta-lactamase (ESBL), vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and Clostridium difficile (C. difficile). In addition, risk assessment for high-risk behaviors for blood-borne pathogens, a thorough detailed medical history and a physical examination to confirm the overall health of the donor were completed. There are no specific considerations for MET-2 recipients. Empiric and targeted antibiotic therapy should be guided by routine standards of care in close consultation with appropriate experts including infectious disease or medical microbiology specialists. The isolated strains were then purified by repeated subculture, initially sequenced for identification and screened for bacterial resistance to ensure no transfer of resistant strains. Within the manufacturing process, there are multiple passaging steps, where purity is subsequently examined on plate culture. Finally, MET-2 product release only occurs when each bacterial culture tests negative for impurities or any bacterial contaminant (e.g. pathogenic organisms) as determined by Sanger sequencing of the 16S rRNA gene (specific to bacteria).

MET-2 is comprised of 40 lyophilized pure bacterial cultures mixed in predefined ratios, with strengths as detailed in Table 6.

Table 6: Strength of MET-2 Capsules

CFU = colony forming unit

ETlcerative colitis (ETC) is a chronic, relapsing, idiopathic, inflammatory disease of the colorectum. In the last decade, there has been an increase in the incidence and prevalence of ETC, making it an important emerging global disease. The main symptoms of UC include bloody diarrhea, abdominal pain, urgency, tenesmus, and incontinence, which cause a reduction in patient quality of life. The severity of UC symptoms ranges from mild disease (<4 stools per day with or without blood) to severe disease (>10 stools per day with intense cramping and continuous bleeding). Depending on the clinical severity of intestinal disease, patients may also develop systemic symptoms and other life-threatening complications.

Management of UC is determined by the clinical severity of disease, and current treatment strategies are focused on regulating the immune system with anti-inflammatory and

immunosuppressive drugs. For mild-to-moderate disease anti-inflammatory agents, e.g. 5- aminosalicyclic acid (5-ASA), are the main treatment options with use of immunomodulators as a steroid sparing agent. While these therapies are able to maintain remission in many cases, current medical treatments are imperfect and there is a subset of patients that do not respond to topical 5-ASA alone or in combinational therapy with corticosteroids. Additionally, 20-30% of UC patients require colectomy to manage acute complications and medically intractable disease. Thus, there is a need for more efficacious drugs with a greater favorable safety profile for the treatment of UC. Although the pathogenesis of UC is complex, multifactorial, and not fully understood, aberrant host immune responses, and a dysfunctional intestinal barrier have been associated with this condition.

The human body is host to more than 10 trillion microbial cells with the majority of these residing in the gut. The collection of microorganisms, their gene products and corresponding metabolic functions in the human gastrointestinal (GI) tract is termed the gut microbiome.

Recent advances in molecular microbiology have revealed the critical role of the gut microbiome in a variety of important processes including: vitamin/nutrient production, regulation of metabolism and host energy demands, intestinal epithelial cell homeostasis, protection against pathogens, and development and maintenance of normal immune function.

Gut dysbiosis can be defined as a pathological imbalance in a microbial community

characterized by a shift in the composition, diversity or function of microbes, which can result in disease. Antibiotics, toxic compounds, diet, medical interventions, and disease can all influence the gut microbiome. However, defining gut microbial dysbiosis is difficult due to the variability in bacterial composition across individuals in both in healthy and disease-states. The gut microbiome has been associated with a multitude of disease indications including, but not limited to: C. difficile infection (CDI), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).

The MET-2 anhydrous composition (drug product) comprises a lyophilized mixture of predetermined ratio of pure cultures of 40 diverse intestinal bacteria, derived from a stool sample of one healthy donor. Each capsule contains 0.5 g of MET-2, with a strength per capsule of 3.59 X 10 ⁷ to 3.59 X 10 ¹¹ colony forming units (CFEi) per capsule. The drug product is shipped and maintained at room temperature; the capsule is sealed in anaerobic packaging and is opened only immediately prior to the subject/patient swallowing the capsule. As indicated above, forty pure bacterial culture isolates have been selected for MET-2 composition from a stool sample of a single donor. The identities of the bacterial isolates have been confirmed microbiologically as well as using 16S ribosomal RNA (rRNA) sequencing.

All isolates included in MET-2 are sensitive to imipenem, ceftriaxone, and piperacillin.

Susceptibility to antimicrobials was determined by directly measuring susceptibility with e-strips and/or Kirby Bauer disks.

List of cultured isolates that have been selected for the drug substance are provided in Table 7 below.

Table 7: MET -2 Composition

aClosest species match was inferred by alignment of the 16S rRNA sequence to the NCBI database; note that in some cases 16S rRNA gene sequences could not resolve identity beyond genus, and that closest match does not infer definitive speciation. Note that some representative strains identify with the same species by 16S rRNA gene sequence alignment but are believed to be different strains based on observed differences in colony morphology, antibiotic resistance patterns and growth rates.

Further to the above, any potential strain having equal to or greater than 97% identity to its closest neighbor by 16S rRNA gene sequence identity is considered in the art to be of the same species. This accepted understanding applies to all percent identities described herein.

Microcrystalline cellulose is added to the mixture of lyophilized drug substances as a flow aid. Two-piece hard Vcaps ^® Enteric Capsules (Capsugel), composed of hypromellose/hypromellose AS and titanium dioxide, are used to encapsulate the MET-2 drug substance mixture (including microcrystalline cellulose). The MET-2 product is double-encapsulated; MET-2 lyophilized material is filled into a size 0 enteric capsule, sealed, and then placed in a size 00 enteric capsule, which is then sealed again.

MET-2 capsules are administered orally in an enteric capsule, for delivery of the live bacteria to the large intestine. MET-2 capsules are to be stored at room temperature, and packaging should be opened only immediately before administration to patients in order to preserve the nitrogen atmosphere within the packages.

Preclinical Studies

Dextran sulfate sodium (DSS) is a commonly-employed mouse model of colitis which involves a chemical disruption of barrier function in the absence of involvement of any specific pathogen.

In order to explore the effects of MET-2 on barrier function and inflammation, mice may be gavaged with MET-2 following an oral antibiotic treatment and then given 3% DSS to induce colitis. Mice receiving MET-2 may be evaluated to measure serum levels of inflammatory cytokines as well as reduced histologic injury compared to controls. In addition, the effect of MET-2 administration following oral antibiotics may be measured to evaluate if MET-2 administration attenuates the DSS-mediated loss of Mucin-2, a mucin protein and major constituent of the protective mucous barrier found in the colon. Impaired gut barrier function can initiate dysbiosis which influences gut barrier integrity and innate and adaptive immune responses in the host. Maintenance of gut barrier integrity is critical in the context of gut homeostasis as inappropriate immune responses to a dysbiotic gut microbiota are hypothesized contribute to the pathogenesis of UC.

In vitro studies have already been performed with MET-2 formulations. These studies have shown that MET-2 protected human intestinal cell lines from cytoskeleton and cell barrier damage caused by C. difficile toxins C. difficile Toxin A (Ted A) and C. difficile Toxin B (TcdB). MET-2 also protected cells from apoptosis.

Results of clinical studies with MET-2 Preliminary evidence suggests that MET-2 is well tolerated with no serious adverse events related to treatment with this therapeutic to date. Additionally, there have been no reported cases of bacteremia, sepsis or invasive infections in rCDI patients undergoing MET-2 treatment to date.

Clinical development for MET-2 includes rigorous donor screening. To summarize, fecal material was obtained from a healthy fecal donor with informed and written consent. The donor was screened for a variety of blood borne disease such as HIV-l and HIV-2; hepatitis A, B and C; syphilis as well as different enteric bacteria {Salmonella species, Shigella species,

Campylobacter species, Escherichia coli Ol57:H7 and Yersinia ) and the presence of C. difficile toxins. The stool was also examined for microscopic presence of ova and parasites. The donor was further screened for colonization with Helicobacter pylori , methicillin-resistant

Staphylococcus aureus and vancomycin-resistant Enterococcus species in stool. A detailed medical history, including high risk behavior and a physical examination were also completed.

Bacterial strains were purified and grown in a bioreactor modeling the conditions of the human distal gut. Susceptibility to antimicrobials was determined. Isolates representing commensal species, sensitive to a range of antimicrobials, were selected for the final stool substitute formulation. Full length 16S rRNA sequences were classified using basic local alignment search tool (BLAST) with the most specific name used to report the DNA maximum likelihood score. MET-2 constituent strains were individually grown in pure culture, snap-frozen, and subjected to lyophilization. After each strain meets CFU/g specifications, lyophilized bacterial product from all strains were combined in pre-determined ratios to make the active pharmaceutical ingredient (API).

The composition and route of delivery of METs differs based on the indication. For example, MET-2 is a lyophilized bacterial product that is given orally, in encapsulated form for UC. MET- 2 for rCDI is supplied in 2 dosage forms: 1) lyophilized powder in capsules for oral ingestion and 2) lyophilized powder for rectal administration by colonoscopy (powder is resuspended in 0.9% saline). MET-l was a live bacterial product (resuspended in 0.9% saline) also administered by colonoscopy. A recent non-inferiority trial showed that oral capsules are equally effective compared to colonoscopy-delivered FMT for rCDI. Notably, there were fewer minor adverse events in patients receiving FMT capsules compared to patients receiving FMT via colonoscopy in the above study. Additionally, several FMT studies have shown that frozen fecal material is as effective as fresh fecal material in treating rCDI. More recently, FMT has been given in lyophilized form by capsule delivery, with an 88% success rate. Accordingly, the MET -2 clinical protocol implemented changes in the route of administration with regards to these recent advances in the literature. Encapsulated lyophilized FMT material has not been studied for use in ETC patients, although lyophilized bacterial product preparations are commonplace in the probiotic industry.

As described herein, MET-2 is a therapeutic composition composed of a defined microbial community of 40 bacterial strains derived from the stool of a healthy fecal donor. The bacteria are prepared as a mixture in a predetermined ratio of pure lyophilized intestinal bacteria. The bacteria are then double encapsulated in enteric capsules. MET-2 capsules contain 0.5 g of MET - 2 (equivalent to 3.59 X 10 ⁷ to 3.59 X 10 ¹² CFET) and are administered to patients via oral route. The donor from where MET-2 strains were derived has been rigorously screened for infectious materials and blood-borne pathogens. Stool from this donor has also been previously used as an FMT donor to successfully treat rCDI. There is no upper toxicity limit is expected due to the safety profile of the MET-2 bacterial community.

A multi-species derivative community such as that described herein will be more generally useful than a single organism probiotic or a mixed culture of such probiotic species. The microbes in MET-2 are derived from a community and are expected to retain community structure to a degree that enables them to colonize the colonic environment. A defined microbial community, isolated from a single healthy donor, may be sufficiently robust to withstand further perturbations by antibiotics as indicated by results presented herein demonstrating augmented robustness responsiveness to perturbations. See, e.g., Figures 3 and 4.

[00126] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

[00127] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

Appendix A

NB2-A29D6 Parabacteroides merdae

ACGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCGACAGGCTTAACACATGCA

AGTCGAGGGGCAGCATGATTTGTAGCAATACAGATTGATGGCGACCGGCGCACGGG

TGAGTAACGCGTATGCAACTTACCTATCAGAGGGGGATAGCCCGGCGAAAGTCGGA

TTAATACCCCATAAAACAGGGGTCCCGCATGGGAATATTTGTTAAAGATTCATCGCT

GATAGATAGGCATGCGTTCCATTAGGCAGTTGGCGGGGTAACGGCCCACCAAACCG

ACGATGGAT AGGGGTTCTGAGAGGAAGGTCCCCC AC ATT GGT ACTGAGAC ACGGAC

C AAACTCCT ACGGGAGGC AGC AGT GAGGAAT ATTGGT C AAT GGCCGAGAGGCTGAA

CCAGCCAAGTCGCGTGAAGGAAGAAGGATCTATGGTTTGTAAACTTCTTTTATAGGG

GAATAAAGTGGAGGACGTGTCCTTTTTTGTATGTACCCTATGAATAAGCATCGGCTA

ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGATGCGAGCGTTATCCGGATTTATTG

GGTTT AAAGGGT GCGT AGGT GGTGATTT AAGTC AGCGGT GAAAGTTT GT GGCTC A AC

CATAAAATTGCCGTTGAAACTGGGTTACTTGAGTGTGTTTGAGGTAGGCGGAATGCG

T GGTGT AGCGGT GAAAT GC AT AG AT ATC ACGC AGAACTCCGATTGCGAAGGC AGCT

TACTAAACCATAACTGACACTGAAGCACGAAAGCGTGGGGATCAAACAGGATTAGA

TACCCTGGTAGTCCACGCAGTAAACGATGATTACTAGGAGTTTGCGATACAATGTAA

GCTCTACAGCGAAAGCGTTAAGTAATCCACCTGGGGAGTACGCCGGCAACGGTGAA

ACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGA

TGATACGCGAGGAACCTTACCCGGGTTTGAACGTAGTCTGACCGGAGTGGAAACAC

TCCTTCTAGCAATAGCAGATTACGAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGT

GAGGTGTCGGCTTAAGTGCCATAACGAGCGCAACCCTTATCACTAGTTACTAACAGG

T G A AGC T G AGG AC T C T GGT GAG AC T GC C AGC GT A AGC T GT G AGG A AGGT GGGG AT G

ACGTCAAATCAGCACGGCCCTTACATCCGGGGCGACACACGTGTTACAATGGCATG

GACAAAGGGCAGCTACCTGGCGACAGGATGCTAATCTCCAAACCATGTCTCAGTTC

GGATCGGAGTCTGCAACTCGACTCCGTGAAGCTGGATTCGCTAGTAATCGCGCATCA

GCCATGGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGG

GAGCCGGGGGTACCTGAAGTCCGTAACCGCAAGGATCGGCCTAGGGTAAAACTGGT

GACTGGGGCTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGAACACCT

CCTTT (SEQ ID NO: 1)

