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WO2025190540A1 - Stimulation de bactéries productrices de butyrate dans le microbiome intestinal - Google Patents

Stimulation de bactéries productrices de butyrate dans le microbiome intestinal

Info

Publication number
WO2025190540A1
WO2025190540A1 PCT/EP2025/051052 EP2025051052W WO2025190540A1 WO 2025190540 A1 WO2025190540 A1 WO 2025190540A1 EP 2025051052 W EP2025051052 W EP 2025051052W WO 2025190540 A1 WO2025190540 A1 WO 2025190540A1
Authority
WO
WIPO (PCT)
Prior art keywords
infant
butyrate
age
bifidobacterium
combination
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/051052
Other languages
English (en)
Inventor
Marc GARCIA-GARCERA
Shaillay Kumar Dogra
Elizabeth FORBES-BLOM
Norbert Sprenger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Nestle SA
Original Assignee
Societe des Produits Nestle SA
Nestle SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Publication of WO2025190540A1 publication Critical patent/WO2025190540A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is related to probiotics and prebiotics for use in promoting butyrate- producing bacteria in the gut microbiome of annfant or young child. of the Invention
  • Bifidobacterium Co-administration of Bifidobacterium and butyrate producers has been described.
  • Bifidobacterium produce lactate/acetate which can be consumed by co-localised butyrate-producing bacteria.
  • the present invention is based, at least in part, on the inventors’ determination that early colonization of the infant gut microbiome with infant-type Bifidobacterium promotes the subsequent abundance and function of butyrate-producing bacteria in the gut microbiome
  • the inventors have determined a negative association between bifidobacteria and butyrate- producing bacteria in multiple cohorts and across ages, indicating a replacement of bifidobacteria with butyrate-producing taxa as the infants get older. Further, in a longitudinal analysis, the inventors determined a positive association in multiple cohorts between infanttype bifidobacteria in infants below 10 months old, and later abundance of butyrate-producing bacteria taxa from 15 months old.
  • HMOs human milk oligosaccharides
  • the present invention provides a bifidogenic prebiotic for use in promoting butyrate-producing bacteria in the gut microbiome of an infant or young child; wherein the bifidogenic prebiotic is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention provides a Bifidobacterium microorganism for use in promoting butyrate-producing bacteria in the gut microbiome of an infant or young child; wherein the Bifidobacterium is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention provides a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism for use in promoting butyrate-producing bacteria in the gut microbiome of an infant or young child wherein the combination is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention provides a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism for use in treating and/or preventing an allergy and/or allergic sensitization in an infant or young child by promoting butyrate-producing bacteria in the gut microbiome of the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate- producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention in another aspect, relates to a use of a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to promote butyrate-producing bacteria in the gut microbiome of the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate- producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention provides a method of promoting butyrate-producing bacteria in the gut microbiome of an infant or young child comprising administering a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • the invention relates to method of treating and/or preventing an allergy and/or allergic sensitization in an infant or young child by promoting butyrate-producing bacteria in the gut microbiome of the infant or young child; comprising administering a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to the infant prior to about 12 months of age; and administration of bifidogenic prebiotic, Bifidobacterium microorganism or a combination promotes butyrate-producing bacteria in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • Figure 1 Scatterplot showing the relationship between the relative abundance of infant type Bifidobacterium spp. at ages below 6 months and the relative abundance of butyrate producers at ages of 12 months and after. Each dot represents one participant; blue line with grey shade represents the non-linear regression line. Values on the top-left corner represent the Spearman correlation coefficient and its associated p-value.
  • Figure 2 Heatmap showing the relationship between different Bifidobacterium species and butyrate producers in two different populations (Central Europe and South Asia).
  • X axis on TOP
  • Bif Bifidobacterium spp.
  • BP Butyrate producers
  • Y axis on the left
  • MH South Asia, Bangladesh
  • ON Central Europe
  • Each coloured square represents one correlation test.
  • Colour represents correlation coefficient.
  • Grey squares represent no measurement.
  • Black Border represents significant associations.
