FIELD OF THE INVENTION

The present invention pertains to methods for improving or stimulating the healthy gut microbiota and/or reducing health risks and/or prevention of disorders in infants delivered via caesarean section (C-section).

BACKGROUND OF THE INVENTION

At birth, human infants start accumulating intestinal microbiota until a relatively stable state is reached. Mode of feeding, the duration of gestation and mode of delivery all affect the rate and trajectory of acquisition of a gut microbiota, which in turn are believed to have a considerable impact on health later in life. Preterms suffer from a permeable, immature intestinal barrier that has yet to develop and which gut immaturity plays an important role in inflammation, infections, diarrhoea and atopic diseases including food allergies.

While the above has been in the art for some time, it is only more recent that the field has become aware that C-section delivered infants - regardless duration of gestation or subsequent mode of feeding - suffer from the consequences of a non-existent transmission of gut microbiota from the mother to the infant at birth, and where colonisation of the infant is impaired. EP1940250 has clarified there is a complete lack of any detectable amounts of Bifidobacterium species in the gut of C-section infants compared to the presence of significant amounts of at least three different Bifidobacterium species of the group of B. longum, B. breve, B. infantis, B. catenulatum, B. pseudocatenulatum, B. adolescentis, B. animalis, B. gallicum, B. lactis and B. bifidum observed in infants born by natural birth. While vaginally delivered infants acquire bacterial communities resembling their own mother's vaginal and gut microbiota, C-section infants harbour bacterial communities similar to those found on the skin surface. All has been illustratively confirmed by Dominguez-Bello et al. "Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns" PNAS (2010) 107 no. 26 11971 - 11975. Yet, the worldwide rate of C-section deliveries has increased over the last decade, making it the most common surgical procedure performed in women of childbearing age today. While the WHO recommends that C-section deliveries be indicated in up to 15 % of all deliveries, in many countries the rate of C-section deliveries significantly exceeds this recommendation.

Over the past years, the medical field has started to realise that a C-section delivery introduces health risks, and the obstetrician is thus advised to assess these long- and short-term health consequences for mother and baby, as well as weigh the risks associated with the procedure itself against not performing the procedure. Laubereau et al. "Caesarean section and gastrointestinal symptoms, atopic dermatitis and sensitisation during the first year of life ^' " Arch. Dis. Child (2004) 89: 993-997 concluded that C-section delivery might be a risk factor for diarrhoea and allergic sensitisation in infants with family history of allergy. Similarly, Hakansson et al. "Caesarean section increases the risk of hospital care in childhood for asthma and gastroenteritis" Clin. Exp. Allergy (2003) 33 : 757-764 described that there was a significant increase of the risk for developing symptoms of asthma and/or gastroenteritis in C-section delivered children, and this increased risk was speculated to be linked to the disturbed intestinal colonisation pattern. These increased health risks associated with C-section delivery are reviewed in Cho et al. "Cesarean section and development of the immune system in the offspring" Am. J. Obstetrics & Gynecology (2012). Furthermore, C-section infants are believed to have an increased risk of developing obesity later in life. Needless to say, in view of foregoing, the art is in need of a solution to restore gut microbiota of C-section delivery infants to those corresponding with normal delivery infants, and as soon as possible after birth.

SUMMARY OF THE INVENTION

Infants delivered via C-section have an intestinal microbiota which is different from the intestinal microbiota of infants born via the vaginal route. This is once more confirmed further below in Figure 1 in the experimental part. Particularly, infants born via C- section have a reduced rate of intestinal colonisation by Bifidobacteria and have a less diverse Bifidobacterium intestinal microbiota with regards to species than infants born via the vaginal route, particularly lacking Bifidobacterium breve, Bifidobacterium longum longum subsp. longum. Bifidobacterium infantis and Bifidobacterium bifidum. Also, the intestinal microbiota of infants delivered via C-section have a high content of (undesirable) Enter ob acted aceae such as Klebsiella, and Escherichia coli, from birth.

