Composition for use in the treatment of delayed colonization by bifidobacteria after birth

Description

Field of the invention

[0001] The present invention relates to therapeutic methods and compositions for therapeutic use in promoting or stimulating the development of a healthy gut microbiota in infants born with a lack of Bifidobacterium species at birth, such as where the mother received antibiotics during delivery (i.e. intrapartum antibiotic prophylaxis (IAP)) and particularly with infants delivered by Caesarean section.Background art

[0002] The worldwide rate of infant deliveries via Caesarean section 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 Caesarean section deliveries be indicated in 10 to 15 % of all deliveries, in many countries the rate of Caesarean section deliveries significantly exceeds this recommendation. Over the past years, the medical field has started to realise that a Caesarean section delivery introduces health risks, and the obstetrician is thus advised to assess these long- and short-term health consequences for mother and infant, as well as weigh the risks associated with the procedure itself against not performing the procedure.

[0003] In recent times the field has started to realize that infants delivered via Caesarean section suffer from the consequences of a non-existent transmission of gut microbiota from the mother to the infant at birth. EP1940250 (or US2016 / 100618) 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 from their own mother's vaginal and gut microbiota, C-section infants acquire bacterial communities from the maternal skin and the surrounding birth environment. EP1940250 (or US2016 / 100618) advocates the use of at least one Bifidobacterium species in combination with a non-digestible oligosaccharide, in order to normalize the gut microbiota in the infant. US2016 / 331792 describes methods and compositions for restoring normal microbiota in pre-term newborns or newborns delivered by Cesarean section and methods for preventing or ameliorating diseases associated with delivery by Cesarean section or pre-term birth comprising administering to said newborns at the time of birth or shortly thereafter an effective amount of a vaginal microbiota inoculum obtained from the newborn's mother or a donor or an effective amount of a probiotic composition.

[0004] Promoting or stimulating healthy gut microbiota in infants delivered by Caesarean section is considered a therapeutic use, given that said infants suffer from bifidobacteria deficits at birth. Compared to the normal 10 7< - 10 9< cfu bifidobacteria counts, an infant born by Caesarean section typically exhibits hardly any bifidobacteria at birth.

[0005] The delayed colonization by bifidobacteria lasts for longer periods, as evidenced in Figure 1A in Chua et al. "Effect of synbiotic on the gut microbiota of cesarean delivered infants: a randomized, double-blind, multicenter study" JPGN vol. 65(1) July 2017, and is believed to have an impact on all kinds of increased health risks associated with C-section such as occurrence or development of food allergy, eczema (e.g. atopic dermatitis), asthma, allergic rhinitis and / or allergic conjunctivitis.The delay in colonization by bifidobacteria can be minimized by administering to said C-section infants infant formula supplemented with synbiotic compositions comprising B. breve and non-digestible oligosaccharides (scGOS / IcFOS), thus restoring bifidobacteria levels within the first days of life (see Figure 1A in Chua et al.). Analysis by quantitative real-time polymerase chain reaction (qPCR) revealed that the synbiotic group showed a higher absolute gene count of bifidobacteria from the first days of intervention (p<0.0001) compared to the control group, and the effect remained significant until week 12 (p=0.032).Summary of the invention

[0006] It was found by the inventors that infants born by C-section that were either exclusively breastfed, or mixed fed, meaning breastfed and supplemented with an infant formula with or without added prebiotic, still exhibited a delayed colonization by Bifidobacterium species in the gut.

[0007] On the contrary, those infants born by C-section that were mixed fed with an infant formula supplemented with a synbiotic composition did not exhibit a delayed colonization by Bifidobacterium, or to a lesser extent. From this it was concluded that breastmilk did not redress the bifidobacteria deficiency, while intervention with synbiotics did.

[0008] More particularly, the inventors found that chronic administration of the synbiotic composition was not necessarily needed, and that bifidobacteria could be restored using ad hoc administration of the synbiotic composition of the invention.

[0009] Reference is made to example 3 as described herein. It is clear from Table 1D in example 3 that two shots in the first week after birth of B. breve M-16V and indigestible oligosaccharides are sufficient to initiate and maintain indigenous growth of bifidobacteria and to stimulate growth of indigenous B. breve, i.e. B. breve other than the strain administered. The support of indigenous bifidobacteria growth lasted for at least 22 weeks, in spite of the observation that the Bifidobacterium strain originally administered dropped rapidly after administration, and no further Bifidobacteria were administered after the above initial period of administration immediately after birth.