NB2-B 13BHI [Eubacterium] hallii

CTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCCTGTACAGGGGGATAA CAGCTGGAAACGGCTGCTAATACCGCATAAGCGCACGAGGAGACATCTCCTTGTGT GAAAAACTCCGGTGGTACAGGATGGGCCCGCGTCTGATTAGCTGGTTGGCAGGGTA ACGGCCT ACC AAGGC AACGAT C AGT AGCCGGTCTGAGAGGAT GAACGGCC AC ATT G GAACTGAGAC AC GGTCC AAACTCCT ACGGGAGGC AGC AGT GGGG AAT ATTGC AC AA TGGGGGAAACCCTGATGCAGCAACGCCGCGTGAGTGAAGAAGTATTTCGGTATGTA AAGCTCT AT C AGC AGGGAAGAT AAT GACGGT ACCTGACT AAGAAGCTCCGGCT AAA T ACGT GCC AGC AGCCGCGGT AAT ACGT AT GGAGC AAGCGTT ATCCGGATTT ACTGGG T GT AAAGGGT GC GT AGGT GGC AGT GCA AGT C AG AT GT G A AAGGC C GGGGC T C A AC C CCGGAGCTGCATTTGAAACTGCTCGGCTAGAGTACAGGAGAGGCAGGCGGAATTCC T AGT GT AGCGGT GAAAT GCGT AG AT ATT AGGAGGA AC AC C AGT GGCGA AGGC GGC C TGCTGGACTGTT ACTGAC ACTGAGGC ACGAAAGCGT GGGGAGC AAAC AGGATT AGA TACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGCCGTATAGGCT TCGGTGCCGCCGCTAACGCAGTAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATG Appendix A

AAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTC

GAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCTTCTGACCGCACCTTAATCG

GTGCTTTCCTTCGGGACAGAAGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC

GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCA

GGT AAGGCTGGGC ACTCTGGAGAGACTGCC AGGGAT AACCTGGAGGAAGGT GGGG

ACGACGTCAAATCATCATGCCCCTTATGATCTGGGCGACACACGTGCTACAATGGCG

GTCACAGAGTGAGGCGAACCCGCGAGGGGGAGCAAACCACAAAAAGGCCGTCCCA

GTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTAATCGCGA

ATCAGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCA

TGGGAGTCGGAAATGCCCGAAGCCAGTGACCCAACCTTTTGGAGGGAGCTGTCGAA

GGTGGAGCCGGTAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCG

GCTGGATCACCTCCTTT (SEQ ID NO: 2)

NB2-A10MRS Parabacteroides distasonis

CTATCAGAGGGGGATAACCCGGCGAAAGTCGGACTAATACCGCATGAAGCAGGGGC

CCCGCATGGGGATATTTGCTAAAGATTCATCGCTGATAGATAGGCATGCGTTCCATT

AGGCAGTTGGCGGGGTAACGGCCCACCAAACCGACGATGGATAGGGGTTCTGAGAG

GAAGGTCCCCCACATTGGTACTGAGACACGGACCAAACTCCTACGGGAGGCAGCAG

TGAGGAATATTGGTCAATGGGCGTAAGCCTGAACCAGCCAAGTCGCGTGAGGGATG

AAGGTTCTATGGATCGTAAACCTCTTTTATAAGGGAATAAAGTGCGGGACGTGTCCT

GTTTTGTATGTACCTTATGAATAAGGATCGGCTAACTCCGTGCCAGCAGCCGCGGTA

ATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAAAGGGTGCGTAGGCGGC

CTTTTAAGTCAGCGGTGAAAGTCTGTGGCTCAACCATAGAATTGCCGTTGAAACTGG

GGGGCTT GAGT ATGTTT GAGGC AGGCGGAAT GCGT GGT GT AGCGGT GAAAT GCTT A

GATATCACGCAGAACCCCGATTGCGAAGGCAGCCTGCCAAGCCATGACTGACGCTG

ATGCACGAAAGCGTGGGGATCAAACAGGATTAGATACCCTGGTAGTCCACGCAGTA

AACGATGATCACTAGCTGTTTGCGATACAGTGTAAGCGGCACAGCGAAAGCGTTAA

GTGATCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGG

CCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACC

CGGGTTTGAACGCATTCGGACCGAGGTGGAAACACCTTTTCTAGCAATAGCCGTTTG

CGAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAGTGCCAT

AACGAGCGCAACCCTTGCCACTAGTTACTAACAGGTGATGCTGAGGACTCTGGTGG

GACTGCCAGCGTAAGCTGCGAGGAAGGCGGGGATGACGTCAAATCAGCACGGCCCT

TACATCCGGGGCGACACACGTGTTACAATGGCGTGGACAAAGGGATGCCACCTGGC

GACAGGGAGCGAATCCCCAAACCACGTCTCAGTTCGGATCGGAGTCTGCAACCCGA

CTCCGTGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCGGTGAATACGT

TCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGGGAGCCGGGGGTACCTGAAGT

CCGTA (SEQ ID NO: 3)

NB2-A12FMET Phascolarctobacterium succinatutens

ATTGGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCATGCCTAACACATGC

AAGTCGAACGGAGAAAGTTCAACACCAAGTATTTCATCCGCTGAAGTGTAGCGGTA

AAAATTGCGAAGCAATTTTTACTACGCATTAAAAGCATGAACTAACACGGTGGTTGA

AGTATTAGGTGTTGAACTTTCTTAGTGGCGAACGGGTGAGTAACGCGTGGGCAACCT

GCCCTCTAGATGGGGACAACATCCCGAAAGGGGTGCTAATACCGAATGTGACAGCA Appendix A

ATCTCGCATGAGGATGCTGTGAAAGATGGCCTCTATTTATAAGCTATCGCTAGAGGA

TGGGCCTGCGTCTGATTAGCTAGTTGGTGGGGTAACGGCCTACCAAGGCGATGATCA

GTAGCCGGTCTGAGAGGATGAACGGCCACATTGGGACTGAGACACGGCCCAGACTC

CTACGGGAGGCAGCAGTGGGGAATCTTCCGCAATGGGCGAAAGCCTGACGGAGCAA

TGCCGCGTGAGTGATGAAGGAATTCGTTCCGTAAAGCTCTTTTGTTTATGACGAATG

T GC AGATTGT A A AT A AT GAT C T GT A AT GAC GGT AGT A A ACGA AT A AGC C AC GGCT A

ACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCGAGCGTTGTCCGGAATTATTG

GGCGTAAAGAGCATGTAGGCGGTTTTTTAAGTCTGGAGTGAAAATGCGGGGCTCAA

CCCCGT AT GGCTCTGGAT ACTGGAAGACTT GAGTGC AGGAGAGGA AAGGGGAATTC

CCAGTGTAGCGGTGAAATGCGTAGATATTGGGAGGAACACCAGTGGCGAAGGCGCC

TTTCTGGACTGTGTCTGACGCTGAGATGCGAAAGCCAGGGTAGCGAACGGGATTAG

ATACCCCGGTAGTCCTGGCCGTAAACGATGGGTACTAGGTGTAGGAGGTATCGACC

CCTTCTGTGCCGGAGTTAACGCAATAAGTACCCCGCCTGGGGAGTACGTCCGCAAG

GAT GAAACTC AAAGGAATTGACGGGGGCCCGC AC A AGCGGT GGAGT AT GTGGTTT A

ATTCGACGCAACGCGAAGAACCTTACCAAGGCTTGACATTGAATGACCGCTCCAGA

GATGGAGCTTTCCCTTCGGGGACATGAAAACAGGTGGTGCATGGCTGTCGTCAGCTC

GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCCTATGTTAC

C AGC GGGT A AT GC CGGGGAC T CAT AGGAGACTGC C A AGGAC A AC TT GGAGGA AGGC

GGGGATGACGTCAAGTCATCATGCCCCTTATGTCTTGGGCTACACACGTACTACAAT

GGTCGGCAACAGAGGGAAGCAAAGCCGTGAGGCAGAGCAAACCCCAGAAACCCGA

TCCCAGTTCGGATTGCAGGCTGCAACTCGCCTGCATGAAGTCGGAATCGCTAGTAAT

CGCAGGTCAGCATACTGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCA

CACCACGAAAGTTGGTAACACCCGAAGCCGGTGGGGTAACCGTAAGGAGCCAGCCG

TCTAAGGTGGGGCCGATGATTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAG

GTGCGGCTGGATCACCTCCTTT (SEQ ID NO: 4)

NB2-B 17NB Ruminococcus lactaris

GAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAAGTC

GAGCGAAGCACTTAGGAAAGATTCTTCGGATGATTTCCTATTTGACTGAGCGGCGGA

CGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGAAATG

ACTGCTAATACCGCATAAGACCACAGCACCGCATGGTGCAGGGGTAAAAACTCCGG

TGGTATGAGATGGACCCGCGTCTGATTAGTTAGTTGGTGGGGTAACGGCCTACCAAG

GCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGACACG

GCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCCT

GATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATCAGC

AGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCAGCAG

CCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAGC

GT AGACGGAGC AGC AAGTCTGATGTGAA AACCCGGGGCTC AACCCCGGGACTGC AT

TGGAAACTGTTGATCTGGAGTGCCGGAGAGGTAAGCGGAATTCCTAGTGTAGCGGT

GAAAT GCGT AG AT ATT AGGAGGAAC ACC AGT GGCGAAGGCGGCTT ACTGGACGGT A

ACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTAGT

CCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAAGCCATTCGGTGCCGCA

GCCAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAAG

GAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGC

GAAGAACCTTACCTGCTCTTGACATCCCGGTGACGGCAGAGTAATGTCTGCTTTTCT Appendix A

TTGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTT GGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCGGTAAGGCCG GGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCAAA T CAT CAT GCCCCTT AT GAGC AGGGCT AC AC ACGT GCT AC AAT GGCGT AAAC AAAGG GAAGCGAACCCGCGAGGGTGGGCAAATCCCAAAAATAACGTCTCAGTTCGGATTGT AGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAATGTC GCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTCAGT AACGCCCGAAGTCAGTGACCCAACC (SEQ ID NO: 5)

NB2-B 16D5 Neglecta timonensis

TTTAGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCGTGCCTAACACATGCA

AGTCGAACGGAGATAGACGCTGAAAGGGAGACAGCTTGCTGTAAGAATTTCTTGTT

TATCTTAGTGGCGGACGGGTGAGTAACGCGTGAGTAACCTGCCTTTCAGAGGGGGA

T AACGTCTGGAAACGGACGCT AAT ACCGC AT GAGACC AC AGCTT C AC ATGGAGCGG

CGGTCAAAGGAGCAATCCGCTGAAAGATGGACTCGCGTCCGATTAGATAGTTGGCG

GGGTAACGGCCCACCAAGTCGACGATCGGTAGCCGGACTGAGAGGTTGAACGGCCA

CATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGAGGGATATTG

GT C AAT GGGGGAAACCCTGAACC AGC A ACGCCGCGT GAGGGAAGACGGTTTTCGGA

TTGTAAACCTCTGTCCTCTGTGAAGATAGTGACGGTAGCAGAGGAGGAAGCTCCGG

CTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGAGCGAGCGTTGTCCGGATTT

ACTGGGT GT AAAGGGTGCGT AGGCGGCTCTGC AAGT C AGAAGT GAAATCC ATGGGC

TTAACCCATGAACTGCTTTTGAAACTGTAGAGCTTGAGTGAAGTAGAGGTAGGCGG

AATTCCCGGTGT AGC GGT GAAAT GCGT AGAGATCGGGAGGAAC ACC AGT GGCGAAG

GCGGCCT ACTGGGCTTT AACTGACGCTGAGGC ACGAAAGC AT GGGT AGC AAAC AGG

ATTAGATACCCTGGTAGTCCATGCCGTAAACGATGATTACTAGGTGTGGGGGGTCTG

ACCCCCTCCGTGCCGGAGTTAACACAATAAGTAATCCACCTGGGGAGTACGACCGC

AAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCAGTGGAGTATGTGGA

TTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCAACTAACGAAGC

AGAGATGCATTAGGTGCCCTTCGGGGAAAGTTGAGACAGGTGGTGCATGGTTGTCG

TCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTACTGT

TAGTTGCTACGCAAGAGCACTCTAGCAGGACTGCCGTTGACAAAACGGAGGAAGGT

GGGGACGACGTCAAATCATCATGCCCCTTATGACCTGGGCCTCACACGTACTACAAT

GGCCATTAACAGAGGGAAGCAAGCCCGCGAGGTGGAGCAAAACCCTAAAAATGGT

CTCAGTTCGGATCGTAGGCTGAAACCCGCCTGCGTGAAGTTGGAATTGCTAGTAATC

GCGGATCAGCATGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAC

ACC ATGGGAGCCGGT AAT ACCCGAAGT C AGT AGTCT AACCGC AAGGGGGACGCTGC

CGAAGGTAGGATTGGCGACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGG

TGCGGCTGGATCACCTCCTTT (SEQ ID NO: 6)

NB2-B 10NB [Clostridium] spiroforme

ATGGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAATACATGCA AGTCGAACGCTTCACTTCGGTGAAGAGTGGCGAACGGGTGAGTAATACATAAGTAA CCTGGCATCTACAGGGGGATAACTGATGGAAACGTCAGCTAAGACCGCATAGGTGT AG AG AT C GC AT G A AC T C T AT AT G A A A AGT GC T AC GGG AC T GGT AG AT GAT GG AC TT ATGGCGCATTAGCTGGTTGGTAGGGTAACGGCCTACCAAGGCGACGATGCGTAGCC Appendix A

GACCTGAGAGGGTGACCGGCCACACTGGGACTGAGACACGGCCCAGACTCCTACGG

GAGGCAGCAGTAGGGAATTTTCGGCAATGGGGGAAACCCTGACCGAGCAACGCCGC

GT GAAGGAAGAAGT AATTCGTT AT GT AAACTTCTGT CAT AGAGGAAGAACGGT GGA

TATAGGGAATGATATCCAAGTGACGGTACTCTATAAGAAAGCCACGGCTAACTACG

TGCCAGCAGCCGCGGTAATACGTAGGTGGCGAGCGTTATCCGGAATTATTGGGCGT

AAAGAGGGAGC AGGCGGC ACT AAGGGTCTGTGGT GAAAGATCGAAGCTT AACTTCG

GTAAGCCATGGAAACCGTAGAGCTAGAGTGTGTGAGAGGATCGTGGAATTCCATGT

GT AGCGGT GAAATGCGT AGAT AT AT GGAGGA AC ACC AGT GGCGAAGGCGACGATCT

GGCGCATAACTGACGCTCAGTCCCGAAAGCGTGGGGAGCAAATAGGATTAGATACC

CTAGTAGTCCACGCCGTAAACGATGAGTACTAAGTGTTGGGAGTCAAATCTCAGTGC

TGCAGTTAACGCAATAAGTACTCCGCCTGAGTAGTACGTTCGCAAGAATGAAACTCA

AAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAA

CGCGAAGAACCTTACCAGGTCTTGACATCGATCTAAAGGCTCCAGAGATGGAGAGA

T AGCT AT AGAGAAGAC AGGT GGT GC AT GGTTGTCGT C AGCTCGTGTCGT GAG AT GTT

GGGTTAAGTCCCGCAACGAGCGCAACCCCTGTTGCCAGTTGCCAGCATTAAGTTGGG

GACTCTGGCGAGACTGCCGGTGACAAGCCGGAGGAAGGCGGGGATGACGTCAAATC

ATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGACAGAGCAGAGGGA

AGCGAAGCCGCGAGGTGGAGCGAAACCCATAAAACTGTTCTCAGTTCGGACTGCAG

TCTGCAACTCGACTGCACGAAGATGGAATCGCTAGTAATCGCGAATCAGCATGTCGC

GGTGAATACGTTCTCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTCGGTAA

CACCCGAAGCCGGTGGCCTAACCGCAAGGAAGGAGCTGTCTAAGGTGGGACTGATG

ATTGGGGTGAAGTCGTAACAAGGTATCCCTACGGGAACGTGGGGATGGATCACCTC

CTTT (SEQ ID NO: 7)