As evidenced in the experimental parts, particularly Figure 1 therein, the differences are most profound in first few weeks, with a Bifidobacterium microbiota population that is 100 x lower for C-section delivery infants than for the reference normal delivery infants, before the Bifidobacterium population of C-section deliverey infants eventually recovers, after about 16 weeks. The inventors found that these C-section specific issues of lack of Bifidobacterium species in the period subsequent to birth can be addressed - and the Bifidobacterium microbiota population recovered, to achieve levels of microbiota in C-section infants that resemble those observed from the reference group of infants (being vaginally delivered), using a probiotic Bifidobacterium species.

Figures 2 and 3 show that it is possible to improve the bifidobacteria microbiota population and achieve bifidobacteria microbiota levels resembling those observed from the reference group of infants (being vaginally delivered) when the C-section infant is provided with the probiotic species early after birth, significantly improving and accellerating Bifidobacterium microbiota population within 3 days, substantially restoring levels within 5 days, and restoring levels to those of a healthy normal delivery breast-fed infant within to weeks. The inventors also found it may be advantageous to administer the probiotic species to the infant in small volume dosages, e.g. by 'inoculating' the infant. A booster form seems most suited, particularly considering the best timing of the intervention. While the advantageous effects are achieved within the first few days after birth, these are the initial feeding stages where patterns have yet to be established. In view thereof, the inventors have found a method for (a) improving or stimulating the health of gut microbiota and/or (b) reducing health risks and/or (c) prevention of disorders in infants delivered via C-section, said method involving providing an infant delivered via C-section with a composition comprising a therapeutically effective amount of at least one probiotic Bifidobacterium species selected from the group consisting of Bifidobacterium breve, Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis and Bifidobacterium bifidum, and optionally a therapeutically effective amount of at least one non-digestible prebiotic oligosaccharide, wherein the composition is administered to the infant delivered via C- section starting at least in the first sixteen weeks after birth, preferably at least within twelve weeks after birth, even more preferably at least within eight weeks after birth, most preferably at least within four weeks after birth. Suitably, the composition is administered to the infant delivered via C-section started at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth. It is of utmost importance to improve and/or accelerate developing the appropriate bifidobacteria population and Bifidobacterium species diversity in the gastrointestinal tract of C-section delivered infants at the onset of life outside the womb, the bifidobacteria microbiota levels staying behind by a factor 100 for C-section delivered infants compared to their normal delivery counterparts.

The consequences of improving the gastrointestinal Bifidobacterium population in terms of numbers and diversity of species according to the invention are a reduced risk of occurrence or development of allergy, preferably food allergy, eczema (e.g. atopic dermatitis), asthma, allergic rhinitis and/or allergic conjunctivitis in infants delivered by C-section. Improvement of the gastrointestinal Bifidobacterium population in terms of numbers and diversity of species may also result in a reduced risk of infections, including gastrointestinal infections, and reducing the occurrence and/or severity of infections including gastrointestinal infections. C-section has also been associated with increased risks of developing allergies and obesity later in life, and the improvements in terms of swift microbiota restoration achieved by the invention thus also relate to reducing the risks of developing allergies and obesity later in life. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a comparison of the reference group and the control group in terms of total Bifidobacteria levels over the time period from day 3-5 until week 22, demonstrating that C-section infants (without any supplemented intervention) experience delayed colonisation of bifidobacteria compared to vaginally delivered and breast-fed infants.

Figure 2 shows the same graph from Figure 1 with the addition of the results from the prebiotic group and the synbiotic group. In these results, it can be observed that levels of bifidobacteria in the synbiotic group were achieved that resemble those observed from the reference group of infants.

Figure 3 shows the percentage of bifidobacteria in each group relative to total bacteria at day 3-5, demonstrating that the effect of the synbiotic group generally described in Figure 2 could be observed from very early days of life.

DETAILED DESCRIPTION OF THE INVENTION

The invention pertains to infants born via caesarean section. A caesarean section (C- section) is a surgical procedure where an infant is delivered through an incision made in the mother's abdominal wall, and then through the wall of the uterus. The infant delivered via C-section may be either term or preterm human infant, where a "preterm infant" is a human infant born before 37 weeks of gestation and a "term infant" is a human born at 37 weeks or later of gestation.