  • FIG 3 Schematic of HMOs trial - Healthy full-term infants were randomly assigned to a standard cow’s milk-based starter infant formula (control group, CG); the same formula with 1.5 g/L HMOs (test group 1 , TG1); or with 2.5 g/L HMOs (test group 2, TG2); or a human milk- fed group (reference, HMG). Fecal samples were collected at enrolment, 3, 6, 12, and 15 months of age.
  • Figure 4 Boxplots representing the association differences between control formula and HMO-enriched formula.
  • X-axis represent time, Y-axis represent relative abundance.
  • Each dot represents one participant.
  • Each dot represents one participant in each formula type.
  • subject refers to a vertebrate, preferably a mammal, more preferably a human.
  • Mammals include but are not limited to murines, simians, humans, farm animals, sport animals and pets.
  • infant means a human subject under the age of 12 months or an age equivalent non-human animal.
  • young child or “toddler” as used herein may mean a human subject aged between 12 months and 5 years of age.
  • a “young child” may refer to an age equivalent non- human animal.
  • composition refers to any kind of composition or formulation that provides a nutritional benefit to an individual and that may be safely consumed by a human or an animal.
  • a nutritional composition may be in solid (e.g. powder), semi-solid or liquid form and may comprise one or more macronutrients, micronutrients, food additives, water, etc.
  • the nutritional composition may comprise the following macronutrients: a source of proteins, a source of lipids, a source of carbohydrates and any combination thereof.
  • the nutritional composition may comprise the following micronutrients: vitamins, minerals, fiber, phytochemicals, antioxidants, prebiotics, probiotics, bioactives, metabolites (e.g.
  • composition may also contain food additives such as stabilizers (when provided in liquid or solid form) or emulsifiers (when provided in liquid form).
  • stabilizers when provided in liquid or solid form
  • emulsifiers when provided in liquid form.
  • the amount of the various ingredients can be expressed in g/100 g of composition on a dry weight basis when it is in a solid form, e.g.
  • a powder or as a concentration in g/L of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as milk, water, e.g. a reconstituted infant formula or follow-on/follow-up formula or infant cereal product or any other formulation designed for infant or young child nutrition).
  • a nutritional composition can be formulated to be taken enterally, orally, parenterally, or intravenously, and it usually includes one of more nutrients selected from: a lipid or fat source, a protein source, and a carbohydrate source.
  • a nutritional composition is for oral use.
  • the nutritional composition is a “synthetic nutritional composition”.
  • synthetic nutritional composition means a mixture obtained by chemical and/or biological means.
  • baby food means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • fortifier refers to liquid or solid nutritional compositions suitable for fortifying or mixing with human milk, infant formula, growing-up milk or human breast milk fortified with other nutrients. Accordingly, the fortifier can be administered after dissolution in human breast milk, in infant formula, in growing-up milk or in human breast milk fortified with other nutrients or otherwise it can be administered as a stand-alone composition. When administered as a stand-alone composition, the milk fortifier can be also identified as being a “supplement”.
  • HMO human milk oligosaccharide(s). These carbohydrates are highly resistant to enzymatic hydrolysis, indicating they may display essential functions not directly related to their caloric value. It has been especially illustrated they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk.
  • Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N- acetylneuraminic acid), fucose and/or N-acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy the terminal position at the non-reducing ends.
  • the HMOs can be divided as non-fucosylated (neutral) or fucosylated (neutral) and sialylated (acidic) and non-sialylated molecules, respectively.
  • the HMOs used in the present invention may be obtained by any suitable method. Suitable methods for synthesising HMOs will be well known to those of skill in the art. For example, processes have been developed for producing HMOs by microbial fermentations, enzymatic processes, chemical syntheses, or combinations of these technologies (see e.g. Zeuner et al., 2019. Molecules, 24(11), p.2033).
  • oligosaccharide refers to an oligosaccharide having a fucose residue. It has a neutral nature.
  • Some examples are 2’-fucosyllactose (2-FL), 3-fucosyllactose (3-FL), difucosyllactose (DiFL), lacto-N-fucopentaose (e.g.