NB2-B10FAA Roseburia intestinalis

ACTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATA

ACAGTTGGAAACGACTGCTAATACCGCATAAGCGCACAGGGTCGCATGACCTGGTG

TGAAAAACTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGCCAGTTGGTGGGGT

AACGGCCTACCAAAGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATT

GGGACTGAGAC ACGGCCC AAACTCCT ACGGGAGGC AGC AGT GGGGAAT ATT GC AC A

ATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGT

AAAGCTCTATCAGCAGGGAAGAAGAAATGACGGTACCTGACTAAGAAGCACCGGCT

AAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACT

GGGTGTAAAGGGAGCGCAGGCGGTACGGCAAGTCTGATGTGAAAGCCCGGGGCTCA

ACCCCGGTACTGCATTGGAAACTGTCGGACTAGAGTGTCGGAGGGGTAAGTGGAAT

TCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCG

GCTTACTGGACGATTACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATT

AGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGAGCATTG

CTCTTCGGTGCCGCAGCAAACGCAATAAGTATTCCACCTGGGGAGTACGTTCGCAAG

AAT GAAACTC AAAGGA ATT GACGGGGACCCGC AC A AGCGGT GGAGC AT GT GGTTT A

ATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCCGATGACAGAACATG

TAATGTGTTTTCTCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTC

GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATTCTTAGTAGC

CAGCGGGTAAGCCGGGCACTCTAGGGAGACTGCCAGGGATAACCTGGAGGAAGGTG

GGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTACAATG Appendix A

GCGTAAACAAAGGGAAGCGAGCCTGCGAGGGGGAGCAAATCTCAAAAATAACGTC

TCAGTTCGGACTGCAGTCTGCAACTCGACTGCACGAAGCTGGAATCGCTAGTAATCG

CGAATCAGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACA

CCATGGGAGTTGGTAATGCCCGAAGTCAGTGACCCAACCGCAAGGAGGGAGCTGCC

GAAGGCAGGATCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGT

GCGGCTGGATCACCTCCTTT (SEQ ID NO: 8)

NB2-A8WC Akkermansia muciniphila

ATGGAGAGTTTGATTCTGGCTCAGAACGAACGCTGGCGGCGTGGATAAGACATGCA

AGTCGAACGAGAGAATTGCTAGCTTGCTAATAATTCTCTAGTGGCGCACGGGTGAGT

AACACGTGAGTAACCTGCCCCCGAGAGCGGGATAGCCCTGGGAAACTGGGATTAAT

ACCGCATAGAATCGCAAGATTAAAGCAGCAATGCGCTTGGGGATGGGCTCGCGGCC

T ATT AGTT AGTTGGT GAGGT AACGGCTC ACC AAGGCGAT GACGGGT AGCCGGTCTG

AGAGGATGTCCGGCCACACTGGAACTGAGACACGGTCCAGACACCTACGGGTGGCA

GCAGTCGAGAATCATTCACAATGGGGGAAACCCTGATGGTGCGACGCCGCGTGGGG

GAATGAAGGTCTTCGGATTGTAAACCCCTGTCATGTGGGAGCAAATTAAAAAGATA

GTACCACAAGAGGAAGAGACGGCTAACTCTGTGCCAGCAGCCGCGGTAATACAGAG

GTCTC AAGCGTTGTTCGGAATC ACTGGGCGT AAAGCGT GCGT AGGCTGTTTCGT AAG

TCGTGTGTGAAAGGCGCGGGCTCAACCCGCGGACGGCACATGATACTGCGAGACTA

G AGT A AT GG AGGGGG A AC C GG A AT TC TC GGT GT AGC AGT G A A AT GC GT AG AT AT C G

AGAGGAACACTCGTGGCGAAGGCGGGTTCCTGGACATTAACTGACGCTGAGGCACG

AAGGCCAGGGGAGCGAAAGGGATTAGATACCCCTGTAGTCCTGGCAGTAAACGGTG

CACGCTTGGTGTGCGGGGAATCGACCCCCTGCGTGCCGGAGCTAACGCGTTAAGCG

T GCCGCCTGGGGAGT ACGGTCGC AAGATT AAAACTC AAAGA AATT GACGGGGACCC

GCACAAGCGGTGGAGTATGTGGCTTAATTCGATGCAACGCGAAGAACCTTACCTGG

GCTTGACATGTAATGAACAACATGTGAAAGCATGCGACTCTTCGGAGGCGTTACAC

AGGTGCTGCATGGCCGTCGTCAGCTCGTGTCGTGAGATGTTTGGTTAAGTCCAGCAA

CGAGCGCAACCCCTGTTGCCAGTTACCAGCACGTGAAGGTGGGGACTCTGGCGAGA

CTGCCCAGATCAACTGGGAGGAAGGTGGGGACGACGTCAGGTCAGTATGGCCCTTA

TGCCCAGGGCTGCACACGTACTACAATGCCCAGTACAGAGGGGGCCGAAGCCGCGA

GGCGGAGGAAATCCTAAAAACTGGGCCCAGTTCGGACTGTAGGCTGCAACCCGCCT

ACACGAAGCCGGAATCGCTAGTAATGGCGCATCAGCTACGGCGCCGTGAATACGTT

CCCGGGTCTTGTACACACCGCCCGTCACATCATGGAAGCCGGTCGCACCCGAAGTAT

CTGAAGCCAACCGCAAGGAGGCAGGGTCCTAAGGTGAGACTGGTAACTGGGATGAA

GTCGTAACAAGGTAGCCGTAGGGGAACCTGCGGCTGGATCACCTCCTTT (SEQ ID

NO: 9)

NB2-A9NA [Ruminococcus] obeum

GCTTAACACATGCAAGTCGAACGAGAAGGCGTAGCAATACGCTTGTAAAGTGGCGA

ACGGGTGAGNAACACNTGGGTAACCTACCCTCGAGTGGGGGATAACCCGCCGAAAG

GCGGGCTAATACCGCGTACGCTTCCGATCTTGCGAGATCGGAAGGAAAGCTGTCCC

AAGGGGATGGCGCTCAAGGATGGGCTCACGTCCNATCAGCTNGTTGGTGNGGTAAC

GGCNNACCAAGGCGACGANGGNTAGCTGGTCTGAGAGGANGANCAGCCACACTGG

GACTGNGACACGGCCCAGACTCCTACGGGAGGCAGCAGTNGGGAATCTTGCGCAAT

GNGCGAAAGCNTGACGCAGCNACGCCGCGTGNGGGANGANGGCCNTCGGGTTGTA Appendix A

AACCNCTTTCAGNAGGGACGAATCTGACGGTACCTGCAGAAGAAGCCCCGGCNAAC

T ACGT GCC AGC AGCCGCGGT AAT ACGT AGGGGGCNAGCGTTGTCCGGATTT ATT GG

GCGTAAAGAGCTCGTAGGCGGCTTGGCAAGTCGGGTGTGAAACCTCCAGGCTTAAC

CTGGAGACGCCACTCGATNCTGCCATGGCTAGAGTCCGGTAGGGGACCACGGAATT

CCTGGTGTAGCGGTGAAATGCGCAGATATCAGGAGGAACNCCGGTGGCGAAGGCGG

NGNTCTGGGNCGGNACTGACGCTGAGGNGCGAAAGCGTGGGNAGCAAACAGGATT

AGATACCCTGGTAGTCCACGCCGTAAACGNTGGGCACTAGGTGTGGGACCTTATCA

ACGGGTTCCGTGCCGTAGCTAACGCATTAAGTGCCCCGCCTGGGGAGTACGGCCGC

AAGGCTAAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGCGGAGCATGTTGC

TTAATTCGATGCAACGCGAAGAACCTTACCTGGGTTGAACTACGCGGGAAAAGCCA

C AG AG AT GT GGT GT C C G A A AGGGC C C GC GAT AGGT GGT GC AT GGC T GT C GT C AGC T

CGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTNTCCNATGTTG

CC AGCGGAT CAT GCCGGGGACTCNT GGGAGACTGCCGGGGT C AACTCGGAGGAAGG

TGGGGATGACGTCAAGTCANCATGCCCCTTATGTCCAGGGCTNNAAACATGCTACA

ATGGCCGGTACAAAGGGTNGCGAGNCNGCGANGNNGAGCNAATCCCATAAAGNNN

GTCTNAGTNCGGATCGNAGTCTGCAACTCGACTNCGTGAAGNCGGAGTNGCTAGTA

ATCNCGNATCAGCANNGNCGNGGTGAATACGTTCCCGGGCCTTGTACACACCGCCC

GT C AC AC C AC GA A AGTTGGT A AC AC CC GA AGCC GGT GG ( SEQ ID NO: 10)

NB2-B20GAM [Clostridium] lactatifermentans

GAGTAATTCGGTATAGGATGGGCCCGCATCTGATTAGCTAGTTGGTGAGATAACAGC

CCACCAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGATCGGCCACATTGGGACT

GAGAC ACGGCCC AAACTCCT ACGGGAGGC AGC AGT GGGGAAT ATT GC AC AAT GGGG

GAAACCCTGATGCAGCAACGCCGCGTGAAGGAAGAAGGTTTTCGGATCGTAAACTT

CTATCAACAGGGACGAAGAAAGTGACGGTACCTGAATAAGAAGCCCCGGCTAACTA

CGT GCC AGC AGCCGCGGT AAT ACGT AGGGGGC AAGCGTT ATCCGGA ATT ACTGGGT

GTAAAGGGAGCGTAGGCGGCACGCCAAGCCAGATGTGAAAGCCCGAGGCTTAACCT

CGCGGATTGCATTTGGAACTGGCGAGCTAGAGTACAGGAGAGGAAAGCGGAATTCC

T AGT GT AGC GGT G A A AT GC GT AG AT ATT AGG A AG A AC AC C AGT GGC G A AGGC GGC T

TTCTGGACTGAAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGA

TACCCTGGTAGTCCACGCCGTAAACGATGAGTGCTAGGTGTCGGGGAGGAATCCTC

GGTGCCGCAGCTAACGCAATAAGCACTCCACCTGGGGAGTACGACCGCAAGGTTGA

AACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCG

AAGCAACGCGAAGAACCTTACCAAGGCTTGACATCCCGATGACCGCTCTAGAGATA

GAGNTTCTCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC

GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCCTTAGTAGCCATCA

TTGAGTTGGGCACTCTAGGGAGACTGCCGTGGATAACACGGAGGAAGGTGGGGATG

ACGTCAAATCATCATGCCCCTTATGTCTTGGGCTACACACGTGCTACAATGGCTGGT

AACAGAGTGAAGCGAGACGGCGACGTTAAGCAAATCACAAAAACCCAGTCCCAGTT

CGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATC

AGAATGTCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGG

GAGTTGGAAGCACCCGAAGTCGGTGACCTAACCGTAAGGAAGGAGCCGCCGAAGGT

GAAGCCAGTGACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCT

GGATCACCTCCTTT (SEQ ID NO: 1 1)

NB2-A15BHI Anaerovorax odorimutans Appendix A

ATATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA

AGT C G AGC G AG A AGC T GAT GATT G AC AC T TC GGTT GAG AG A AT C AGT GG A A AGC GG

CGGACGGGTGAGTAACGCGTAGGCAACCTGCCCTTTGCAGAGGGATAGCCTCGGGA

AACCGGGATTAAAACCTCATGATGCTGTATGTCCGCATGGGCAGACGGTCAAAGAT

TTATCGGCAGAGGATGGGCCTGCGTCTGATTAGTTAGTTGGTGGGGTAACGGCCTAC

CAAGGCAACGATCAGTAGCCGACCTGAGAGGGTGATCGGCCACATTGGAACTGAGA

C ACGGTCC A AACTCCT ACGGGAGGC AGC AGT GGGGAAT ATT GC AC AAT GGGGGAAA

CCCTGATGCAGCAACGCCGCGTGAGCGAAGAAGGCCTTTGGGTCGTAAAGCTCTGT

CCTTGGGGAAGAAAAAATGACGGTACCCAAGGAGGAAGCCCCGGCTAACTACGTGC

CAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGAATTATTGGGCGTAAA

GAGT AT GT AGGT GGTTTCTT AAGCGC AGGGT AT AAGGC AAT GGCTT AACC ATTGTT C

GCCCCGTGAACTGAGAGACTTGAGTGCTGGAGAGGAAAGCGGAATTCCTAGTGTAG

CGGT GA A AT GC GT AG AT ATT AGGAGGA AC AC C AGT GGCG AAGGC GGC TTTC T GGAC

AGT AACTGAC ACTGAGAT ACGAAAGCGT GGGGAGC A AAC AGGATT AGAT ACCCTGG

TAGTCCACGCCGTAAACGATGAGCACTAGGTGTCGGGCTCGCAAGAGTTCGGTGCC

GGAGTTAACGCATTAAGTGCTCCGCCTGGGGAGTACGCACGCAAGTGTAAAACTCA

AAGGAATTGACGGGGACCCGCACAAGCAGCGGAGCATGTGGTTTAATTCGAAGCAA

CGCGAAGAACCTTACCAGGGCTTGACATCCCTCCGACCGGTCCTTAATCGGACCTTT

CTACGGACGGGGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATG

TTGGGTTAAGTCCCGCAACGAGCGCAACCCTTGTCATTAGTTGCTAACAGTAAGATG

AG A AC TC T AAT GAG AC T GC C GT GG AT A AC AC GG AGG A AGGT GGGG AT G AC GT C AAA

TCATCATGCCCCTTATGTCCTGGGCTACACACGTGCTACAATGGTCGGTACAAAGAG

AAGCAAGACCGCGAGGTGGAGCAAATCTCAAAAACCGATCCCAGTTCGGATTGCAG

GCTGCAACTCGCCTGCATGAAGTCGGAGTTGCTAGTAATCGCAGATCAGAATGCTGC

GGTGAATGCGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGAAGTTGGGGG

CGCCCGAAGTCGGCTAGTAAATAGGCTGCCTAAGGCGAAATCAATGACTGGGGTGA

AGTCGT AAC AAGGT AGCCGT ATCGGAAGGT GCGGCTGGATC ACCTCCTTT (SEQ ID

NO: 12)