The invention particularly pertains to a method for (a) improving or stimulating a healthy gut microbiota and/or (b) reducing health risks and/or (c) prevention of disorders in infants delivered via caesarean section (C-section), said method involving providing an infant delivered via C-section with a composition comprising a therapeutically effective amount of at least one probiotic Bifidobacterium species selected from the group consisting of Bifidobacterium breve, Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis and Bifidobacterium bifidum, wherein the composition is administered to the infant delivered via C-section starting at least in the first sixteen weeks after birth or any of the preferred time windows described herein. In the context of the invention, the health risks and disorders according to embodiments (b) and (c) are preferably understood being risks and disorders associated with the impaired gut microbiota, particularly the lack of bifidobacteria microbiota that a C-section delivery infant experiences. The invention also pertains to the use of a composition for the manufacture of a medicament for (a) improving or stimulating a healthy gut microbiota and/or (b) reducing health risks and/or (c) prevention of disorders in infants delivered via caesarean section (C-section), wherein said composition comprises a therapeutically effective amount of at least one probiotic Bifidobacterium species as described herein, and wherein the composition is administered to the infant delivered via C-section starting at least in the first sixteen weeks after birth or any of the preferred time windows described herein. The invention also pertains to a composition for use in (a) improving or stimulating a healthy gut microbiota and/or (b) reducing health risks and/or (c) prevention of disorders in infants delivered via caesarean section (C-section), wherein said composition comprises a therapeutically effective amount of at least one probiotic Bifidobacterium species as described herein, and wherein the composition is administered to the infant delivered via C-section starting at least in the first sixteen weeks after birth or any of the preferred time windows described herein.

It is a preferred option of the above method, use and composition for use that the composition further comprises a therapeutically effective amount of at least one non- digestible prebiotic oligosaccharide as described herein.

Probiotic Bifidobacterium species

The composition according to the invention comprises a probiotic Bifidobacterium species. In the context of the present invention, the term "probiotic" refers to a strain of bacteria which is perceived as probiotic bringing a health benefit to the targeted infants delivered via C-section. Probiotic bifidobacteria are known in the art. It should be noted that it is preferably neither the object nor the effect of the treatment of the invention to promote colonisation by the species of probiotic that is administered but rather to promote colonisation also with other lactic acid producing bacteria, preferably bifidobacteria species so as to achieve an early bifidogenic intestinal microbiota comparable with that found in healthy, breast-fed, vaginally-delivered infants. Thus, in one embodiment, the improvement or stimulation of a healthy gut microbiota concerns the promotion of the bifidobacteria! colonization of gut of C-section infants, preferably the colonization of at least one Bifidobacterium species other than the one(s) present in the composition according to the invention is promoted. Thus, in an especially preferred embodiment, the composition according to the invention comprises B. breve (preferably the sole added probiotic) and the improvement or stimulation of a healthy gut microbiota concerns the promotion of the intestinal colonization of at least one, preferably at least two Bifidobacterium species other than B. breve.

The present composition preferably comprises at least one Bifidobacterium selected from the group consisting of B. breve, B. longum subsp. longum, B. longum subsp. infantis, B. bifidum and B. catenulatum, even more preferably at least one Bifidobacterium selected from the group consisting of B. breve and B. longum subsp. longum, most preferably at least B. breve.

In one embodiment, the composition comprises at least two different Bifidobacterium species, preferably including at least one, more preferably two of the above list, more preferably B. breve and B. longum subsp. longum. In one embodiment, the present composition comprises at least three, most preferably at least four different Bifidobacterium species. In a preferred embodiment, the composition comprises a maximum of one or two Bifidobacterium species. The above-mentioned combinations commonly aim to increase the diversity and/or the quantity of microorganisms in the intestine of the C-section delivered infant.

In one embodiment, the probiotic species in the composition consists of one or two, preferably one of the above Bifidobacterium species, and the probiotics in the composition preferably consists of B. breve and B. longum subsp. longum, most preferably consists of B. breve.