  • lacto-N-fucopentaose I lacto-N- fucopentaose II, lacto-N-fucopentaose III, lacto-N-fucopentaose V)
  • lacto-N-fucohexaose lacto-N-difucohexaose I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose, difucosyllacto- N-hexaose I, difucosyllacto-N-neohexaose II and any combination thereof.
  • Fucosylated oligosaccharides represents the largest fraction of human milk with 2’-FL constituting up to 30% of the total HMOs. Fucosylated oligosaccharides are thought to reduce the risk of infections and inflammations and to boost growth and metabolic activity of specific commensal microbes reducing inflammatory response.
  • the expression “N-acetylated oligosaccharide(s)” encompasses both “N-acetyl-lactosamine” and “oligosaccharide(s) containing N-acetyl-lactosamine”. They are neutral oligosaccharides having an N-acetyl-lactosamine residue.
  • LNT lacto-N-tetraose
  • para- lacto-N-neohexaose para-LNnH
  • LNnT lacto-N-neotetraose
  • DSLNT disialyllacto-N- tetraose
  • lacto-N-hexaose lacto-N- neohexaose, para- lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-octaose, lacto-N- neooctaose, iso- lacto-N-octaose, para- lacto-N-octaose and lacto-N-decaose.
  • At least one fucosylated oligosaccharide and “at least one N-acetylated oligosaccharide” should be understood as “at least one type of fucosylated oligosaccharide” and “at least one type of N-acetylated oligosaccharide”.
  • sialylated oligosaccharide refers to an oligosaccharide having a charged sialic acid residue. It has an acidic nature.
  • Some examples are 3’-sialyllactose (3-SL), 6’-sialyllactose (6- SL), sialyllacto-N-tetraose (Lst - e.g. Lst-a, Lst-b or Lst-c).
  • fibers is used herein to refer to carbohydrates that are indigestible by a human or animal. Such fibers are also discussed in relation to carbohydrates herein.
  • the fiber can be fermented by one or more Bifidobacterium microorganisms provided in the present use or composition and/or within one or more regions in the gastrointestinal tract within an organism, such as a human or non-human animal.
  • the expressions “fiber” or “fibers” or “dietary fiber” or “dietary fibers” within the context of the present invention indicate the indigestible portion, in small intestine, of food derived from plants which comprises two main components: soluble fiber, which dissolves in water and insoluble fiber. Mixtures of fibers are comprised within the scope of the terms above mentioned.
  • Soluble fiber is readily fermented in the colon into gases and physiologically active byproducts and can be prebiotic and viscous. Insoluble fiber does not dissolve in water, is metabolically inert and provides bulking, or it can be prebiotic and metabolically ferment in the large intestine.
  • dietary fiber consists of carbohydrate polymers with three or more monomeric units which are not hydrolyzed by endogenous enzymes in the small intestine such as arabinoxylans, cellulose, and many other plant components such as resistant starch, resistant dextrins, inulin, lignin, chitins, pectins, arabinans, arabinogalactans, galactans, xylans, beta-glucans, and oligosaccharides.
  • endogenous enzymes in the small intestine such as arabinoxylans, cellulose, and many other plant components such as resistant starch, resistant dextrins, inulin, lignin, chitins, pectins, arabinans, arabinogalactans, galactans, xylans, beta-glucans, and oligosaccharides.
  • Non-limiting examples of dietary fibers are: prebiotic fibers such as Fructooligosaccharides (FOS), inulin, galacto-oligosaccharides (GOS), fruit fiber, vegetable fiber, cereal fiber, resistant starch such as high amylose corn starch.
  • GOS may include raffinose, stachyose, or verbascose; for example.
  • “added fiber” or “added dietary fiber” indicates an ingredient mainly or totally constituted by fiber which is added to the complementary nutritional composition and whose content in fiber contributes to the total fiber content of the composition.
  • the total fiber content of the complementary nutritional composition is provided by the sum of amount of fiber naturally present in ingredients used in the recipe (for example from whole grain cereal flour) plus amount of added fiber.