NB2-A14FMU [Ruminococcus] torques

AACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA

AGTCGAGCGAAGCACTTTGCTTAGATTCTTCGGATGAAGAGGATTGTGACTGAGCGG

CGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGA

AAT GACTGCT AAT ACCGC AT AAGACC AC AGC ACCGC AT GGTGCGGGGGT AAAAACT

CCGGTGGTATGAGATGGACCCGCGTCTGATTAGCTAGTTGGT AAGGT AACGGCTT AC

CAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGA

CACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAA

CCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATC

AGC AGGGAAGAAAAT GACGGT ACCTGACT AAGAAGC ACCGGCT AAAT ACGT GCC AG

CAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGG

AGCGTAGACGGATGGGCAAGTCTGATGTGAAAACCCGGGGCTCAACCCCGGGACTG

CATTGGAAACTGTTCATCTAGAGTGCTGGAGAGGTAAGTGGAATTCCTAGTGTAGCG

GTGAAATGCGT AGAT ATT AGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACAG

TAACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTA

GTCCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAAGCCATTCGGTGCCG Appendix A

CAGCAAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAA

AGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAAC

GCGAAGAACCTTACCTGCTCTTGACATCCCGCTGACCGGACGGTAATGCGTCCTTCC

CTTCGGGGCAGCGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATG

TTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTTAGTAGCCAGCGGCCAGGCC

GGGCACTCTAGAGAGACTGCCGGGGATAACCCGGAGGAAGGTGGGGATGACGTCA

AATCATCATGCCCCTTATGAGCAGGGCTACACACGTGCTACAATGGCGTAAACAAA

GGGAAGCGAGACCGCGAGGTGGAGCAAATCCCAAAAATAACGTCTCAGTTCGGATT

GTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAAT

GTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC

AGTAACGCCCGAAGTCAGTGACCCAACCGTAAGGAGGGAGCTGCCGAAGGCGG

(SEQ ID NO: 13)

NB2-A17FMU [Eubacterium] rectale

ATTTTGT GACTGAGT GGCGGACGGGT GAGT AACGCGT GGGT A ACCTGCCTT GT AC AG

GGGGATAACAGTTGGAAACGGCTGCTAATACCGCATAAGCGCACAGCATCGCATGA

TGCAGTGTGAAAAACTCCGGTGGTATAAGATGGACCCGCGTTGGATTAGCTAGTTGG

TGAGGTAACGGCCCACCAAGGCGACGATCCATAGCCGACCTGAGAGGGTGACCGGC

C AC ATT GGGACTGAGAC ACGGCCC AAACTCCT ACGGGAGGC AGC AGT GGGGAAT AT

TGCACAATGGGCGAAAGCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCG

GT AT GT A A AGC T C T AT C AGC AGGG A AG AT A AT G AC GGT AC C T G AC T A AG A AGC AC C

GGCTAAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATT

TACTGGGTGTAAAGGGAGCGCAGGCGGTGCGGCAAGTCTGATGTGAAAGCCCGGGG

CTCAACCCCGGTACTGCATTGGAAACTGTCGTACTAGAGTGTCGGAGGGGTAAGCG

GAATTCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAA

GGCGGCTTACTGGACGATAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAG

GATT AG AT ACCCTGGT AGTCC ACGCCGT AAACGAT GAAT ACT AGGT GTT GGGAAGC

ATTGCTTCTCGGTGCCGTCGCAAACGCAGTAAGTATTCCACCTGGGGAGTACGTTCG

C A AG A AT GA A ACTC A A AGGA ATT GACGGGGACC CGC AC A AGC GGT GG AGC AT GT G

GTTTAATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCTTCTGACCGGT

ACTTAACCGTACCTTCTCTTCGGAGCAGGAGTGACAGGTGGTGCATGGTTGTCGTCA

GCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTTAG

TAGCCAGCGGTTCGGCCGGGCACTCTAGAGAGACTGCCAGGGATAACCTGGAGGAA

GGCGGGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTAC

AATGGCGTAAACAAAGGGAAGCAAAGCTGTGAAGCCGAGCAAATCTCAAAAATAA

CGTCTCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTA

ATCGCAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGT

CACACCATGGGAGTTGGGAATGCCCGAAGCCAGTGACCTAACCGAAAGGAAGGAG

CTGTCGAAGGC AGGCTCGAT AACTGGGGT GAAGTCGT AAC AAGGT AGCCGT ATCGG

AAGGTGCGGCTGGATCACCTCCTTT (SEQ ID NO: 14)

NB2-B 14D5 Bacteroides eggerthii

ATGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCTACAGGCTTAACACATGCA

AGTCGAGGGGCAGCATGATTGAAGCTTGCTTCAATCGATGGCGACCGGCGCACGGG

TGAGTAACACGTATCCAACCTGCCGATAACTCGGGGATAGCCTTTCGAAAGAAAGA Appendix A

TTAATACCCGATAGTATAGTATTTCCGCATGGTTTCACTATTAAAGAATTTCGGTTA T

CGATGGGGATGCGTTCCATTAGATAGTTGGCGGGGTAACGGCCCACCAAGTCAACG

ATGGATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAA

ACTCCTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGACGAGAGTCTGAACCA

GCCAAGTAGCGTGAAGGATGACTGCCCTATGGGTTGTAAACTTCTTTTATACGGGAA

T AAAGTGGAGT AT GC AT ACTCCTTT GT AT GT ACCGT AT GAAT AAGGATCGGCT AACT

CCGTGCCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGT

TTAAAGGGAGCGTAGGCGGGTGCTTAAGTCAGTTGTGAAAGTTTGCGGCTCAACCGT

AAAATTGCAGTTGATACTGGGTACCTTGAGTGCAGCATAGGTAGGCGGAATTCGTG

GTGTAGCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTTA

CTGGACTGTAACTGACGCTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATA

CCCTGGTAGTCCACACAGTAAACGATGAATACTCGCTGTTGGCGATACACAGTCAGC

GGCCAAGCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAAC

TCAAAGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATG

ATACGCGAGGAACCTTACCCGGGCTTAAATTGCAGCGGAATGTAGTGGAAACATTA

CAGCCTTCGGGCCGCTGTGAAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGG

TGTCGGCTTAAGTGCCATAACGAGCGCAACCCTTATCTATAGTTACTATCAGGTCAT

GCTGAGGACTCTATGGAGACTGCCGTCGTAAGATGTGAGGAAGGTGGGGATGACGT

CAAATCAGCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACA

GAAGGCAGCTACCTGGCGACAGGATGCTAATCCCTAAAACCTCTCTCAGTTCGGATT

GGAGTCTGCAACCCGACTCCATGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCAC

GGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGC

CGGGGGT ACCTGAAGT ACGT AACCGC AAGGAGCGTCCT AGGGT AAAACTGGT GATT

GGGGCTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGAACACCTCCTT

T (SEQ ID NO: 15)

NB2-B26FMU Roseburia inulinivorans

ACTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCACACAGGGGGATA

ACAGTTGGAAACGGCTGCTAATACCGCATAAGCGCACAGTACCGCATGGTACAGTG

TGAAAAACTCCGGTGGTGTGAGATGGACCCGCGTCTGATTAGCTAGTTGGCAGGGC

AACGGCCTACCAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATT

GGGACTGAGAC ACGGCCC AAACTCCT ACGGGAGGC AGC AGT GGGGAAT ATT GC AC A

ATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGT

AAAGCTCTATCAGCAGGGAAGAAGAAATGACGGTACCTGACTAAGAAGCACCGGCT

AAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACT

GGGTGTAAAGGGAGCGCAGGCGGAAGGCTAAGTCTGATGTGAAAGCCCGGGGCTCA

ACCCCGGTACTGCATTGGAAACTGGTCATCTAGAGTGTCGGAGGGGTAAGTGGAAT

TCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCG

GCTT ACTGGACGAT AACTGACGCTGAGGCTCGA AAGCGT GGGGAGC AAAC AGGATT

AGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGAAAGCACAG

CTTTTCGGTGCCGCCGCAAACGCATTAAGTATTCCACCTGGGGAGTACGTTCGCAAG

AAT GAAACTC AAAGGA ATT GACGGGGACCCGC AC A AGCGGT GGAGC AT GT GGTTT A

ATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCCGGTGACCGGACAGT

AATGTGTCCTTTTCTTCGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTC

GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCCCCAGTAGC Appendix A

CAGCATTTTGGATGGGCACTCTGAGGAGACTGCCAGGGATAACCTGGAGGAAGGTG GGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTACAATG GCGT AAAC AAAGGGAAGCGAGACCGT GAGGT GGAGC AAATCCC AAAA AT AACGT C TCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTAATCG CAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACA CCATGGGAGTTGGAAATGCCCGAAGTCAGTGACCCAACCGCAAGGAGGGAGCTGCC GAAGGCAGGTTCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGT GCGGCTGGATCACCTCCTTT (SEQ ID NO: 16)

NB2-B20DS [Clostridium] hylemonae

ACGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCGTGCCTAACACATGCAA

GTCGAACGAGAATCTTTGGGATGATTCTTTCGGGATGAATTCCAAAGAGGAAAGTG

GCGGACGGGCGAGTAACGCGTGAGTAACCTGCCCATAAGAGGGGGATAATCCATGG

AAACGTGGACTAATACCGCATATTGTAGTTAAGTTGCATGACTTGATTATGAAAGAT

TTATCGCTTATGGATGGACTCGCGTCAGATTAGATAGTTGGTGAGGTAACGGCTCAC

CAAGTCAACGATCTGTAGCCGAACTGAGAGGTTGATCGGCCGCATTGGGACTGAGA

CACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCGCAATGGGGGCAA

CCCTGACGCAGCAACGCCGCGTGCAGGAAGAAGGTCTTCGGATTGTAAACTGTTGTC

GC AAGGGAAGAAGAC AGT GACGGT ACCTT GTGAGAAAGT C ACGGCT AACT ACGT GC

CAGCAGCCGCGGTAATACGTAGGTGACAAGCGTTGTCCGGATTTACTGGGTGTAAA

GGGCGCGTAGGCGGACTGTCAAGTCAGTCGTGAAATACCGGGGCTTAACCCCGGGG

CTGCGATTGAAACTGAC AGCCTTGAGT ATCGGAGAGGAAAGCGGA ATTCCT AGT GT

AGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTTCTGG

ACGAC AACTGACGCTGAGGCGCGAAAGT GT GGGGAGC AA AC AGGATT AGAT ACCCT

GGTAGTCCACACCGTAAACGATGGATACTAGGTGTAGGAGGTATCGACCCCTTCTGT

GCCGCAGTTAACACAATAAGTATCCCACCTGGGGAGTACGACCGCAAGGTTGAAAC

T C AAAGGAATTGACGGGGGCCCGC AC AAGC AGT GGAGT ATGT GGTTT AATTCGAAG

CAACGCGAAGAACCTTACCTGGGCTTGACATCCCTGGAATCGAGTAGAGATACTTG

AGT GCCTTCGGGAAT C AGGT GAC AGGT GGT GC AT GGTT GTCGTC AGCTCGT GTCGT G

AGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATTGTCAGTTGCCATCATTA

AGTTGGGCACTCTGGCGAGACTGCCGGTGACAAATCGGAGGAAGGTGGGGACGACG

TCAAATCATCATGCCCCTTATGCCCAGGGCTACACACGTACTACAATGGCCGATAAC

AAAGT GC AGCGAAACCGT GAGGT GGAGC GAAT C AC AA AACTCGGTCTC AGTTC AGA

TTGCAGGCTGCAACTCGCCTGCATGAAGTTGGAATTGCTAGTAATCGCGGATCAGAA

TGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGT

CGATAACACCCGAAGCCTGTGAGCTAACCTTTTAGGAGGCAGCAGTCGAAGGTGGG

GTTGATGATTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGA

TCACCTCCTTT (SEQ ID NO: 17)

NB2-B3WC Barnesiella intestinihominis

CGGCGACCGGCGCACGGGTGAGTAACACGTATGCAATCCACCTGTAACAGGGGGAT AACCCGGAGAAATCCGGACTAATACCCCATAATATGGGCGCTCCGCATGGAGAGCC CATTAAAGAGAGCAATCTTGGTTACAGACGAGCATGCGCTCCATTAGCCAGTTGGCG GGGTAACGGCCCACCAAGGCGACGATGGATAGGGGTTCTGAGAGGAAGGTCCCCCA C ATTGGA ACTGAGAC AC GGTCC A A AC TC C T AC GGGAGGC AGC AGT GAGGA AT ATT G Appendix A

GTCAATGGTCGGCAGACTGAACCAGCCAAGTCGCGTGAGGGAAGACGGCCCTACGG

GTTGTAAACCTCTTTTGTCGGAGAGTAAAGTACGCTACGTGTAGCGTATTGCAAGTA

TCCGAAGAAAAAGCATCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGAT

GCAAGCGTTATCCGGATTTATTGGGTTTAAAGGGTGCGTAGGCGGCACGCCAAGTCA

GCGGTGAAATTTCCGGGCTCAACCCGGAGTGTGCCGTTGAAACTGGCGAGCTAGAG

T GC AC AAGAGGC AGGCGGAAT GCGT GGT GT AGCGGT GAAAT GC AT AG AT ATC ACGC

AGAACCCCGATTGCGAAGGCAGCCTGCTAGGGTGAAACAGACGCTGAGGCACGAA

AGC GT GGGT ATC G A AC AGG ATT AG AT AC C C T GGT AGT C C AC GC AGT A A AC GAT G A A

TACTAACTGTTTGCGATACAATGTAAGCGGTACAGCGAAAGCGTTAAGTATTCCACC

TGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGGCCCGCACAA

GCGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACCCGGGCTCAA

ACGCAGGGGGAATATATATGAAAGTATATAGCTAGCAATAGTCACCTGCGAGGTGC

TGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAGTGCCATAACGAGCG

CAACCCCTATGGACAGTTACTAACGGGTGAAGCCGAGGACTCTGTCGAGACTGCCG

GCGCAAGCCGCGAGGAAGGTGGGGATGACGTCAAATCAGCACGGCCCTTACGTCCG

GGGCGACACACGTGTTACAATGGCAGGTACAGAAGGCAGCCAGTCAGCAATGACGC

GCGAATCCCGAAAACCTGTCTCAGTTCGGATTGGAGTCTGCAACCCGACTCCATGAA

GCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCGGTGAATACGTTCCCGGGCC

TTGTACACACCGCCCGTCAAGCCATGGAAGCCGGGAGTACCTGAAGCATGCAACCG

CAAGGAGCGTACGAAGGTAATACCGGTAACTGGGGCTAAGTCGTAACAAGGTAGCC

GTACCGGAAGGTGCGGCTGGAACACCTCCTTT (SEQ ID NO: 18)