In one embodiment, the present composition further comprises a Lactobacillus selected from the group consisting of L. casei, L. reuteri, L paracasei, L. rhamnosus, L. acidophilus, L. johnsonii, L. lactis, L. salivarius, L. crispatus, L. gasseri, L. zeae, L. fermentum and L. plantarum, more preferably L. casei, L. paracasei, L. rhamnosus, L. johnsonii, L. acidophilus, L. fermentum and most preferably L. paracasei. The probiotic(s) is(are) present in the composition in a therapeutically effective amount or "amount effective for treating" in the context of the invention. Suitably, the probiotic is included in the present composition in an amount of 10 ² - 10 ¹³ cfu per g dry weight of the composition, suitably 10 ⁵ - 10 ¹² cfu/g, most suitably 10 ⁷ - 10 ¹⁰ cfu/g. The aforementioned content of probiotics is especially suitable in case the composition according to the invention is a complete nutrition, in particular an infant formula. In case the composition according to the invention is in the form of a supplement to be added to a nutritional product, the content of the probiotics therein is preferably such that after admixing with the nutritional product, the final product that is to be administered comprises prebiotics in the aforementioned amounts. The supplement according to the invention may contain probiotics in an amount of 10 ⁴ to 10 ¹⁶ cfu/g,

7 13 10 12

suitably 10 to 10 cfu/g, more suitably 10 to 10 cfu/g, based on dry weight of the supplement. Non-digestible prebiotic oligosaccharides

Preferably the present composition comprises at least one non-digestible prebiotic oligosaccharide. The term "oligosaccharide" as used in the present invention refers to saccharides with an average degree of polymerization (DP) of 2 to 250, preferably an average DP 2 to 100, more preferably 2 to 60.

In the context of the present invention, the term "prebiotic" refers to one or more non- digestible oligosaccharides. Advantageously, the non-digestible oligosaccharide is water-soluble (according to the method disclosed in L. Prosky et al, J. Assoc. Anal. Chem 71 : 1017-1023, 1988). Non-digestible oligosaccharides are not digested in the intestine by the action of digestive enzymes present in the upper digestive tract (small intestine and stomach) of the C-section infant but instead are fermented by the intestinal microbiota of said infant, thus conferring benefits upon the host wellbeing and health. Preferably the growth of at least bifidobacteria and preferably also Lactobacilli is stimulated. An increased content of bifidobacteria and/or lactobacilli stimulate the formation of a healthy intestinal microbiota.

Suitable non-digestible oligosaccharides are selected from the group consisting of fructo-oligosaccharide, non-digestible dextrin, galacto-oligosaccharide, xylo- oligosaccharide, arabino-oligosaccharide, arabinogalactooligosaccharide, gluco- oligosaccharide, glucomannooligosaccharide, galactomanno-oligosaccharide, mannanoligosaccharide, chito-oligosaccharide, uronic acid oligosaccharide, sialyl- oligosaccharide and fuco-oligosaccharide. In some embodiments, the non-digestible oligosaccharides comprise those obtainable from human milk.

The present non-digestible oligosaccharide is preferably selected from the group consisting of galacto-oligosaccharides and fructo-oligosaccharides (including fructo- polysaccharides such as inulin). Preferably at least 50 wt.% of the present non- digestible oligosaccharides have an average degree of polymerisation of 2 to 60. In one embodiment, the non-digestible oligosaccharide comprises galacto-oligosaccharides, in particular β-galacto-oligosaccharides. The galacto-oligosaccharides are preferably [galactose] _n -glucose; wherein n is an integer between 1 and 60, i.e. 2, 3,4,5, 6,...., 59, 60; preferably n is 2, 3, 4, 5, 6, 7, 8, 9 and/or 10, a good example being tram'-galacto- oligosaccharides. The galacto-oligosaccharides preferably comprise saccharides with an average DP of 2 to 10 (scGOS). (Trans)galactooligosaccharide is for example available under the trade name Vivinal®GOS (Borculo Domo Ingredients, Zwolle, Netherlands), Bimuno (Clasado), Cup-oligo (Nissin Sugar) and 01igomate55 (Yakult). Fructo-oligosaccharides may be inulin hydrolysate products having an average DP within the aforementioned (sub-)ranges. Such fructo-oligosaccharide products are for instance commercially available as short-chain fructo-oligosaccharide (scFOS), e.g. the product sold under the trade mark Beneo® P95 or Raftilose P95 (Orafti). A particular type of long-chain fructo-oligosaccharide (lcFOS) is inulin, such as Raftilin HP. In a particular preferred embodiment the present composition comprises at least galacto-oligosaccharides and fructooligosaccharides and/or fructopolysaccharides, preferably scGOS and lcFOS, suitably in a weight ratio 5 : 1 - 20: 1, even more suitably 7: 1 - 15: 1, even more suitably 8: 1 - 10: 1, most suitably about 9: 1. The prebiotics are present in therapeutically effective or prebiotic amount. The present composition suitably comprises 0.05 to 20 wt% of said non-digestible oligosaccharides, more suitably 0.5 to 15 wt%, even more suitably 1 to 10 wt%, most suitably 2 to 10 wt%, based on dry weight of the present composition. The aforementioned content of prebiotics is especially suitable in case the composition according to the invention is a complete nutrition, in particular an infant formula. In case the composition according to the invention is in the form of a supplement to be added to a nutritional product, the content of the prebiotics therein is preferably such that after admixing with the nutritional product, the final product that is to be administered comprises prebiotics in the aforementioned amounts. A supplement according to the invention may contain prebiotics in a amounts of 0.5 to 80 wt%, suitably 1 to 50 wt%, more suitably 5 to 30 wt%, based on dry weight of the supplement. LCPUFAs