  • prebiotic means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of healthy bacteria, such as bifidobacteria, in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-12).
  • a “bifidogenic prebiotic” means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and/or the activity of bifidobacteria in the gut microbiota of the infant or young child.
  • probiotic means microbial cell preparation or components of microbial cells with a beneficial effect on the health or well-being of the host (Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: how should they be defined” Trends Food Sci. Technol. 1999:10 107-10).
  • the microbial cells according to the present invention are generally bacteria.
  • a probiotic may comprise between 10 3 to 10 12 cfu of probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 10 1 ° cfu of probiotic strain per g of composition on a dry weight basis
  • the “gut microbiota” is the composition of microorganisms (including bacteria, archaea and fungi) that live in the digestive tract.
  • gut microbiome may encompass both the “gut microbiota” and their “theater of activity”, which may include their structural elements (nucleic acid, proteins, lipids, polysaccharides), metabolites (signaling molecules, toxins, organic and inorganic molecules) and molecules produced by coexisting hosts and structured by the surrounding environmental conditions (Berg, G., et al., 2020. Microbiome, 8(1), pp.1-22).
  • promoting may refer to increasing and/or augmenting the growth and/or survival of the bacteria in the gut microbiota.
  • Growth and/or survival of a bacteria may be determined by measuring bacteria cell number, cell density (e.g. measured by optical density) and/or the abundance of 16S rDNA - for example using PCR methods. Promoting growth and/or survival of the bacteria may increase the number of a given bacterial microorganism in an anaerobic culture by at least 20%, at least 30%, at least 40%, at least 50%, at least 75% or at least 100% compared to the number of that bacterial microorganism in a control anaerobic culture which does not comprise the treatment or composition.
  • a bifidogenic prebiotic may refer to a prebiotic that is capable of being metabolized by a Bifidobacterium.
  • the bifidogenic prebiotic is capable of promoting growth and/or survival of the Bifidobacterium.
  • a bifidogenic prebiotic capable of promoting growth and/or survival of Bifidobacterium may be determined by e.g. anaerobic culture of Bifidobacterium with the prebiotic. Growth and/or survival of the Bifidobacterium may be determined by measuring bacteria cell number, cell density (e.g.
  • a bifidogenic prebiotic capable of promoting growth and/or survival of the Bifidobacterium may increase the number of Bifidobacterium in an anaerobic culture by at least 20%, at least 30%, at least 40%, at least 50%, at least 75% or at least 100% compared to the number of Bifidobacterium bacteria in a control anaerobic culture which does not comprise the prebiotic.
  • a prebiotic capable of promoting growth and/or survival of the Bifidobacterium may increase the number of Bifidobacterium bacteria in an anaerobic culture by a statistically significant amount (e.g. p- value ⁇ 0.05 as determined by one-way ANOVA) compared to the number of Bifidobacterium bacteria in a control anaerobic culture which does not comprise the prebiotic.
  • bifidogenic prebiotics are known in the art.
  • the bifidogenic prebiotic may comprise a HMO and/or a GOS.
  • the bifidogenic prebiotic comprises one or more HMOs, most preferably one or more human HMOs.
  • HMOs most preferably one or more human HMOs.
  • Suitable HMOs, and mixtures thereof, are described in further detail herein.
  • ANI is similar to the aforementioned 70% DDH cutoff value and can be used for species delineation. ANI has been evaluated in multiple labs and has become the gold standard for species delineation (see e.g., Kim et al., 2014, “Towards a taxonomic coherence between average nucleotide identity and 16S rRNA gene sequence similarity for species demarcation of prokaryotes”, Int.
  • ANI of the shared genes between two strains is known to be a robust means to compare genetic relatedness among strains, and that ANI values of about 95% correspond to the 70% DNA-DNA hybridization standard for defining a species. See, e.g., Konstantinidis and Tiedje, Proc Natl Acad Sci USA, 102(7):2567-72 (2005); and Goris et al., Int Syst Evol Microbiol. 57(Pt 1 ):81 -91 (2007).