[0010] The inventors have thus found that the lack of bifidobacteria at birth can be tackled even faster if an infant born with a lack of Bifidobacterium species at birth is administered a composition comprising between 10 3< and 10 16< colony forming units (cfu) per serving of Bifidobacterium breve, preferably B. breve M-16V, and between 0.1-5 gram per serving of at least one indigestible oligosaccharide, wherein said non-digestible oligosaccharide comprises galactooligosaccharides (GOS) immediately after birth, i.e. once or twice within one week after birth, preferably once or twice within 5 days after birth, most preferably twice within 3 days after birth. That is, once or twice only, and within the first week after birth only, preferably within 5 days from birth, most preferably within 3 days from birth only. This is particularly suited for infants whose mothers received antibiotics during delivery and / or in infants delivered via C-section, most preferably in infants delivered via C-section.

[0011] Conveniently, there is no need to interfere with breastfeeding. Chronic administration of the synbiotic composition may thus conveniently be avoided and is preferably disclaimed. The acute treatment results in optimum effects, and bifidobacteria levels are restored to levels beyond 1*10 7< within 5 days from birth (Table 1D).

[0012] The administration of said composition is limited to once or twice within one week after birth only, preferably once or twice within 5 days after birth only, most preferably twice within 3 days after birth only. With the term 'only' it is intended that the synbiotic composition is preferably administered in said period exclusively. Surprisingly, the incidental and limited boost with B. breve and indigestible oligosaccharides promotes the endogenous growth of B. breve species, in infants born via caesarean section otherwise lacking bifidobacteria at birth, and all well within the first week, in fact even after 5 days after birth.

[0013] Based on these findings, the inventors realized a simplified way of redressing the impaired gut bifidobacteria in caesarean section delivered infants, regardless the mode of feeding, preferably in breastfed caesarean section delivered infants, by minimizing the administration with synbiotics to once or twice immediately after birth.

[0014] In a preferred embodiment, the C-section infant receives breastfeeding, which is still the golden standard and is known to further optimize the gut microbiota once the initial C-section associated delayed bifidobacteria colonization is solved.

[0015] The inventors believe that administration with one or two dosages of the synbiotic early in life also works advantageously for vaginally delivered infants lacking bifidobacteria at birth to an extent similar as the delayed levels reported for C-section delivered infants, for instance where the mother received antibiotics during delivery (Intrapartum Antibiotic Prophylaxis / IAP). In one embodiment, the infant born with a lack of Bifidobacterium species at birth is an infant from a mother receiving IAP.Description of embodiments

[0016] The inventors have found a method for therapeutically improving or stimulating the development of a healthy gut microbiota, by stimulating Bifidobacterium intra-species growth in infants born with a lack of Bifidobacterium species at birth, including infants where the mother received antibiotics during delivery (IAP), and particularly in the case of infants delivered via C-section, said method involving administering said infant, particularly an infant delivered via C-section, once or twice only a composition comprising between 10 3< and 10 16< colony forming units (cfu) per serving of Bifidobacterium breve, preferably a Bifidobacterium breve M-16V strain, and between 0.1-5 gram per serving of at least one non-digestible oligosaccharide, wherein said non-digestible oligosaccharide comprises galactooligosaccharides, more preferably therapeutically effective amounts of non-digestible galactooligosaccharides and fructans, wherein the composition is only administered to the infant once or twice, preferably an infant delivered via C-section, within the first week after birth only, preferably within 5 days, most preferably within 3 days from birth.

[0017] It is of utmost importance to improve and / or accelerate the development of the appropriate bifidobacteria population and Bifidobacterium species diversity in the gastrointestinal tract of said infants at the onset of life outside the womb. Without intervention, the bifidobacteria microbiota levels stay behind by a factor 1000 for C-section delivered infants compared to their normal delivery counterparts for a period of many weeks.