The composition may further comprise long chain polyunsaturated fatty acids (LC- PUFA). LC-PUFA are fatty acids wherein the acyl chain has a length of 20 to 24 carbon atoms (preferably 20 or 22 carbon atoms) and wherein the acyl chain comprises at least two unsaturated bonds between said carbon atoms in the acyl chain. More preferably the present composition comprises at least one LC-PUFA selected from the group consisting of eicosapentaenoic acid (EPA, 20:5 n3), docosahexaenoic acid (DHA, 22:6 n3), arachidonic acid (ARA, 20:4 n6) and docosapentaenoic acid (DP A, 22:5 n3), comprising at least DHA. LC-PUFA further have anti-inflammatory effects and promote the adhesion of lactic acid producing bacteria to mucosal surfaces, thereby stimulating the development of a healthy microbiota, which are further advantages for use in C-section delivered infants. The LC-PUFA may be provided as free fatty acids, in triglyceride form, in diglyceride form, in monoglyceride form, in phospholipid form, or as a mixture of one of more of the above. The present composition preferably comprises at least one of ARA and DHA in phospholipid form.

Administration

The composition is enterally administered, and the term "enteral" is intended to refer to the delivery directly into the gastrointestinal tract of the infant (e.g., orally or via a tube, catheter or stoma), but it also encompasses rectal or anal administration.

The present composition may be in any form known in the art, such as in solid form, in semi-solid form or in liquid form. Preferably, the composition is a nutritional composition or a nutritional supplement, preferably in the form of a powder, capsule or tablet. The composition is not a human milk composition. Preferably, the composition comprises the probiotic in freeze-dried form, which is especially suitable when the composition is in powder, capsule or tablet form. Preferably, the present composition, when in powder, capsule or tablet form, especially when in powder form, is contained within a container, preferably a stick or stickpack or a sachet.

In some embodiments, the composition of the invention is in the form of complete nutrition. Suitably, the composition is intended for oral administration. For instance, the composition may comprise an infant formula, preferably in powder form suited to be reconstituted with water. In one preferred embodiment, the composition according to the invention is an infant formula.