  • the ANI between two bacterial genomes is calculated from pair-wise comparisons of all sequences shared between any two strains and can be determined, for example, using any of a number of publicly available ANI tools, including but not limited to OrthoANI with usearch (Yoon et al. Antonie van Leeuwenhoek 110:1281-1286 (2017)); ANI Calculator, JSpecies (Richter and Rossello-Mora, Proc Natl Acad Sci USA 106:19126-19131 (2009)); and JSpeciesWS (Richter et al., Bioinformatics 32:929-931 (2016)). Other methods for determining the ANI of two genomes are known in the art. See, e.g., Konstantinidis, K.
  • the ANI between two bacterial genomes can be determined, for example, by averaging the nucleotide identity of orthologous genes identified as bidirectional best hits (BBHs).
  • Protein-coding genes of a first genome (Genome A) and second genome (Genome B) are compared at the nucleotide level using a similarity search tool, for example, NSimScan (Novichkov et al., Bioinformatics 32(15): 2380-23811 (2016)). The results are then filtered to retain only the BBHs that display at least 70% sequence identity over at least 70% of the length of the shorter sequence in each BBH pair.
  • the ANI of Genome A to Genome B is defined as the sum of the percent identity times the alignment length for all BBHs, divided by the sum of the lengths of the BBH genes.
  • the genome relatedness may be compared to a type strain for a given species.
  • the type strain for Faecalibacterium prausnitzii may be Faecalibacterium prausnitzii ATCC27768.
  • the type strain for Roseburia inulinivoran may be Roseburia inulinivoran DSM16841.
  • the type strain for Eubacterium rectale may be Eubacterium rectale ATCC33656.
  • the present invention is based on the determination that early colonization of the infant gut microbiome with infant-type bifidobacteria promotes the subsequent abundance and function of butyrate-producing bacteria in the gut microbiome.
  • the butyrate-producing bacteria may be promoted in the gut microbiota of the infant or young child between about 1 and 5 years of age, between about 1 and 4 years of age, between about 1 and 3 years of age, or between about 1 and 2 years of age.
  • the butyrate-producing bacteria may be promoted in the gut microbiota of the infant or young child between about 1 and 3 years of age.
  • the butyrate-producing bacteria may be promoted in the gut microbiota of the infant or young child at about 12, 18, 24 and/or 36 months of age.
  • Bifidobacterium are Gram-positive, non-motile, non-spore forming, anaerobic, saccharolytic microorganisms with a Y-shaped or ‘bifid’ morphology, and a high G + C DNA content.
  • the presence of Bifidobacterium in the mammalian intestine supports the development of the host immune system by improving gut homeostasis and functionality, promoting the intestinal barrier integrity, limiting the onset of certain gut diseases and providing protection against pathogen proliferation.
  • Bifidobacterium may be identified at the genus level using methods which are known in the art, for example 16S rRNA-sequencing.
  • Species of Bifidobacterium may be identified based on 16S rRNA-sequencing or Average Nucleotide Identity (ANI), for example.
  • ANI Average Nucleotide Identity
  • an ANI of >95% is indicative that two Bifidobacterium belong to the same species.
  • the bifidobacteria may be selected from one or more of B. longum, B. bifidum, B. breve, and B. kashiwanohense.
  • the bifidobacteria may be selected from one or more of B. longum infantis, B. longum longum, B. bifidum, B. breve, and B. kashiwanohense.
  • the B. longum may be selected from B. longum infantis, and B. longum longum.
  • the B. longum may be B. longum infantis.
  • the type strain for B. longum infantis may be B. longum infantis ATCC15697.
  • the type strain for B. longum longum may be B. longum longum ATCC15707.
  • the type strain for B. bifidum may be B. bifidum ATCC29521.
  • the type strain for B. breve may be B. breve ATCC15700.
  • the type strain for B. kashiwanohense may be B. kashiwanohense DSM21854.
  • the present invention may comprise administering a Bifidobacterium microorganism to an infant or young child in order to promote butyrate-producing bacteria in the gut microbiome of the infant or young child.