[0018] The invention pertains to a composition for therapeutic use in improving or stimulating the development of a healthy gut microbiota, by stimulating Bifidobacterium intra-species growth, in infants born with a lack of Bifidobacterium species at birth, preferably in infants whose mothers received antibiotics during delivery and / or in infants delivered via C-section, preferably in infants delivered via C-section, involving administering to the infant a composition comprising between 10 3< and 10 16< colony forming units (cfu) per serving of Bifidobacterium breve and between 0.1-5 gram per servingof at least one non-digestible oligosaccharide, wherein said non-digestible oligosaccharide comprises galactooligosaccharides, wherein the composition is administered to the infant once or twice only, and within the first week after birth only, preferably within 5 days from birth, most preferably within 3 days from birth only.

[0019] The composition is fed to said infant in the first week exclusively, preferably within 5 days from birth only, most preferably within 3 days from birth only.

[0020] In a preferred embodiment, the use involves stimulating the growth of indigenous B. breve species other than the B. breve M-16V strain administered.

[0021] Within the context of the invention, the composition comprising between 10 3< and 10 16< colony forming units (cfu) per serving of Bifidobacterium breve, preferably a Bifidobacterium breve M-16V strain, and between 0.1-5 gram per serving of at least one non-digestible oligosaccharide, wherein said non-digestible oligosaccharide comprises galactooligosaccharides,, more preferably therapeutically effective amounts of non-digestible galactooligosaccharides and fructans, may be referred to as the 'synbiotic composition'.

[0022] The composition according to one embodiment of the invention is for promoting indigenous bifidobacteria growth in the gut of an infant delivered via Caesarean section (C-section). In a preferred method according to the invention, the composition according to the invention is administered to an infant delivered via Caesarean section. Caesarean 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. A Caesarean section is typically performed when it is safer for the mother or the infant than a vaginal delivery, or in case the mother prefers to have a caesarean section rather than deliver her infant vaginally.

[0023] Infants born via Caesarean section are known to have an impaired or delayed gastrointestinal Bifidobacterium population, which is attributed to the mode of delivery. With an impaired or delayed bifidobacteria population it is generally understood total bifidobacteria levels are less than 1*10 6< cfu, preferably less than 1*10 5< cfu.

[0024] The consequences of improving the gastrointestinal Bifidobacterium population according to the invention are a reduced risk of occurrence or development of food allergy, eczema (e.g. atopic dermatitis), asthma, allergic rhinitis and / or allergic conjunctivitis in infants delivered by C-section.

[0025] 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.

[0026] 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.

[0027] The composition according to the invention is typically suitable for enteral administration to the infant. The composition may be provided in any form known in the art to be suitable for such administration, such as in solid form, in semi-solid form or in liquid form. Preferably, the composition is a nutritional composition or a nutritional supplement. The composition may be referred to as a nutritional composition, preferably a nutritional composition for providing nutrition to infants, in particular infants delivered via Caesarean section. Preferably, the composition is in the form of a liquid or in the form of a powder supplement, which can be reconstituted with a liquid (typically water) to obtain a liquid composition. Alternatively, the composition is in the form of a capsule or tablet. In one embodiment, the composition is not an infant formula.

[0028] The composition according to the invention is preferably a powder supplement, wherein the powder supplement weighs between 0.1-20 gram per serving, more preferably between 0.2-10 gram per serving and most preferably between 0.5-5 gram per serving.

[0029] The composition according to the invention is preferably a suppository, pill or tablet, wherein the suppository, pill or tablet weighs between 0.1-10 gram per serving, more preferably between 0.2-5 gram per serving and most preferably 0.5-2.5 gram per serving.

[0030] The B. breve strain is provided in therapeutically effective amounts. The present composition preferably contains between 10 3< and 10 13< colony forming units (cfu) B. breve per gram dry weight of the present composition, preferably between 10 4< and 10 12< , more preferably between 10 5< and 10 10< . Preferably, the present composition contains between 10 3< and 10 13< colony forming units (cfu) bifidobacteria per g dry weight of the present composition, more preferably between 10 4< and 10 12< , most preferably between 10 5< and 10 12< .

[0031] In terms of doses, the present composition provides between 10 3< and 10 16< cfu, more preferably between 10 4< and 10 15< cfu, most preferably between 10 5< and 10 12< cfu B. breve per serving. Preferably, the present composition provides between 10 3< and 10 16< cfu, more preferably between 10 4< and 10 15< cfu, most preferably between 10 5< and 10 12< cfu bifidobacteria per serving. An especially suitable strain of B. breve to be used in the present invention is B. breve M-16V.