NB2-A14DS [Clostridium] aerotolerans

TTCCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGAC

TTCACCCCAGTTATCAGTCCCGCCTTCGGCAGCTCCCTCCTTRCGGTTGGGTCACTG A

CTTCGGGCGTTACCAACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAA

CGTATTCACCGCGACATTCTGATTCGCGATTACTAGCGATTCCAGCTTCATGTAGTC G

AGTTGCAGACTACAATCCGAACTGAGACGTTATTTTTGAGATTTGCTTAAGCTCACA

CTCTCGCTTCCCTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAGTCATAAGGG G

CATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCTCCA G

AGTGCCCGACCGAATCGCTGGCTACTGAAGATAAGGGTTGCGCTCGTTGCGGGACTT

AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCACCGATG

CTCCGAAGAGAAGGYYCCATTACRRACCGGTCATCGGGATGTCAAGACTTGGTAAG

GTTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGT C

AATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTATTGCGT T

TGCGGCGGCACCGAAGAGCTGTGCTCCCCGACACCTAGTATTCATCGTTTACGGCGT

GGACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAG

TTACTGTCCAGTAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTC A

CCGCTACACTAGGAATTCCGCTTACCTCTCCAGCACTCTAGCCAAACAGTTTCAAAA

GCAGTCCCGGGGTTGAGCCCCAGCCTTTCACTTCTGACTTGCTTARCCGTCTACGCT C

CCTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCT

GGCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGAT A

GAGCTTTACATACCGAAATACTTCTTCACTCACGCGGCGTCGCTGCATCAGGGTTTC

CCCCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCA

GTCCCAATGTGGCCGTTCACCCTCTCAGGCCGGCTATGGATCGTCGCCTTGGTAGGC Appendix A

CGTTACCCTGCCAACTAGCTAATCCAACGCGGGTCCATCTCACACCGATAAATCTTT TCCGTCCGGGCCATGCGGCCCTAGCGGGTTATGCGGTATTAGCGGTCGTTTCCAACT GTTATCCCCCTGTGTGAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTAAG TCGCAAGAGAAATCATCCGAAGAATCAATCTCAAGCGCTTCGTTCGACTTGCATGTG TTAAGCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCGATTAA (SEQ ID NO: 19)

NB2-A15DCM Bacteroides stercorirosoris

ATGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCTACAGGCTTAACACATGCA

AGTCGAGGGGCAGCATGACCTAGCAATAGGTTGATGGCGACCGGCGCACGGGTGAG

TAACACGTATCCAACCTACCGGTTATTCCGGGATAGCCTTTCGAAAGAAAGATTAAT

ACCGGATAGTATAACGAGAAGGCATCTTCTTGTTATTAAAGAATTTCGATAACCGAT

GGGGAT GCGTTCC ATT AGTTTGTT GGCGGGGT AACGGCCC ACC AAGAC ATCGAT GG

ATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAAACTC

CT ACGGGAGGC AGC AGT GAGGAAT ATT GGT C AAT GGACGAGAGTCTGAACC AGCC A

AGTAGCGTGAAGGATGACTGCCCTATGGGTTGTAAACTTCTTTTATATGGGAATAAA

GTGAGCCACGTGTGGCTTTTTGTATGTACCATACGAATAAGGATCGGCTAACTCCGT

GCCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAA

AGGGAGCGTAGGCGGACTATTAAGTCAGCTGTGAAAGTTTGCGGCTCAACCGTAAA

ATTGCAGTTGATACTGGTCGTCTTGAGTGCAGTAGAGGTAGGCGGAATTCGTGGTGT

AGCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTTACTGG

ACTGTAACTGACGCTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATACCCTG

GTAGTCCACACAGTAAACGATGAATACTCGCTGTTTGCGATATACAGCAAGCGGCC

AAGCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAA

AGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATAC

GCGAGGAACCTT ACCCGGGCTT AAATT GC A AATGAAT AT AGT GGAAAC ATT AT AGC

CGC AAGGC ATTT GT GAAGGT GCTGC AT GGTT GTCGT C AGCTCGT GCCGT GAGGTGT C

GGCTTAAGTGCCATAACGAGCGCAACCCTTATCTTTAGTTACTAACAGGTCATGCTG

AGGACTCTAGAGAGACTGCCGTCGTAAGATGTGAGGAAGGTGGGGATGACGTCAAA

TCAGCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACAGAAG

GCAGCTACACAGCGATGTGATGCTAATCCCAAAAGCCTCTCTCAGTTCGGATTGGAG

TCTGCAACCCGACTCCATGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCACGGCG

CGGTGAATACGTTCNCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGCCGGG

GGTACCTGAAGTCCGTAACCGCAAGGAG (SEQ ID NO: 20)

NB2-A20GAM Flavonifractor plautii

TATTGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCA

AGTCGAACGGGGT GCTC AT GACGGAGGATTCGTCC AACGGATT GAGTT ACCT AGT G

GCGGACGGGTGAGTAACGCGTGAGGAACCTGCCTTGGAGAGGGGGATAACACTCCG

AAAGGAGT GCT AAT ACCGC AT GAT GC AGTTGGGTCGC AT GGCTCTGACTGCC AAAG

ATTTATCGCTCTGAGATGGCCTCGCGTCTGATTAGCTAGTAGGTGGGGTAACGGCCC

ACCTAGGCGACGATCAGTAGCCGGACTGAGAGGTTGACCGGCCACATTGGGACTGA

GACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGGGCAATGGGCGC

AAGCCTGACCCAGCAACGCCGCGTGAAGGAAGAAGGCTTTCGGGTTGTAAACTTCT

TTTGTCAGGGACGAAACAAATGACGGTACCTGACGAATAAGCCACGGCTAACTACG Appendix A

TGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTATCCGGATTTACTGGGTGTA

AAGGGCGTGTAGGCGGGATTGCAAGTCAGATGTGAAAACTGGGGGCTCAACCTCCA

GCCTGCATTTGAAACTGTAGTTCTTGAGTGCTGGAGAGGCAATCGGAATTCCGTGTG

TAGCGGTGAAATGCGTAGATATACGGAGGAACACCAGTGGCGAAGGCGGATTGCTG

GACAGTAACTGACGCTGAGGCGCGAAAGCGTGGGGAGCAAACAGGATTAGATACCC

TGGTAGTCCACGCCGTAAACGATGGATACTAGGTGTGGGGGGTCTGACCCCCTCCGT

GCCGCAGTTAACACAATAAGTATCCCACCTGGGGAGTACGATCGCAAGGTTGAAAC

T C AAAGGAATTGACGGGGGCCCGC AC AAGCGGT GGAGT ATGT GGTTT AATTCGAAG

CAACGCGAAGAACCTTACCAGGGCTTGACATCCCACTAACGAAGCAGAGATGCATT

AGGTGCCCTTCGGGGAAAGTGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC

GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATTGTTAGTTGCTACGC

AAGAGCACTCTAGCGAGACTGCCGTTGACAAAACGGAGGAAGGTGGGGACGACGTC

AAATCATCATGCCCCTTATGTCCTGGGCCACACACGTACTACAATGGTGGTTAACAG

AGGGAGGCAAAACCGCGAGGTGGAGCAAATCCCTAAAAGCCATCCCAGTTCGGATT

GCAGGCTGAAACCCGCCTGTATGAAGTTGGAATCGCTAGTAATCGCGGATCAGCAT

GCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTC

GGGAACACCCGAAGTCCGTAGCCTAACCG (SEQ ID NO: 21)

NB2-A3NA Dorea longicatena

GCATGGTACAGTGGTAAAAACTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGG

T AGTT GGT GGGGT A AC GGC C T AC C A AGC C G AC GAT C AGT AGC C G AC C T G AG AGGGT

GACCGGCCACATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGG

GGAAT ATTGC AC AAT GGAGGAAACTCTGAT GC AGCGACGCCGCGT GAAGGAT GAAG

TATTTCGGTATGTAAACTTCTATCAGCAGGGAAGAAAATGACGGTACCTGACTAAGA

AGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTAT

CCGGATTTACTGGGTGTAAAGGGAGCGTAGACGGCACGGCAAGCCAGATGTGAAAG

CCCGGGGCTCAACCCCGGGACTGCATTTGGAACTGCTGAGCTAGAGTGTCGGAGAG

GCA AGT GGA ATTNCT AGT GT AGC GGT GA A AT GC GT AG AT ATT AGGAGGA AC ACC AG

TGGCGAAGGCGGCTTGCTGGACGATGACTGACGTTGAGGCTCGAAAGCGTGGGGAG

CAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGACTGCTAGGTGTC

GGGTGGCAAAGCCATTCGGTGCCGCAGCTAACGCAATAAGCAGTCCACCTGGGGAG

TACGTTCGCAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGA

GCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCTGATCTTGACATCCCGAT

GACCGCTTCGTAATGGAAGNTTTTCTTCGGAACATCGGTGACAGGTGGTGCATGGTT

GTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTA

TCTT C AGT AGC C AGC AGGTT A AGC T GGGC ACTCTGGAGAGAC T GC C AGGGAT A AC C

TGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATNACCAGGGCTACAC

ACGTGCTACAATGGCGTAAACAAAGAGACGCGAACTCGCGAGGGTAAGCAAATCTC

A A A A AT A AC GT C TC AGTT C GG ATT GT AGTC T GCA AC T C G AC T AC AT G A AGC T GGAAT

CGCTAGTAATCGCAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACA

CCGCCCGTCACACCATGGGAGTCAGTAACGCCCGAAGTCAGTGACCCAACCGTAAG

GAGGGAGCTGCCGAAGGTGGGACCGATAACTGGGGTGAAGTCGTAACAAGGTAGCC

GTATCGGAAGGTGCGGCTGGATCACCTCCTTT (SEQ ID NO: 22)

NB2-A5TSAB Blautia stercoris Appendix A

TTCGCTTCCCTCTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAATCATAAGGGGC

ATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCCTCAG A

GTGCCCACCATTACATGCTGGCTACTGGGGATAGGGGTTGCGCTCGTTGCGGGACTT

AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTTGCCTGT

CCCGAAGGAAAGGTGACGTTACTCACCGGTCAGGCAGATGTCAAGACTTGGTAAGG

TTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTC A

ATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTAATGCGTT T

GCGGCGGCACCGAAGAGCTGTGCTCCCCGACACCTAGTATTCATCGTTTACGGCGTG

GACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAGT T

ACCGTCCAGTAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCAC C

GCTACACTAGGAATTCCGCTTACCCCTCCGGCACTCAAGCTTAACAGTTTCCAATGC

AGTCCCGGGGTTAAGCCCCAGCCTTTCACATCAGACTTGTTATGCCGTCTACGCTCC

CTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCTG

GCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGATA G

AAGTTTACATACCGAGATACTTCTTCCTTCACGCGGCGTCGCTGCATCAGGGTTTCC C

CCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGT

CCCAATGTGGCCGTTCACCCTCTCAGGCCGGCTATGGATCGTCGCTTTGGTAGGCCG

TTACCCTGCCAACTGGCTAATCCAACGCGGGTCCATCTTATACCACCTCAGTTTTTC A

CACCGGGCCATGCGGCCCTGTGCGCTTATGCGGTATTAGCAGCCATTTCTGACTGTT

ATCCCCCTGTATAAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTAGGATT

AAATCAAATCTGCCGAAGCTTCAATAAAATAATCCCCGTTCGACTTGCATGTGTTAA

GCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCTGATAAAGTTTGATGT

CTCAAGACAACCAACTAGCTTAGTTATCTCTCGTCATTACTGTTTTAAAGTTCATTC T

TCCGAATGTGATTGTAAAAGAATTTTCGAGAATCGTATGTGTTTCACTGTTTAGTTA T

CAATGTTCATTGCTTTTTACTGTCTCTCGACAGCTTATTTACTTTACCACATCTTTT TT

TGTTTGTCAACAACTTTTTTGAAGTTTTTCAAACTTTTTTTCCGAAGATGAAGTTTT GT

CATCCGTGTTGACGACTTGACTACTTTATCATAGATAAGTCAGTTTGTCAACAGG

(SEQ ID NO: 23)

NB2-B11FAA Bifidobacterium longum

GT GGAGGGTTCGATTCTGGCTC AGGAT GAACGCTGGCGGCGT GCTT AAC AC AT GCA

AGTCGAACGGGATCC ATC AGGCTTT GCTTGGTGGT GAGAGT GGCGAACGGGT GAGT

AATGCGTGACCGACCTGCCCCATACACCGGAATAGCTCCTGGAAACGGGTGGTAAT

GCCGGATGCTCCAGTTGATCGCATGGTCTTCTGGGAAAGCTTTCGCGGTATGGGATG

GGGTCGCGTCCTATCAGCTTGACGGCGGGGTAACGGCCCACCGTGGCTTCGACGGG

TAGCCGGCCTGAGAGGGCGACCGGCCACATTGGGACTGAGATACGGCCCAGACTCC

T ACGGGAGGC AGC AGT GGGGAAT ATT GC AC AATGGGCGC AAGCCTGAT GC AGCGAC

GCCGCGTGAGGGATGGAGGCCTTCGGGTTGTAAACCTCTTTTATCGGGGAGCAAGC

GAGAGTGAGTTTACCCGTTGAATAAGCACCGGCTAACTACGTGCCAGCAGCCGCGG

TAATACGTAGGGTGCAAGCGTTATCCGGAATTATTGGGCGTAAAGGGCTCGTAGGC

GGTTCGTCGCGTCCGGTGTGAAAGTCCATCGCTTAACGGTGGATCCGCGCCGGGTAC

GGGCGGGCTTGAGTGCGGTAGGGGAGACTGGAATTCCCGGTGTAACGGTGGAATGT

GTAGATATCGGGAAGAACACCAATGGCGAAGGCAGGTCTCTGGGCCGTTACTGACG

CTGAGGAGCGAAAGCGTGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCACGCC

GTAAACGGTGGATGCTGGATGTGGGGCCCGTTCCACGGGTTCCGTGTCGGAGCTAAC Appendix A

GCGTT AAGC ATCCCGCCTGGGGAGT ACGGCCGC AAGGCT AAAACTC AAAGAAATT G

ACGGGGGCCCGCACAAGCGGCGGAGCATGCGGATTAATTCGATGCAACGCGAAGA

ACCTTACCTGGGCTTGACATGTTCCCGACGGTCGTAGAGATACGGCTTCCCTTCGGG

GCGGGTTCACAGGTGGTGCATGGTCGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTA

AGTCCCGCAACGAGCGCAACCCTCGCCCCGTGTTGCCAGCGGATTATGCCGGGAAC

T C ACGGGGGACCGCCGGGGTT AACTCGGAGGAAGGT GGGGAT GACGT C AGAT CAT C

ATGCCCCTTACGTCCAGGGCTTCACGCATGCTACAATGGCCGGTACAACGGGATGCG

ACGCGGCGACGCGGAGCGGATCCCTGAAAACCGGTCTCAGTTCGGATCGCAGTCTG

CAACTCGACTGCGTGAAGGCGGAGTCGCTAGTAATCGCGAATCAGCAACGTCGCGG

TGAATGCGTTCCCGGGCCTTGTACACACCGCCCGTCAAGTCATGAAAGTGGGCAGC

ACCCGAAGCCGGTGGCCTAACCCCTTGTGGGATGGAGCCGTCTAAGGTGAGGCTCG

T GATT GGGACT AAGTCGT AAC AAGGT AGCCGT ACCGGAAGGT GCGGCTGGATC ACC

TCCTTT (SEQ ID NO: 24)

NB2-A2FAA Coprococcus comes

GAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAAGTC

GAACGAAGCACCTGGATTTGATTCTTCGGATGAAGATCCTTGTGACTGAGTGGCGGA

CGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGAAATG

ACTGCTAATACCGCATAAGACCACAGGGTCGCATGACCTGGTGGGAAAAACTCCGG

TGGTATGAGATGGACCCGCGTCTGATTAGGTAGTTGGTGGGGTAACGGCCTACCAA

GCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGACAC

GGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCC

TGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATCAG

CAGGGAAGAAAATGACGGTACCTGACTAAGAAGCACCGGCTAAATACGTGCCAGCA

GCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAG

CGTAGACGGCTGTGTAAGTCTGAAGTGAAAGCCCGGGGCTCAACCCCGGGACTGCT

TTGGAAACTATGCAGCTAGAGTGTCGGAGAGGTAAGTGGAATTCCCAGTGTAGCGG

T G A A AT GC GT AGAT ATT GGG AGG A AC AC C AGT GGC G A AGGC GGC T T AC T GG AC G AT

G AC T G AC GT T G AGGC T C G A AAGC GT GGGG AGC A A AC AGG ATT AGAT AC C C T GGT AG

TCCACGCCGTAAACGATGACTACTAGGTGTCGGGGAGCAAAGCTCTTCGGTGCCGC

AGC AAACGC AAT AAGT AGTCC ACCTGGGGAGT ACGTTCGC AAGAAT GAAACTC AAA

GGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACG

CGAAGAACCTTACCTGCTCTTGACATCCCGGTGACCGGCATGTAATGATGCCTTTTC

TTCGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGT

TGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTCAGTAGCCAGCATTTCGGGTG

GGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCAAA

T CAT CAT GCCCCTT AT GAGC AGGGCT AC AC ACGT GCT AC AAT GGCGT AAAC AAAGG

GAAGCGAACCTGTGAGGGTAAGCAAATCTCAAAAATAACGTCTCAGTTCGGATTGT

AGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGCATGTC

GCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTTGGT

AACGCCCGAAGTCAGTGACTCAACCGTAAGGAGAGAGCTGCCGAAGGTGGGACCG

AT AACTGGGGTGAAGTCGTAAC AAGGT AGCCGTATCGGAAGGTGCGGCTGGATCAC

CTCCTTT (SEQ ID NO: 25)

NB2-B6CNA [Eubacterium] eligens Appendix A

TTCCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGAC

TTCACCCCAGTTATCAAACCTGCCTTCGGCGGCTCCTTCTTTCGTTAGGTCACCGAC T

TCGGGCATTTTCGACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAACGT

ATTCACCGCAGCATTCTGATCTGCGATTACTAGCGATTCCAGCTTCATGTAGTCGAG

TTGCAGACTACAATCCGAACTGAGACGTTATTTTTGTGATTTGCTTGGCCTCACGAC T

TCGCTTCACTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAGTCATAAGGGGCA

TGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCCCTAGA G

TGCCCATCTTACTGCTGGCTACTAAGGATAGGGGTTGCGCTCGTTGCGGGACTTAAC

CCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTCCACTGTCCC

GAAGGAAAGGAC AC ATT ACTGTCCGGT C AGT GGGAT GTC AAGACTTGGT AAGGTT C

TTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTCAAT T

CCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTATTGCGTTTGC T

GCGGCACCGAAGCCCTTATGGGCCCCGACACCTAGTATTCATCGTTTACGGCGTGGA

CTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAGTGTCAGTTA C

AGTCCAGTGAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCACCG C

TACACTAGGAATTCCACTCACCCCTCCTGCACTCCAGCCTTACAGTTTCAAAAGCAG

TTCCGGGGTTGAGCCCCGGATTTTCACTTCTGACTTGCATGGCCACCTACACTCCCT T

TACACCCAGTAAATCCGGATAACGCTTGCTCCATACGTATTACCGCGGCTGCTGGCA

CGTATTTAGCCGGAGCTTCTTAGTCAGGTACCGTCACTATCTTCCCTGCTGATAGAG C

TTTACATAACGAATTACTTCTTCACTCACGCGGCGTCGCTGCATCAGAGTTTCCTCC A

TTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGTCCC

AATGTGGCCGGTCACCCTCTCAGGTCGGCTACTGATCGTCGCCTTGGTGGGCTGTTA

TCTCACCAACTAGCTAATCAGACGCGGGTCCATCTTATACCACCGGAGTTTTTCACA

CCATGTCATGCAACATTGTGCGCTTATGCGGTATTACCAGCCGTTTCCAGCTGCTAT C

CCCCAGTACAAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTCAGTCATAA

AGAACTTCAAACCGAAGTAATCCGTTCTAAATGCTTCGTTCGACTTGCATGTGTTAA

GCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCATA (SEQ ID NO: 26)

NB2-BAERMRS02 Lactobacillus paracasei

CCAAGGCGATGATACGTAGCCGAACTGAGAGGTTGATCGGCCACATTGGGACTGAG

ACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCA

AGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGCTTTCGGGTCGTAAAACTCTG

TTGTTGGAGAAGAATGGTCGGCAGAGTAACTGTTGNCGNCGTGACGGTATCCAACC

AGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCG

TTATCCGGATTTATTGGGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGA

AAGCCCTCGGCTTAACCGAGGAAGCGCATCGGAAACTGGGAAACTTGAGTGCAGAA

GAGGAC AGT GGAACTCC ATGT GT AGCGGT GAAAT GCGT AG AT AT AT GGAAGAAC AC

CAGTGGCGAAGGCGGCTGTCTGGTCTGTAACTGACGCTGAGGCTCGAAAGCATGGG

TAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAATGCTAGGT

GTTGGAGGGTTTCCGCCCTTCAGTGCCGCAGCTAACGCATTAAGCATTCCGCCTGGG

GAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGT

GGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCTT

TTGATCACCTGAGAGATCAGGTTTCCCCTTCGGGGGCAAAATGACAGGTGGTGCATG

GTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCC

TTATGACTAGTTGCCAGCATTTAGTTGGGCACTCTAGTAAGACTGCCGGTGACAAAC Appendix A

CGGAGGAAGGT GGGGAT GACGT C AAAT CAT CAT GCCCCTT ATGACCTGGGCT AC AC

ACGTGCTACAATGGATGGTACAACGAGTTGCGAGACCGCGAGGTCAAGCTAATCTC

TTAAAGCCATTCTCAGTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGTCGGAAT

CGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACA

CCGCCCGTCACACCATGAGAGTTTGTAACACCCGAAGCCGGTGGCGTAACCCTTTTA

GGG AGC G AGC C GT C T A AGGT GGG AC A A AT GATT AGGGT G A AGT C GT A AC A AGGT AG

CCGTAGGAGAACCTGCGGCTGGATCACCTCCTTT (SEQ ID NO: 27)

NB2-B 13CNA [Clostridium] oroticum

CCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGACTT

CACCCCAGTTATCGGTCCCACCTTCGGCAGCTCCCTCCTTGCGGTTGGGTCACTGAC T

TCGGGCGTTACCAACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAACG

TATTCACCGCGACATTCTGATTCGCGATTACTAGCGATTCCAGCTTCATGTAGTCGA

GTTGCAGACTACAATCCGAACTGAGACGTTATTTTTGAGATTTGCTTACCCTCGCAG

GCTCGCTTCCCTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCTGCTCATAAGGGG C

ATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCTCTAG A

GTGCCCGGCCRWACCGCTGGCTACTAAAGATAGGGGTTGCGCTCGTTGCGGGACTT

AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCATCCCTGT

CCCGAAGGAAAGGC AAC ATT ACTT GCCGGT C AGGGAGAT GTCAAG AGC AGGT AAGG

TTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTC A

ATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGACTACTTATTGCGTT G

GCTGCGGCACCGAATAGCTCTGCTACCCGACACCTAGTAGTCATCGTTTACGGCGTG

GACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAGT

CATCGTCCAGCAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCA C

CGCTACACTAGGAATTCCACTTGCCTCTCCGACACTCTAGTTCGACAGTTTCCAATG

CAGTCCCAGGGTTGAGCCCTGGCCTTTCACATCAGACTTGCCATACCGTCTACGCTC

CCTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCT

GGCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGAT A

GAAGTTTACATACCGAAATACTTCATCCTTCACGCGGCGTCGCTGCATCAGGGTTTC

CCCCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCA

GTCCCAATGTGGCCGGTCACCCTCTCAGGTCGGCTACTGATCGTCGCCTTGGTAGGC

CGTTACCCCACCAACYAGCTAATCAGACGCGGGTCCATCTCATACCACCGGAGTTTT

TACCCCTGCACCATGCGGTGCTGTGGTCTTATGCGGTATTAGCAGYCATTTCTAACT

GTTATCCCCCTGTATGAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTCAG

TCACAAAAGTCTTCATCCGAAGAATCAAACTTAAGTGCTTCGTTCGACTTGCATGTG

TTAAGCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCGT (SEQ ID NO:

28)

NB2-B 15DCM Dorea formicigenerans

TTAAACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATG

CAAGTCGAGCGAAGCACTTAAGTTCGATTCTTCGGATGAAGACTTTTGTGACTGAGC

GGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTA

GAAATGGCTGCTAATACCGCATAAGACCACAGTACTGCATGGTACAGTGGTAAAAA

CTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGGTAGTTGGTGAGGTAACGGCCC

ACCAAGCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGA Appendix A

GACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGCGA

AAGCCTGATGCAGCGACGCCGCGTGAAGGATGAAGTATTTCGGTATGTAAACTTCTA

TCAGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCC

AGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAG

GGAGCGTAGACGGCTGTGCAAGTCTGAAGTGAAAGGCATGGGCTCAACCTGTGGAC

T GCTTTGGAAACTGT GC AGCT AGAGT GTCGGAGAGGT AAGT GGAATTCCT AGTGT AG

CGGT GA A AT GC GT AG AT ATT AGGAGGA AC AC C AGT GGC GA AGGCGGC TT ACTGGAC

GATGACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGG

TAGTCCACGCCGTAAACGATGACTGCTAGGTGTCGGGTAGCAAAGCTATTCGGTGCC

GCAGCTAACGCAATAAGCAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCA

AAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAA

CGCGAAGAACCTTACCTGATCTTGACATCCCGATGACCGCTTCGTAATGGAAGCTTT

TCTTCGGAACATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGAT

GTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTCAGTAGCCAGCATTTAAGA

TGGGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCA

AATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTAAACAAA

GGGAAGCAGAGCCGCGAGGCCGAGCAAATCTCAAAAATAACGTCTCAGTTCGGATT

GTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCAGATCAGAAT

GCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC

AGTAACGCCCGAAGTCAGTGACCCAACCGAAAGGAGGGAGCTGCCGAAGGTGGGA

CCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGAT

CACCTCCTTTCT (SEQ ID NO: 29)

NB2-BBHI1 Escherichia coli

ACGAGTGGCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATAAC

TACTGGAAACGGTAGCTAATACCGCATAACGTCGCAAGACCAAAGAGGGGGACCTT

CGGGCCTCTTGCCATCGGATGTGCCCAGATGGGATTAGCTAGTAGGTGGGGTAACG

GCTCACCTAGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGAA

CTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGG

GCGCAAGCCTGATGCAGCCATGCCGCGTGTATGAAGAAGGCCTTCGGGTTGTAAAG

TACTTTCAGCGGGGAGGAAGGGAGTAAAGTTAATACCTTTNCTCATTGACGTTACCC

GCAGAAGAAGCACCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCA

AGCGTT AATCGGAATT ACTGGGCGT AAAGCGC ACGC AGGCGGTTTGTT AAGTC AGA

TGTGAAATCCCCGGGCTCAACCTGGGAACTGCATCTGATACTGGCAAGCTTGAGTCT

C GT AG AGGGGGGT AG A AT T C C AGGT GT AGC GGT G A A AT GC GT AG AG AT C T GG AGG A

ATACCGGTGGCGAAGGCGGCCCCCTGGACGAAGACTGACGCTCAGGTGCGAAAGCG

TGGGGAGCAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGTCGACT

TGGAGGTTGTGCCCTTGAGGCGTGGCTTCCGGAGCTAACGCGTTAAGTCGACCGCCT

GGGGAGTACGGCCGCAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAGC

GGTGGAGCATGTGGTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGACAT

CCACNGAANTTTNCAGAGATGAGAATGTGCCTTCGGGAACNGTGAGACAGGTGCTG

CATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCGCAACGAGCGCA

ACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACTCAAAGGAGACTGCCAGTGA

T AAACTGGAGGAAGGT GGGGAT GACGTC AAGT CAT CAT GGCCCTT ACGACC AGGGC

T AC AC ACGT GCT AC AAT GGCGC AT AC AAAGAGAAGCGACCTCGCGAGAGC A AGCGG Appendix A

ACCTCATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGACTCCATGAAGTC GGAATCGCTAGTAATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCCTTGT AC AC ACCGCCCGT C AC ACC AT GGGAGT GGGTTGC AAAAGAAGT AGGT AGCTT AACC TTCGGGAGGGCGCTTACCACTTTGTGATTCATGACTGGGGTGAAGTCGTAACAAGGT AACCGTAGGGGAACCTGCGGTTGGATCACCTCCTT (SEQ ID NO: 30)