  • the Bifidobacterium microorganism may be provided as a probiotic as described herein.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic for use according to the present invention promote bifidobacteria in the gut microbiome of the infant or young child.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic for use according to the present invention promote bifidobacteria in the gut microbiome of the infant.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to the infant prior to about 12 months of age.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to the infant prior to about 6 months of age.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to the infant at least from about 0 months to about 6 months after birth.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered starting about 7 to about 21 days after birth.
  • Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered until about 6 months to about 12 months after birth.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic is administered starting about 7 to about 21 days after birth until about 12 months after birth, starting about 7 to about 21 days after birth until about 9 months after birth, or starting about 7 to about 21 days after birth until about 6 months after birth.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to the infant prior to about 6 months of age.
  • the bifidogenic prebiotic may be administered to the infant prior to about 6 months of age.
  • the bifidogenic prebiotic may be administered to the infant until at least about 6 months of age.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to the infant until at least about 6 months of age and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 3 years of age.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered starting about 7 to about 21 days after birth until at least about 6 months after birth and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 3 years of age.
  • the bifidogenic prebiotic may be administered to the infant prior to about 6 months of age and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 3 years of age.
  • the bifidogenic prebiotic may be administered starting about 7 to about 21 days after birth until at least about 6 months after birth and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 3 years of age.
  • Allergy may refer to an allergic disorder or an allergic reaction (including symptoms thereof).
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be for use in treating and/or preventing an allergy and/or allergic sensitization in an infant or young child by promoting butyrate-producing bacteria in the gut microbiota of the infant or young child; wherein the Bifidobacterium microorganism and/or bifidogenic prebiotic is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 5 years of age.
  • Treating may refer to administering the Bifidobacterium microorganism and/or bifidogenic prebiotic to a subject having an existing disease or condition in order to lessen, reduce or improve at least one symptom associated with the disease and/or to slow down, reduce or block the progression of the disease.
  • Preventing may refer to administering the Bifidobacterium microorganism and/or bifidogenic prebiotic to a subject who has not yet contracted the disease and/or who is not showing any symptoms of the disease to prevent or impair the cause of the disease or to reduce or prevent development of at least one symptom associated with the disease.
  • the subject may have a predisposition for, or be thought to be at risk of developing, the disease.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may be administered to a subject in order to reduce the likelihood of the infant or young child developing an allergy and/or allergic sensitization.
  • allergies in childhood can be the first step of an allergic cascade leading to multiple allergies later in life, a process commonly referred to as the “Atopic March”.
  • children with persistent food hypersensitivity early in life have a dramatically increased risk to develop allergic rhinitis (hay fever) or asthma later in childhood (Ostblom, E. et al. (2008); Clinical and Experimental Allergy, 38 (8): 1325- 1332).
  • preventing and/or reducing the risk of developing an allergy and/or allergic sensitization is by primary prevention.
  • Primary prevention is the effect of preventing or reducing the risk of sensitization of patients to allergens, characterized by absence or reduced levels of allergen-specific IgE antibodies. Preventing or reducing sensitization may result in absence or reduction of allergic symptoms upon exposure to the same allergen.
  • the subsequent allergic response may also be modulated.
  • Food allergens are among the first allergens that infants encounter in their early life: typically, cow's milk proteins may be encountered by infants not receiving exclusive breast-feeding. Milk-proteins are indeed among the most frequently observed causes for food allergy in infancy, followed by eggs and wheat proteins. In general, food allergies can manifest in cutaneous (rash, eczema, others) and gastrointestinal symptoms (abdominal cramps; pain, especially in the abdomen; vomiting) in infants and young children. Food allergies are the most common trigger of severe allergic reactions, which may lead to life-threatening anaphylaxis.
  • Animals particularly small animals such as pets - and especially companion animals such as dogs and cats, may also suffer from food allergies and food intolerances, as well as environmental allergens. These typically manifest in similar symptoms to humans, e.g. gastrointestinal disturbances such as diarrhoea, vomiting and abdominal discomfort, and also dermatitis or pruritis.