[0032] In one embodiment, the composition does not comprise any Bifidobacterium species other than B. breve M-16V.

[0033] In one embodiment, stimulating the development of a healthy gut microbiota involves stimulating Bifidobacterium intra-species growth other than the Bifidobacterium species part of the synbiotic composition of the invention.

[0034] Preferably, the composition comprises B. breve in freeze-dried form, which is especially suitable when the composition is in powder, capsule or tablet form.

[0035] In one embodiment, the composition according to the invention comprises a mixture of galacto-oligosaccharides and fructans.

[0036] Galacto-oligosaccharides and fructans are non-digestible oligosaccharides, also referred to as a "prebiotic" or "prebiotic fibre". In the context of the present invention, the term "non-digestible oligosaccharide" refers to oligosaccharides which are not digested in the intestine by the action of digestive enzymes present in the upper digestive tract (small intestine and stomach) of the infant but instead are fermented by the intestinal microbiota of said infant, thus conferring benefits upon the host wellbeing and health.

[0037] Preferably the present non-digestible oligosaccharides have a degree of polymerisation (DP) of 2 to 250, preferably an average DP 2 to 100, more preferably 2 to 60. Preferably, at least 50 wt.% of the present non-digestible oligosaccharides have an average degree of polymerisation in the range of 2 to 60.

[0038] The terms "prebiotic" and "prebiotic fibre" refer to non-digestible fibres that beneficially affects the host by selectively stimulating the growth and / or activity of one or a limited number of bacterial species in the colon. Health effects of prebiotics, also in combination with probiotics, are described in Collins, Am. J. Clin. Nutr. 1999, 69(suppl.), 10525-10575.

[0039] Preferably, the present non-digestible oligosaccharide is soluble. The term "soluble" as used herein, when having reference to a fibre or oligosaccharide, means that the substance is at least 50% soluble according to the method described by Prosky et al. in J. Assoc. Off. Anal. Chem. 1988, 71, 1017-1023.

[0040] The non-digestible oligosaccharides of the invention comprise galacto-oligosaccharides, in particular beta-galacto-oligosaccharides. Herein, galactose units make up for at least 50% of the monosaccharide units. 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 trans-galacto-oligosaccharides. The galactose units are preferably beta-linked. The galacto-oligosaccharides preferably comprise saccharides with an average degree of polymerisation (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 Oligomate55 (Yakult).

[0041] Preferably, the non-digestible oligosaccharides may further comprise fructans. Preferred fructans include fructo-oligosaccharides, fructo-polysaccharides, inulin and mixtures thereof, most preferably fructo-oligosaccharides. Preferred fructo-oligosaccharides are short-chain fructo-oligosaccharides (scFOS), having an average DP in the range of 2 to 10, and long-chain fructo-oligosaccharide (IcFOS), having an average DP in the range of 10 to 60, preferably in the range of 15 - 40. scFOS is commercially available as Beneo ®< P95 or Raftilose P95 (Orafti). A particular type of IcFOS is inulin, such as Raftilin HP.

[0042] In an especially preferred embodiment, the present composition comprises galacto-oligosaccharides and fructo-oligosaccharides and / or fructo-polysaccharides, most preferably scGOS and IcFOS (preferably said IcFOS having an average DP > 15). In the present embodiment, galacto-oligosaccharides and fructans are preferably present in a weight ratio 5:1 - 20:1, even more preferably 7:1 - 15:1, even more preferably 8:1 - 10:1, most preferably about 9:1.

[0043] The non-digestible oligosaccharides are present in therapeutically effective amounts. The present composition preferably comprises 0.05 to 50 wt% of said non-digestible oligosaccharides, more preferably 0.5 to 25 wt%, even more preferably 1 to 15 wt%, most preferably 2 to 10 wt%, based on dry weight of the composition. In terms of doses, the present composition provides between 0.1 and 5 gram non-digestible oligosaccharides per serving.

[0044] Administration of the present composition to the infant preferably occurs by administering to the infant directly. Administration typically occurs enterally, i.e. directly into the gastrointestinal tract of the infant. Enteral administration includes oral administration, tube feeding, stoma feeding and rectal administration. Oral administration is preferred.