NB2-B9DCM Anaerostipes hadrus

ATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAA

GTCGAACGAAGCGCCTTATTTGATTTTCTTCGGAACTGAAGATTTGGTGACTGAGTG

GCGGACGGGTGAGTAACGCGTGGGTAACCTGCCCTGTACAGGGGGATAACAATCAG

AAAT GACTGCT AAT ACCGC AT AAGACC AC AGC ACCGC AT GGT GC AGGGGT AAAAAC

TCCGGTGGTACAGGATGGACCCGCGTCTGATTAGCTGGTTGGTGAGGTAACGGCTCA

CCAAGGCGACGATCAGTAGCCGGCTTGAGAGAGTGAACGGCCACATTGGGACTGAG

ACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGGA

ACCCTGATGCAGCGACGCCGCGTGAGTGAAGAAGTATTTCGGTATGTAAAGCTCTAT

CAGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCA

GC AGC C GC GGT A AT AC GT AGGGGGC A AGC GT T AT C C GG A ATT ACT GGGT GT A A AGG

GTGCGTAGGTGGTATGGCAAGTCAGAAGTGAAAACCCAGGGCTTAACTCTGGGACT

GCTTTTGAAACTGT C AGACTGGAGT GC AGG AG AGGT AAGCGGAATTCCT AGT GT AG

CGGT GAAAT GCGT AGAT ATT AGGAGGAAC AT C AGT GGCGAAGGCGGCTT ACTGGAC

TGA AACTGAC ACTGAGGC ACGAAAGCGT GGGGAGC AAAC AGGATT AGAT ACCCTGG

TAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGCCGTAGAGGCTTCGGTGC

CGCAGCCAACGCAATAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTC

AAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCA

ACGCGAAGAACCTTACCTGGTCTTGACATCCTTCTGACCGGTCCTTAACCGGACCTT

TCCTTCGGGACAGGAGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGA

TGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTTAGTAGCCAGCATTTAAG

GTGGGCACTCTAGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGACGACGTC

AAATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTAAACAG

AGGGAAGCAGCCTCGTGAGAGTGAGCAAATCCCAAAAATAACGTCTCAGTTCGGAT

TGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAAT

GTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC

AGTAACGCCCGAAGTCAGTGACCCAACCGTAAGGAGGGAGCTGCCGAAGGCGGGA

CCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGAT

CACCTCCTTT (SEQ ID NO: 31)

NB2-B9FAA Blautia luti

GTTGGT GGGGT AACGGCCC ACC A AGGCGACGATCC AT AGCCGGCCTGAGAGGGT GA ACGGCCACATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGG AAT ATT GC AC AATGGGGGAAACCCTGAT GC AGCGACGCCGCGT GAAGGA AGAAGT A TCTCGGTATGTAAACTTCTATCAGCAGGGAAGATAGTGACGGTACCTGACTAAGAA GCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATC CGGATTTACTGGGTGTAAAGGGAGCGTAGACGGTGTGGCAAGTCTGATGTGAAAGG CATGGGCTCAACCTGTGGACTGCATTGGAAACTGTCATACTTGAGTGCCGGAGGGGT AAGCGGAATTCCT AGT GT AGC GGT GAAAT GCGT AGAT ATT AGGAGGAAC ACC AGTG Appendix A

GCGAAGGCGGCTTACTGGACGGTAACTGACGTTGAGGCTCGAAAGCGTGGGGAGCA

AACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGG

GGAGC AAAGCTCTTCGGT GCCGTCGC AAACGC AGT AAGT ATTCC ACCTGGGGAGT A

CGTTCGCAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGC

ATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAAATCTTGACATCCCTCTGA

CCGGTCTTTAATCGGACCTTCTCTTCGGAGCAGAGGTGACAGGTGGTGCATGGTTGT

CGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATC

CTCAGTAGCCAGCATTTAAGGTGGGCACTCTGGGGAGACTGCCAGGGATAACCTGG

AGGAAGGCGGGGATGACGTCAAATCATCATGCCCCTTATGATTTGGGCTACACACGT

GCTACAATGGCGTAAACAAAGGGAAGCGAGATCGTGAGATGGAGCAAATCCCAAA

AATAACGTCCCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCG

CTAGTAATCGCGGATCAGAATGCCGCGGTGAATACGTTCCCGGGTCTTGTACACACC

GCCCGTCACACCATGGGAGTCAGTAACGCCCGAAGTCAGTGACCTAACTGCAAAGA

AGGAGCTGCCGAAGGCGGGACCGATGACTGGGGTGAAGTCGTAACAAGGTAGCCGT

ATCGGAAGGTGCGGCTGGATCAC (SEQ ID NO: 32)

NB2-A7D5 [Clostridium] scindens

AACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA

AGTCGAACGAAGCGCTTCCGCCTGATTTTCTTCGGAGATGAAGGCGGCTGCGACTGA

GTGGCGGACGGGTGAGTAACGCGTGGGCAACCTGCCTTGCACTGGGGGATAACAGC

C AG A A AT GGC T GC T A AT ACC GC AT A AGAC CGA AGC GCC GC AT GGC GC AGC GGCC A A

AGCCCCGGCGGTGCAAGATGGGCCCGCGTCTGATTAGGTAGTTGGCGGGGTAACGG

CCCACCAAGCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGAC

TGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGG

GGAAACCCTGATGCAGCGACGCCGCGTGAAGGATGAAGTATTTCGGTATGTAAACT

TCTATCAGCAGGGAAGAAGATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACG

TGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGT

AAAGGGAGCGTAGACGGCGATGCAAGCCAGATGTGAAAGCCCGGGGCTCAACCCC

GGGACTGCATTTGGAACTGCGTGGCTGGAGTGTCGGAGAGGCAGGCGGAATTCCTA

GTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCCTG

CTGGACGATGACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATA

CCCTGGTAGTCCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAGGCCATTC

GGTGCCGCAGC AAACGC AATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGA

AACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCG

AAGCAACGCGAAGAACCTTACCTGATCTTGACATCCCGATGCCAAAGCGCGTAACG

CGCTCTTTCTTCGGAACATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC

GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCA

TTCCGGATGGGCACTCTGGAGAGACTGCCAGGGACAACCTGGAGGAAGGTGGGGAT

GACGTCAAATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTA

AACAAAGGGAGGCGAACCCGCGAGGGTGGGCAAATCCCAAAAATAACGTCTCAGTT

CGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATC

AGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGG

GAGTCAGTAACGCCCGAAGCCGGTGACCCAACCCGCAAGGGAGGGAGCCGTCGAA

GGTGGGACCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCG

GCTGGATCACCTCCTTT (SEQ ID NO: 33) Appendix A

NB2-B10MRS Eubacterium desmolans

TTTAGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA

AGTCGAACGGAGTCGTTTTGGAAAATCCTTCGGGATTGGAATTCTCGACTTAGTGGC

GGACGGGTGAGTAACGCGTGAGCAATCTGCCTTTAAGAGGGGGATAACAGTCGGAA

ACGGCTGCTAATACCGCATAAAGCATTGAATTCGCATGTTTTCGATGCCAAAGGAGC

AATCCGCTTTTAGATGAGCTCGCGTCTGATTAGCTAGTTGGTGGGGTAACGGCCCAC

C AAGGCGACGATC AGT AGCCGGACTGAGAGGTTGAACGGCC AC ATT GGGACTGAGA

CACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCGCAATGGGGGAAA

CCCTGACGCAGCAACGCCGCGTGATTGAAGAAGGCCTTCGGGTTGTAAAGATCTTTA

ATCAGGGACGAAAAATGACGGTACCTGAAGAATAAGCTCCGGCTAACTACGTGCCA

GCAGCCGCGGTAATACGTAGGGAGCAAGCGTTATCCGGATTTACTGGGTGTAAAGG

GCGCGCAGGCGGGCCGGCAAGTTGGAAGTGAAATCCGGGGGCTTAACCCCCGAACT

GCTTT C AAAACTGCTGGTCTTGAGT GATGGAGAGGC AGGCGGAATTCCGT GT GT AGC

GGTGAAATGCGTAGATATACGGAGGAACACCAGTGGCGAAGGCGGCCTGCTGGACA

TTAACTGACGCTGAGGCGCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGT

AGTCCACGCCGTAAACGATGGATACTAGGTGTGGGAGGTATTGACCCCTTCCGTGCC

GC AGTT AAC AC AAT AAGT ATCCC ACCTGGGGAGT ACGGCCGC AAGGTT GAAACTC A

AAGGAATTGACGGGGGCCCGCACAAGCAGTGGAGTATGTGGTTTAATTCGAAGCAA

CGCGAAGAACCTTACCAGGCCTTGACATCCCGATGACCGGCTTAGAGATAAGCCTTC

TCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGAT

GTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTACGGTTAGTTGATACGCAAGATCA

CTCT AGCCGGACTGCCGTT GAC AAAACGGAGGAAGGTGGGGACGACGTC AAAT CAT

CATGCCCCTTATGGCCTGGGCTACACACGTACTACAATGGCAGTCATACAGAGGGA

AGCAAAATCGCGAGGTGGAGCAAATCCCTAAAAGCTGTCCCAGTTCAGATTGCAGG

CTGCAACCCGCCTGCATGAAGTCGGAATTGCTAGTAATCGCGGATCAGCATGCCGC

GGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGCCGTCAA

TACCCGAAGTCCGTAGCCTAACCGCAAGGAGGGCGCGGCCGAAGGTAGGGGTGGTA

ATTAGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCACCTC

CTTT (SEQ ID NO: 34)

NB2-B19DCM Faecalibacterium prausnitzii

AGAAAGGAGGTGATCCAGCCGCAGGTTCTCCTACGGCTACCTTGTTACGACTTCACC

CCAATCACCAGTTTTACCTTCGGCGGCGTCCTCCTTGCGGTTAGACTACCGACTTCG

GGTCCCCCCGGCTCTCATGGTGTGACGGGCGGTGTGTACAAGGCCCGGGAACGTATT

CACCGTGGCATGCTGATCCACGATTACTAGCAATTCCGACTTCGTGCAGGCGAGTTG

CAGCCTGCAGTCCGAACTGGGACGTTGTTTCTGAGTTTTGCTCCACCTCGCGGTCTT G

CTTCTCTTTGTTTAACGCCATTGTAGTACGTGTGTAGCCCAAGTCATAAAGGGCATG

ATGATTTGACGTCATCCCCACCTTCCTCCGTTTTGTCAACGGCAGTCCTGCCAGAGT C

CTCTTGCGTAGTAACTGACAGTAAGGGTTGCGCTCGTTGCGGGACTTAACCCAACAT

CTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTCCTTGCTCCGAAGAGA

AAACATATTTCTATGTGCGTCGCAGGATGTCAAGACTTGGTAAGGTTCTTCGCGTTG

CGTCGAATTAAACCACATACTCCACTGCTTGTGCGGGCCCCCGTCAATTCCTTTGAG

TTTCAACCTTGCGGTCGTACTCCCCAGGTGGATTACTTATTGTGTTAACTGCGGCAC T

GAAGGGGTCAATCCTCCAACACCTAGTAATCATCGTTTACGGTGTGGACTACCAGGG

TATCTAATCCTGTTTGCTACCCACACTTTCGAGCCTCAGCGTCAGTTGGTGCCCAGT A Appendix A

GGCCGCCTTCGCCACTGGTGTTCCTCCCGATATCTACGCATTCCACCGCTACACCGG

GAATTCCGCCTACCTCTGCACTACTCAAGAAAAACAGTTTTGAAAGCAGTTTATGGG

TTGAGCCCATAGATTTCACTTCCAACTTGTCTTCCCGCCTGCGCTCCCTTTACACCC A

GTAATTCCGGACAACGCTTGTGACCTACGTTTTACCGCGGCTGCTGGCACGTAGTTA

GCCGTCACTTCCTTGTTGAGTACCGTCATTATCTTCCTCAACAACAGGAGTTTACAA T

CCGAAGACCTTCTTCCTCCACGCGGCGTCGCTGCATCAGGGTTTCCCCCATTGTGCA

ATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGTCCCAATGTGG

CCGTTCAACCTCTCAGTCCGGCTACCGATCGTTGCCTTGGTGGGCCATTACCTCACC

AACTAGCTAATCGGACGCGAGGCCATCTCAAAGCGGATTGCTCCTTTTCCCTCTGGT

CGATGCCGACCTGTGGGCTTATGCGGTATTAGCAGTCGTTTCCAACTGTTGTCCCCC T

CTTTGAGGCAGGTTCCTCACGCGTTACTCACCCGTTCGCCACTCGCTYGAGAAAGCA

AGCTCTCTCTCGCTCGTTCGACTTGCATGTGTTAGGCGCGCCGCCAGCGTTCGTCCT G

AGC C AGGAT C A A AC T C THAT AAA (SEQ ID NO: 35)