  • gastrointestinal disturbances such as diarrhoea, vomiting and abdominal discomfort, and also dermatitis or pruritis.
  • the most frequent cause of chronic diarrhoea is food-responsive enteropathy (diet-responsive enteropathy or food-responsive diarrhoea).
  • an allergic response is a specific IgE-associated immune response and/or a T cell-dependent hypersensitive reaction.
  • treating and/or preventing and/or reducing the risk of developing an allergy and/or allergic sensitization comprises reducing or preventing specific IgE-associated immune responses and/or a T celldependent hypersensitive reaction.
  • allergic inflammation is reduced and/or tolerance (e.g. oral tolerance) is enhanced.
  • the allergic disorder is selected from one or more of the group consisting of: a food allergy, a respiratory allergy and a dermatological allergy.
  • the allergic disorder is selected from one or more of the group consisting of: rhinitis, asthma, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, psoriasis, eosinophilic oesophagitis and an eosinophilic-associated gastrointestinal disease.
  • the allergen in the allergic disorder is selected from one or more of: a food allergen, dust mite, pollen, molds or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, pollution or pet dander.
  • the allergen in the allergic disorder is a food allergen.
  • the food allergen is selected from: a nut, tree nut, peanut, fish, shellfish, molluscs, crustaceans, milk, egg, soy, gluten, cereals, wheat, oats, barley, rye, celery, corn, lupin, sulphites, sesame, mustard, rice, poultry and meat.
  • the allergen is an aeroallergen.
  • the aeroallergen is selected from dust mite, pollen, moulds or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, pollution or pet dander.
  • treating, preventing or reducing the risk of an allergy and/or allergic sensitization may refer to reducing or ameliorating one or more symptoms as described herein.
  • a “food allergy” as used herein refers to an abnormal immune response to one or more food allergens, typically an IgE reaction caused by the release of histamine but also encompassing non-lgE immune responses.
  • Symptoms of food allergy may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. When the symptoms are severe, it is known as anaphylaxis.
  • the term “food allergen” refers to proteins or derivatives thereof that cause abnormal immune responses.
  • Purified food allergens may be named using the systematic nomenclature of the Allergen Nomenclature Sub-Committee of the World Health Organization and International Union of Immunological Societies. Allergen names are composed of an abbreviation of the scientific name of its source (genus: 3-4 letters; species: 1-2 letters) and an Arabic numeral, for example Der p 1 for the first allergen to be described from the house dust mite Dermatophagoides pteronyssinus.
  • Food allergens are derived from proteins with a variety of biologic functions, including proteases, ligand-binding proteins, structural proteins, pathogenesis-related proteins, lipid transfer proteins, profilins, and calcium-binding proteins.
  • a list of food allergens is provided on the official website of the WHO/IUIS Allergen Nomenclature Database, http://www.allergen.org/index.php. (Radauer, C., et al., 2014. Allergy, 69(4), pp.413-419 and Pomes, A., et al., 2018. Molecular immunology).
  • a “respiratory allergy” or “aeroallergen” as used herein refers to an abnormal immune response to one or more airborne allergens.
  • Airborne allergens may include pollen, molds or mold spores, weed pollen, tree pollen, grass pollen, and dander.
  • Respiratory allergies may include for example allergic rhinitis and allergic asthma. Symptoms of allergic rhinitis (hay fever) include a runny or stuffy nose, sneezing, red, itchy, and watery eyes, and swelling around the eyes. Symptoms of allergic asthma include episodes of wheezing, coughing, chest tightness, and shortness of breath.
  • a “dermatological allergy” as used herein refers to an abnormal immune response caused by contact with one or more environmental allergens.
  • Environmental allergens may include a food allergen, dust mite, pollen, molds or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers or pet dander.
  • Dermatological allergies may include for example dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, and psoriasis. These are typically a group of diseases that results in inflammation of the skin and symptoms include itchiness, red skin and a rash.