[0045] The composition may be in any form known in the art to be suitable for enteral administration, such as in solid form, in semi-solid form or in liquid form. The composition is preferably a powder suited to be reconstituted with water, a nutritional supplement, a suppository, a pill or a tablet. Wherever doses per serving are defined above for the composition according to the invention, the method according to the inventions preferably involves administration of a serving containing said dose.

[0046] In one embodiment, the composition is administered to the infant, provided in the form of (i) a liquid having a volume between 0.5 to 5 ml for oral administration, wherein said liquid is preferably administered to said infant with a syringe, pipette or tube; or (ii) a suppository, pill or tablet, and wherein said composition is administered to the infant rectally.

[0047] In one embodiment, the composition may be provided in the form of a 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). Preferably, the present composition is accompanied with instructions for use.Examples Example 1

[0048] A single use sachet comprising about 2 grams of a powdered composition for providing one serving. The powdered composition is suitable for addition to infant formula or breast milk in the first week after birth.

[0049] The serving comprises 1.0 g of scGOS / IcFOS (about 9:1 weight ratio), 9 x 10^8 cfu B. breve M-16V and soluble digestible carbohydrates. 'scGOS' were short-chain galactooligosaccharides (Vivinal-GOS ™< ; Borculo Domo Ingredients, Netherlands; Degree of Polymerisation [DP] 2 - 8), 'IcFOS' were long-chain fructooligosaccharides (Raftiline HP ™< , Orafti, Tienen, Belgium; average DP 22 - 25).Example 2

[0050] A total of 183 infants born to healthy pregnant mothers were enrolled in a clinical study. Eligible participants included healthy term neonates born by elective C-section. In the study, infants born by C-section were randomized to receive a control formula (n=50), or the same formula containing synbiotics (scGOS / IcFOS and Bifidobacterium breve M-16V, n=52), or prebiotics (scGOS / IcFOS, n=51) immediately after birth, for a period of 16 weeks, and a 6 weeks follow-up. Thirty subjects born vaginally were included as a non-randomized reference group.

[0051] Fecal samples were collected during the study to determine the efficacy of the nutritional intervention. The composition of the gut microbiota was determined through qPCR targeting total bacteria, total Bifidobacterium species, total B. breve species and the probiotic strain B. breve M-16V. The limit of detection in this assay was around 4.6 log 10 copies / g of feces, meaning that if for example no B. breve is present in the sample, then the qPCR measurement for B. breve will be 4.6 log 10 copies / g of feces.Example 3

[0052] The gut microbiota distributions that are described in Table's 1A-1D are taken from the clinical study, which is described in Example 2. Table's 1A-1D describe the levels of bacteria determined by qPCR in the stool samples of four individual subjects.

[0053] Table 1A (Subject 77) and 1B (Subject 150) show the gut microbiota distribution of two individual infants born via C-section who received breastfeeding from birth until day 2, and a mix of formula feeding (without synbiotics) and breastfeeding onwards. These 'control' infants did not receive the composition of the invention. For Table 1A, no bifidobacteria were detected at day 3; data are missing at day 5 and at week 2; for Table 1B, no bifidobacteria were detected at day 3, day 5 and week 2; data are missing at week 12. Both infants show increased bifidobacteria levels at week 4. Breast-milk was not found to redress bifidobacteria levels in C-section born infants 77 and 150 in the first weeks of life.

[0054] Table 1C (subject 74) shows the gut microbiota distribution of an individual infant born via C-section who received breastfeeding until day 5, followed by mixed feeding including synbiotic formula with B. breve M-16V and scGOS / IcFOS. No Bifidobacterium species and B. breve M-16V were detected at day 5; normal bifidobacteria levels were found at week 2. Data are missing for day 3.