NB2-A12BBE Bacteroides ovatus

CCGTGTCTCAGTTCCAATGTGGGGGACCTTCCTCTCAGAACCCCTATCCATCGTTGTC

TTGGTGGGCCGTTACCCCGCCAACAAACTAATGGAACGCATCCCCATCGATAACCG

AAATTCTTTAATAGTAAAACCATGCGGTTTTAATATACCATCGGATATTAATCTTTC T

TTCGAAAGGCTATCCCCGAGTTATCGGCAGGTTGGATACGTGTTACTCACCCGTGCG

CCGGTCGCCATCTTTAGTTTGCAAGCAAACTAAAATGCTGCCCCTCGACTTGCATGT

GTTAAGCCTGTAGCTAGCGTTCATCCTGAGCTATTAAAGAATTTCGGTTATCGATGG

GGATGCGTTCCATTAGTTTGTTGGCGGGGTAACGGCCCACCAAGACAACGATGGAT

AGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAAACTCCT

ACGGGAGGC AGC AGT GAGGA AT ATT GGT C A AT GGGC GAGAGCC T GA AC C AGC C A A

GT AGCGT GAAGGAT GAAGGCTCT AT GGGTCGT AAACTTCTTTT AT AT GGGAAT AAAG

TATTCCACGTGTGGAATTTTGTATGTACCATATGAATAAGGATCGGCTAACTCCGTG

CCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAAA

GGGAGCGTAGGTGGATTGTTAAGTCAGTTGTGAAAGTTTGCGGCTCAACCGTAAAAT

TGCAGTTGAAACTGGCAGTCTTGAGTACAGTAGAGGTGGGCGGAATTCGTGGTGTA

GCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTCACTAGA

CTGTCACTGACACTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATACCCTGG

TAGTCCACACAGTAAACGATGAATACTCGCTGTTTGCGATATACAGTAAGCGGCCAA

GCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAG

GAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATACGC

GAGGAACCTTACCCGGGCTTAAATTGCATTTGAATAATCTGGAAACAGGTTAGCCGC

A AGGC A A AT GT G A AGGT GC T GC AT GGTT GT C GT C AGC T C GT GC C GT G AGGT GT C GGC

TTAAGTGCCATAACGAGCGCAACCCTTATCTTTAGTTACTAACAGGTTATGCTGAGG

ACTCT AGAGAGACTGCCGTCGT AAGAT GTGAGGAAGGT GGGGATGACGT C AAAT C A

GCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACAGAAGGCA

GCTACCTGGCGACAGGATGCTAATCCCAAAAACCTCTCTCAGTTCGGATCGAAGTCT

GCAACCCGACTTCGTGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCG

GTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGCCGGGGG

TACCTGAAGTACGTAACCGCAAGGAGCGTCCTAGGGTAAAACTGGTAATTGGGGCT

(SEQ ID NO: 36)

NB2-A13NA Coprococcus catus Appendix A

ATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAA

GTCGAACGGACGATGAAGAGCTTGCTTTTCAGAGTTAGTGGCGGACGGGTGAGTAA

CGCGTGGGTAACCTGCCTCATACAGGGGGATAGCAGCTGGAAACGGCTGATAAAAC

CGC AT A AGCGC AC AGC AT C GC AT GAT GC AGT GT GA A A A AC T C CGGT GGT AT GAG AT

GGACCCGCGTCTGATTAGCTGGTTGGTGAGGTAACGGCCCACCAAGGCGACGATCA

GTAGCCGGCCTGAGAGGGTGACCGGCCACATTGGGACTGAGACACGGCCCAAACTC

CT ACGGGAGGC AGC AGT GGGGAAT ATT GC AC AATGGGGGAAACCCTGAT GC AGCGA

C GC C GC GT G A AGG A AG A AGT ATC TC GGT AT GT A A AC TT C T ATC AGC AGGG A AG AT A

ATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAAT

ACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAGCGTAGGCGGCG

GAGCAAGTCAGAAGTGAAAGCCCGGGGCTCAACCCCGGGACGGCTTTTGAAACTGC

CCTGCTTGATTTCAGGAGAGGTAAGCGGAATTCCTAGTGTAGCGGTGAAATGCGTAG

AT ATT AGGAGGAAC ACC AGTGGCGAAGGCGGCTT ACTGGACTGAC AAT GACGCTGA

GGCTCGA AAGCGT GGGGAGC AAAC AGGATT AG AT ACCCTGGT AGTCC ACGCCGT AA

AC GAT GAAT ACT AGGTGTCGGGGCTC AT AAGAGCTTCGGT GCCGC AGC AAACGC AA

TAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAAGGAATTGACGG

GGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTT

ACCAGGCCTTGACATCCCGGTGACCGTCCCGTAATGGGGACCTCTCTTCGGAGCACC

GGT GAC AGGTGGT GC AT GGTT GTCGT C AGCTCGT GTCGT GAGATGTT GGGTT AAGT C

CCGCAACGAGCGCAACCCCTATGTTCAGTAGCCAGCAGGTAAAGCTGGGCACTCTG

GACAGACTGCCGGGGATAACCCGGAGGAAGGCGGGGATGACGTCAAATCATCATGC

CCCTTACGGCCTGGGCTACACACGTGCTACAATGGCGTAAACAAAGGGAAGCGAGA

GGGTGACCTGGAGCGAATCCCAAAAATAACGTCCCAGTTCGGACTGTAGTCTGCAA

CCCGACTACACGAAGCTGGAATCGCTAGTAATCGCGAATCAGCATGTCGCGGTGAA

TACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTTGGAAATGCCCG

AAGTCAGTGACCTAACCGCAAGGGAGGAGCTGCCGAAGGTGGAGCCGATGACTGGG

GTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCACCTCCTTTCTA

AGGAA (SEQ ID NO: 37)

NB2-B 16TSAB Bifidobacterium adolescentis

TGTGGAGGGTTCGATTCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCA

AGTCGAACGGGATCCCAGGAGCTTGCTCCTGGGTGAGAGTGGCGAACGGGTGAGTA

ATGCGTGACCGACCTGCCCCATACACCGGAATAGCTCCTGGAAACGGGTGGTAATG

CCGGATGCTCCAGTTGACCGCATGGTCCTCTGGGAAAGCTTTTGCGGTATGGGATGG

GGTCGCGTCCTATCAGCTTGATGGCGGGGTAACGGCCCACCATGGCTTCGACGGGTA

GCCGGCCTGAGAGGGCGACCGGCCACATTGGGACTGAGATACGGCCCAGACTCCTA

CGGGAGGC AGC AGT GGGGAAT ATT GC AC AAT GGGCGC AAGCCTGATGC AGCGACGC

CGCGTGCGGGATGACGGCCTTCGGGTTGTAAACCGCTTTTGACTGGGAGCAAGCCCT

TCGGGGTGAGTGTACCTTTCGAATAAGCACCGGCTAACTACGTGCCAGCAGCCGCG

GTAATACGTAGGGTGCAAGCGTTATCCGGAATTATTGGGCGTAAAGGGCTCGTAGG

CGGTTCGTCGCGTCCGGTGTGAAAGTCCATCGCTTAACGGTGGATCCGCGCCGGGTA

CGGGCGGGCTTGAGTGCGGTAGGGGAGACTGGAATTCCCGGTGTAACGGTGGAATG

T GT AGAT ATCGGGAAGAAC ACC AATGGCGAAGGC AGGTCTCTGGGCCGT C ACTGAC

GCTGAGGAGCGAAAGCGTGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCACGC

CGTAAACGGTGGATGCTGGATGTGGGGACCATTCCACGGTCTCCGTGTCGGAGCCA Appendix A

ACGCGTTAAGCATCCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGAAAT

TGACGGGGGCCCGCACAAGCGGCGGAGCATGCGGATTAATTCGATGCAACGCGAAG

AACCTTACCTGGGCTTGACATGTTCCCGACAGCCCCAGAGATGGGGCCTCCCTTCGG

GGCGGGTTCACAGGTGGTGCATGGTCGTCGTCAGCTCGTGTCGTGAGATGTTGGGTT

AAGTCCCGCAACGAGCGCAACCCTCGCCCTGTGTTGCCAGCACGTCGTGGTGGGAA

CTCACGGGGGACCGCCGGGGTCAACTCGGAGGAAGGTGGGGATGACGTCAGATCAT

CATGCCCCTTACGTCCAGGGCTTCACGCATGCTACAATGGCCGGTACAACGGGATGC

GACACCGCGAGGTGGAGCGGATCCCTTAAAACCGGTCTCAGTTCGGATTGGAGTCT

GCAACCCGACTCCATGAAGGCGGAGTCGCTAGTAATCGCGGATCAGCAACGCCGCG

GTGAATGCGTTCCCGGGCCTTGTACACACCGCCCGTCAAGTCATGAAAGTGGGTAGC

ACCCGAAGCCGGTGGCCCAACCTTTTGGGGGGAGCCGTCTAAGGTGAGACTCGTGA

TTGGGACTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGATCACCTCC

TTT (SEQ ID NO: 38)

NB2-B 13DCM Collinsella aerofaciens

CGGAGAGTTCGATCCTGGCTCAGGATGAACGCTGGCGGCGCGCCTAACACATGCAA

GTCGAACGGCACCCACCTCCGGGTGGAAGCGAGTGGCGAACGGCTGAGTAACACGT

GGAGAACCTGCCCCCTCCCCCGGGATAGCCGCCCGAAAGGACGGGTAATACCGGAT

ACCCCGGGGTGCCGCATGGCACCCCGGCTAAAGCCCCGACGGGAGGGGATGGCTCC

GCGGCCCATCAGGTAGACGGCGGGGTGACGGCCCACCGTGCCGACAACGGGTAGCC

GGGTTGAGAGACCGACCGGCCAGATTGGGACTGAGACACGGCCCAGACTCCTACGG

GAGGC AGC AGT GGGGAATCTTGCGC AAT GGGGGGAACCCTGACGC AGCGACGCCGC

GTGCGGGACGGAGGCCTTCGGGTCGTAAACCGCTTTCAGCAGGGAAGAGTCAAGAC

TGTACCTGCAGAAGAAGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTA

GGGGGCGAGCGTTATCCGGATTCATTGGGCGTAAAGCGCGCGTAGGCGGCCCGGCA

GGCCGGGGGTCGAAGCGGGGGGCTCAACCCCCCGAAGCCCCCGGAACCTCCGCGGC

T T GGGT C C GGT AGGGG AGGGT GG A AC AC C C GGT GT AGC GGT GG A AT GC GC AG AT AT

CGGGTGGAACACCGGTGGCGAAGGCGGCCCTCTGGGCCGAGACCGACGCTGAGGCG

CGAAAGCTGGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCCAGCCGTAAACGA

TGGACGCTAGGTGTGGGGGGACGATCCCCCCGTGCCGCAGCCAACGCATTAAGCGT

CCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGGAATTGACGGGGGCCCG

CACAAGCAGCGGAGCATGTGGCTTAATTCGAAGCAACGCGAAGAACCTTACCAGGG

CTTGACATATGGGTGAAGCGGGGGAGACCCCGTGGCCGAGAGGAGCCCATACAGGT

GGT GC AT GGCTGTCGT C AGCTCGTGTCGT GAGATGTTGGGTT AAGTCCCGC A ACGAG

CGCAACCCCCGCCGCGTGTTGCCATCGGGTGATGCCGGGAACCCACGCGGGACCGC

CGCCGTCAAGGCGGAGGAGGGCGGGGACGACGTCAAGTCATCATGCCCCTTATGCC

CTGGGCTGCACACGTGCTACAATGGCCGGTACAGAGGGATGCCACCCCGCGAGGGG

GAGCGGATCCCGGAAAGCCGGCCCCAGTTCGGATTGGGGGCTGCAACCCGCCCCCA

TGAAGTCGGAGTTGCTAGTAATCGCGGATCAGCATGCCGCGGTGAATGCGTTCCCGG

GCCTTGTACACACCGCCCGTCACACCACCCGAGTCGTCTGCACCCGAAGTCGCCGGC

CCAACCGTCAAGGGGGGAGGCGCCGAAGGTGTGGAGGGTGAGGGGGGTGAAGTCG

TAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGATCACCTCCTTT (SEQ ID NO: 39)

14LG Acidaminococcus intestini Appendix A

GACTTCACCCCAATCATNGGCCCCANTTAGACAGCTGACTCCTAAAAGGTTATCTCA

CCGGCTTCGGGTGTTACCAACTTTCGTGGTGTGACGGGCGGTGTGTACAAGGCCCGG

GAACGTATTCACCGCAGTATGCTGACCTGCGATTACTAGCGATTCCAACTTCACGTA

GGCGGGTTGCAGCCTACGATCCGAACTGGGGTCGGGTTTCTGGGATTTGCTCCACCT

CGCGGTTTCGCTGCCCTTTGTTGCCGACCATTGTAGTACGTGTGTAGCCCAAGACAT

AAGGGGCATGATGACTTGACGTCATCCCCGCCTTCCTCCAAGTTATCCCTGGCAGTC

TCCTATGAGTCCCCGCCTTTACGCGCTGGTAACATAGGATAGGGGTTGCGCTCGTTG

CGGGACTTAACCCAACATCTCACGACACGAGCTGACGACAGCCATGCACCACCTGT

TTTCGTGTCCCCGAAGGGAGGGACCTATCTCTAGGTCTTTCACTCAATGTCAAGCCT T

GGTAAGGTTCTTCGCGTTGCGTCGAATTAAACCACATACTCCACCGCTTGTGCGGGC

CCCCGTCAATTCCTTTGAGTTTCAATCTTGCGATCGTAGTCCCCAGGCGGGATACTT A

TTGCGTTAACTCCGGCACAGAAGGGGTCGATACCTCCTACACCTAGTATCCATCGTT

TACGGCCAGGACTACCGGGGTATCTAATCCCGTTTGCTACCCTGGCTTTCGCATCTC

AGCGTCAGACACAGTCCAGAAAGGCGCCTTCGCCACTGGTGTTCCTCCCAATATCTA

CGCATTTCACCGCTACACTGGGAATTCCCCTTTCCTCTCCTGCACTCAAGACTTCCA G

TATCCAACGCCATACGGGGTTAAGCCCCGCATTTTCACGTCAGACTTAAAAGCCCGC

CTACATGCTCTTTACGCCCAATAATTCCGGACAACGCTTGCCACCTACGTATTACCG

CGGCTGCTGGCACGTAGTTAGCCGTGGCTTCCTCGTTAGGTACCGTCAACACCATGA

CCTGTTCGAACACGGTGCTTTCGTCCCTAACAACAGAGTTTTACAATCCGAAGACCT

TCATCACTCACGCGGCGTTGCTCCGTCAGACTTTCGTCCATTGCGGAAGATTCCCCA

CTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCAGTCCCAATGTGGCCGTTCATCC T

CTCAGACCGGCTACTGATCATCGCCTTGGTGAGCCGTTACCCCACCAACTAGCTAAT

CAGACGCGGGCCCATCTTCCAGCGATAGCTTGCAAGCAGAGGCCATCTTTCCTCCCT

CCTCCATGCGGAGGAGGGAGCACATTCGGTATTAGCATCCCTTTCGGAATGTTGTCC

CCAACTGGAGGGCAGGTTGCCCACGCGTTACTCACCCGTTCGCCACTAAGAACTTAC

CGAAATAAGTTCTCCGTTCGACTTGCATGTGTTAAGCACGCCGCCAGCGTTCGTCCT

GAGCC (SEQ ID NO: 40)