An infant formula for use according to the present invention may contain a protein source in an amount of not more than 2.0 g/lOOkcal, preferably 1.8 to 2.0 g/lOOkcal. The protein preferably provides 5 to 15% of the total calories. Preferably the composition comprises protein that provides 6 to 12% of the total calories. More preferably protein is present in the infant formula below 9% based on calories. The source of the protein should be selected in such a way that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Hence protein sources based on cow's milk proteins such as whey, casein and mixtures thereof and proteins based on soy, potato or pea are preferred. Preferably, the infant formula comprises casein and whey protein. In case whey proteins are used, the protein source is preferably based on acid whey or sweet whey, whey protein isolate or mixtures thereof and may include alpha-lactalbumin and alpha-lactoglobulin. More preferably, the protein source is based on acid whey or sweet whey from which caseino-glyco- macropeptide (CGMP) has been removed. Preferably the infant formula comprises casein, preferably it comprises at least 3 wt.% casein based on dry weight. Preferably the casein is intact and/or non-hydrolyzed. For the present invention protein includes peptides and free amino acids. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in whatever proportions are desired. The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. The infant formula may contain a carbohydrate source. Any carbohydrate source conventionally found in infant formulae such as lactose, saccharose, maltodextrin, starch and mixtures thereof may be used although the preferred source of carbohydrates is lactose. Preferably the carbohydrate sources contribute between 35 and 65% of the total energy of the formula. The infant formula may also contain a source of lipids. The lipid source may be any lipid or fat which is suitable for use in infant formulas. Suitably the infant formula contains at least one, suitably at least two lipid sources selected from the group consisting of rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), high oleic sunflower oil, high oleic safflower oil, olive oil, marine oils, microbial oils, coconut oil, palm kernel oil and milk fat. The lipid component of the infant formula suitably provides 2.9 to 6.0 g, more suitably 4 to 6 g per 100 kcal of the composition. When in liquid form, the infant formula suitably comprises 2.1 to 6.5 g lipid per 100 ml, more suitably 3.0 to 4.0 g per 100 ml. Based on dry weight the infant formula suitably comprises 12.5 to 40 wt% lipid, more suitably 19 to 30 wt%. The fat source preferably has a ratio of n-6 to n-3 fatty acids of about 5: 1 to about 15: 1; for example about 8: 1 to about 10: 1. The infant formula may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the infant formula include vitamin A, vitamin B l, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The infant formula may optionally contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.

In other embodiments, the composition of the invention is not in the form of complete nutrition. In such embodiments, the composition of the invention may be intended to be administered to the infant directly and in addition to breast-milk or infant formula ingested by the infant. Such compositions are typically of small size, e.g. 0.5 - 5 ml or 0.5 - 5 g, and may be referred to as supplement or fortifier. In one aspect, the invention thus pertains to a method for the manufacture of a nutritional product for infants born via caesarean section comprising admixing: (i) human breast milk, infant formula or a mixture thereof; and (ii) the composition (e.g. supplement or fortifier) according to the invention. In a further embodiment, the invention concerns a method for providing nutrition to an infant, said method comprising the admixing of (i) and (ii) to manufacture a nutritional product as defined above and administering the nutritional product to an infant born via caesarean section, preferably in the aforementioned short time frames after birth.

The 'small volume' compositions may also be administered to the infant, e.g. by 'inoculating' the infant, preferably with a syringe, pipette or tube, thus especially useful for C-section infants in hospital settings. In case of oral administration, the composition is preferably administered in liquid form having a volume between 0.5 to 5 ml. The compositions may be provided in the form of unit dose form, which refers to individual single-use packages. The composition may be present in a container containing one single or more unit dose(s).

In some other embodiments, the composition of the invention is intended to be added to another product before ingestion by the infant. Preferably, the present composition is accompanied with instructions to add the composition to a nutritional product before ingestion. The nutritional product to which the present composition is to be added may be any suitable nutritional product for C-section infants, such as breast-milk or infant formula.

In a further preferred embodiment, the present composition is rectally or anally administered to the infant delivered via C-section, preferably in the form of a suppository, pill or tablet. Hence, the present invention also provides a suppository, pill or tablet suitable for rectal administration to the infant, comprising the composition according as detailed here above. Any base components commonly used for suppositories can be used as a base component of the suppository of the present invention, including oils and fats, waxes, and the like of animal, vegetable or mineral origins. They may be partially or totally synthesised materials. Applications

The composition of the present invention is for improving or stimulating the healthy gut microbiota and/or reducing health risks and/or prevention of disorders in infants delivered via C-section.

Suitably, the composition is administered to the infant delivered via C-section starting at least in the first sixteen weeks after birth, preferably at least within twelve weeks after birth, more preferably at least within eight weeks after birth, even more preferably at least within four weeks after birth. The present inventors observed that the composition of the present invention achieved levels of bifidobacteria in the C-section infants which resembled those of the reference group of vaginally-born infants in the first sixteen weeks after birth. In embodiments where the composition is administered in small volume booster form, the treatment of the C-section delivery infant may be limited to the first sixteen weeks after birth, preferably the first twelve weeks after birth, more preferably the first eight weeks after birth, even more preferably the first four weeks after birth, particularly to the first two weeks after birth.