[0055] Table 1D (subject 109) shows the gut microbiota distribution of an individual infant born via C-section who received breastfeeding, but also one shot of a formula (85ml, 0.7 g of scGOS / IcFOS, 6.4 × 10 8< cfu B. breve M-16V) at birth and another at day 2 (65ml, 0.5 g of scGOS / IcFOS, 4.9 × 10 8< cfu B. breve M-16V). Data are missing at day 3 and week 2. While B. breve M-16V levels drop rapidly after the two shots of the intervention formula, total bifidobacteria including B. breve show normal levels already at day 5. It evidences that the synbiotic shots according to the invention stimulate indigenous growth, at the onset. These normal bifidogenic levels are maintained even after 22 weeks. Since the level of B. breve species was maintained across the whole study period, those data indicate that a one / two shot supplementation of synbiotic in the first days of life promoted intra-species diversity of Bifidobacterium breve that was sustained by breastfeeding, and already after 5 days. Table 1A - Subject no. 77Count (log 10 copies / g of feaces) Day 3 Day 5 Wk 02 Wk 04 Wk 08 Wk 12 Wk 16 Wk 22 B. breve M-16V4.6--4.64.64.64.64.6B. breve4.7--8.388.477.787.847.29Total bifidobacteria4.6--8.528.297.587.867.10Total bacteria8.65--9.169.088.278.617.78 Table 1B - Subject no. 150 Count (log 10 copies / g of feaces) Day 3 Day 5 Wk 02 Wk 04 Wk 08 Wk 12 Wk 16 Wk 22 B. breve M-16V4.64.64.64.64.6-4.64.6B. breve4.74.74.74.79.12-8.748.37Total bifidobacteria4.64.64.67.768.21-7.698.05Total bacteria7.128.528.488.238.72-8.899.55 Table 1C - Subject no. 74 Count (log 10 copies / g of feaces) Day 3 Day 5 Wk 02 Wk 04 Wk 08 Wk 12 Wk 16 Wk 22 B. breve M-16V-4.67.447.357.258.729.176.84B. breve-4.77.867.677.588.929.327.05Total bifidobacteria-4.67.557.87.429.169.167.48Total bacteria-6.888.498.808.899.539.637.90 Table 1D - Subject no. 109 Count (log 10 copies / g of feaces) Day 3 Day 5 Wk 02 Wk 04 Wk 08 Wk 12 Wk 16 Wk 22 B. breve M-16V-7.69-4.64.64.64.64.6B. breve-7.81-8.047.467.578.037.99Total bifidobacteria-7.70-7.957.557.478.017.79Total bacteria-8.18-8.788.978.408.678.67

Claims

1. A composition for therapeutic use in improving or stimulating the development of a healthy gut microbiota, by stimulating Bifidobacterium intra-species growth, in infants born with a lack of Bifidobacterium species at birth, preferably in infants whose mothers received antibiotics during delivery and / or in infants delivered via C-section, preferably in infants delivered via C-section, involving administering to the infant a composition comprising between 103 and 1016 colony forming units (cfu) per serving of Bifidobacterium breve and between 0.1-5 gram per serving of at least one non-digestible oligosaccharide, wherein said non-digestible oligosaccharide comprises galactooligosaccharides, wherein the composition is administered to the infant once or twice only, and within the first week after birth only.

2. The composition for use according to claim 1, wherein said Bifidobacterium breve is Bifidobacterium breve M-16V.

3. The composition for use according to any one of the preceding claims, wherein said non-digestible oligosaccharide comprises short-chain galacto-oligosaccharides with an average degree of polymerisation (DP) of 2 to 10.

4. The composition for use according to any one of the preceding claims, wherein said non-digestible oligosaccharide comprises galactooligosaccharides and fructans.

5. The composition for use according to claim 4, wherein the fructans include fructo-oligosaccharides, fructo-polysaccharides, inulin and mixtures thereof, preferably short-chain fructo-oligosaccharides (scFOS) having an average DP in the range of 2 to 10 and / or long-chain fructo-oligosaccharide (IcFOS) having an average DP in the range of 10 to 60.

6. The composition for use according to any one of the preceding claims, wherein said composition is administered within 5 days from birth.

7. The composition for use according to any one of the preceding claims, wherein said infant is breastfed.

8. The composition for use according to any one of the preceding claims, stimulating Bifidobacterium intra-species growth other than the Bifidobacterium breve administered.

9. The composition for use according to any one of the preceding claims, wherein the composition is administered to the infant within 5 days from birth exclusively.

10. The composition for use according to any one of the preceding claims, wherein the composition is a powder supplement, a suppository, pill or tablet.

11. The composition for use according to claim 10, wherein the composition is a powder supplement, wherein the powder supplement weighs between 0.1-20 gram per serving; or wherein the composition is a suppository, pill or tablet, wherein the suppository, pill or tablet weighs between 0.1-10 gram per serving.