It is of utmost importance to improve and/or accelerate developing the appropriate Bifidobacteria population and Bifidobacterium species diversity in the gastrointestinal tract of C-section delivered infants at the onset of life outside the womb, and that will contribute to create a favourable gut ecosystem milieu through their metabolic capability. It is thus preferred that the composition is administered to the infant delivered via C-section starting at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth. It shows from Figures 2 and 3 that the impact is most dramatic in the early onset. In one embodiment, administration to the C-section infant is started at least one day after birth. Improvement of the gastrointestinal Bifidobacterium population in terms of numbers and diversity of species results in a reduced risk of occurrence of allergy, preferably food allergy, eczema (e.g. atopic dermatitis), asthma, allergic rhinitis and/or allergic conjunctivitis in infants delivered by C-section. Improvement of the gastrointestinal Bifidobacterium population in terms of numbers and diversity of species may also result in a reduced risk of infections, including gastrointestinal infections, and including reducing the occurrence and/or severity of infections, such as infections due to reduction of intestinal concentrations of pathogens particularly Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus haemolyticus, Streptococcus, Clostridium difficile, Bacilus subtilis, Pseudomonas aeruginosa, Enter obacter, Klebsiella, Acinetobacter, Proteus, Aeromonas and Escherichia coli. This is achieved by (i) stimulating the growth of the lactic acid producing bacteria, (ii) decreasing the growth of pathogenic bacteria; and/or (iii) decreasing the adhesion of pathogenic bacteria to the intestinal epithelial cells and/or intestinal mucus.

C-section has also been associated with increased risks of developing allergies and obesity later in life, and the improvements in terms of swift microbiota restoration achieved by the invention thus also relate to reducing the risks of developing allergies and obesity later in life, meaning at an age exceeding the age at which the infant receives the composition, suitably exceeding the age by at least 12 months, more suitably by 24 months, by 36 months, by 5 years, most suitably by 8 years. Suitably, "later in life" means at toddler age, childhood age, adolescence age, or adult age.

In this document and in its claims, the verb "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". EXAMPLES Example 1:

Method & Materials: In a multi-country, double-blind, randomised controlled study, infants born by C-section were randomly assigned to receive (1) a standard infant formula (control group, n = 45), (2) the standard formula supplemented with scGOS/lcFOS (about 9: 1 weight ratio) (0.8g/100ml) (prebiotic group, n = 39), and (3) the standard formula supplemented with scGOS/lcFOS (about 9: 1 weight ratio) (0.8g/100ml) and B. breve M-16V (7.5 l0 ⁸ CFU/lOOml) (i.e. synbiotic group, n = 45), from birth until age 16 weeks. 'scGOS' are short-chain galactooligosaccharides (Vivinal-GOS™; Borculo Domo Ingredients, Netherlands; Degree of Polymerisation [DP] 2 - 8), 'lcFOS' are long-chain fructooligosaccharides (Raftiline HP™, Orafti, Tienen, Belgium; average DP 22 - 25). One further group of infants delivered vaginally and breastfed as long as possible were included as the reference group (n = 28).

Stool samples were collected at day 3 - 5, week 2, week 4, week 8, week 12, week 16, and week 22 (6 weeks post-intervention). Bifidobacteria levels were analysed by q- PCR. Faecal pH and short chain fatty acids (SCFA) were assessed.

Results: The results are shown in the figures and described below.

Figure 1 shows a comparison of the reference group and the control group in terms of total Bifidobacteria levels over the time period from day 3-5 until week 22, demonstrating that C-section infants (without any supplemented intervention) experience delayed colonisation of bifidobacteria compared to vaginally delivered and breast-fed infants.

Figure 2 shows the same graph from Figure 1 with the addition of the results from the prebiotic group and the synbiotic group. In these results, it can be observed that levels of bifidobacteria in the synbiotic group were achieved that resemble those observed from the reference group of infants. Figure 3 shows the percentage of bifidobacteria in each group relative to total bacteria at Day 3-5, demonstrating that the effect of the synbiotic group generally described in Figure 2 could be observed from very early days of life. In terms of the faecal pH and SCFA analysis, it was noted that the synbiotic group resulted in a favourable pH intestinal milieu in the C-section delivered infants (data not shown), and that the lower pH in the synbiotic group could be attributed to a high production of acetate (data not shown).