  • Allergic disorders may also include other allergic inflammatory conditions, for example eosinophilic oesophagitis and an eosinophilic-associated gastrointestinal disease.
  • Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. Symptoms are swallowing difficulty, food impaction, vomiting, and heartburn.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may modulate the permeability of the gut epithelial barrier of the infant or young child by promoting butyrate- producing bacteria in the gut microbiota of the infant or young child.
  • the Bifidobacterium microorganism and/or bifidogenic prebiotic may decrease the permeability of the gut epithelial barrier by promoting butyrate-producing bacteria in the gut microbiota of the infant or young child.
  • Increased permeability of the gut epithelial barrier may be associated with an increase crossing of e.g. haptens and antigens across the intestinal epithelium.
  • Such changes in the intestinal flora may also have a negative impact on the integrity of the intestinal barrier.
  • Impaired barrier function termed “leaky gut” has long been considered a predisposing factor for gastrointestinal diseases (Heyman M., Eur. J. Gastroenterol. Hepatol. 17:1279-1285; Odenwald M., Nature Reviews Gastroenterology & Hepatology, (2017), (14), 9 21).
  • alterations in gut barrier integrity/function have multiple consequences facilitating the onset of numerous diseases depending on other hits and on genetic and epigenetic constellations.
  • Food allergy patients often demonstrate with increased intestinal permeability, which correlates with the severity of their clinical symptoms (Ventura , M. T et al. 2006. Dig. Dis. Sci.
  • Preclinical animal models further provide corroborative evidence supporting a role for intestinal barrier dysfunction and leaky gut, predisposing to oral sensitization and subsequent development of food allergy.
  • Western diet-induced alterations in intestinal permeability promote food allergen sensitization and clinical allergy symptoms in mice in response to dietary antigens (Hussain M. et al. J. Allergy Clin. Immunol. (2019).
  • Probiotics represent one nutritional attempt to improve/reinforce intestinal barrier integrity and/or function (Ewaschuk JB et al., Am J Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G1025-34).
  • Reinforcing intestinal barrier integrity by means of probiotic supplementation may thus prevent sensitization to oral allergens in at risk individuals.
  • Teu J Microorganisms. 2019 Oct 16;7(10).
  • uncontrolled immune responses towards dietary or environmental antigens foster the development of type-2 immune mediated allergic disorders.
  • Probiotic cultures or mixes of probiotics have well known immunomodulatory properties that can prevent or alleviate allergic responses.
  • the epithelial barrier of human newborns is not fully mature at birth. Transfer of macromolecules or antigens across the intestinal epithelium of an infant or young child induces differentiation of regulatory T-cells (Tregs) and is essential for the induction of tolerance and protection from allergic diseases.
  • Tregs regulatory T-cells
  • lacto-N-fucopentaose I lacto-N-fucopentaose II, lacto-N-fucopentaose III, lacto-N-fucopentaose V)
  • lacto-N-fucohexaose lacto-N-difucohexaose I, fucosyllacto-N- hexaose, fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose I, difucosyllacto-N- neohexaose II and any combination thereof
  • an N-acetylated oligosaccharide e.g.
  • LNT lacto-N-tetraose
  • para-lacto-N-neohexaose para-LNnH
  • LNnT lacto-N-neotetraose
  • DSLNT dialyllacto-N-tetraose
  • lacto-N-hexaose lacto-N-neohexaose
  • para- lacto-N- hexaose para-lacto-N-neohexaose
  • lacto-N-octaose lacto-N- neooctaose
  • sialylated oligosaccharide e.g.
  • the mixture of HMOs may comprise at least one fucosylated oligosaccharide, at least one N- acetylated oligosaccharide, and at least one sialylated oligosaccharide.
  • the mixture of HMOs comprises at least one fucosylated oligosaccharide, at least one N-acetylated oligosaccharide, and/or at least one sialylated oligosaccharide. In some embodiments, the mixture of HMOs comprises at least one fucosylated oligosaccharide, at least one N-acetylated oligosaccharide, and at least one sialylated oligosaccharide.
  • the mixture of HMOs comprises or consists of 2’-fucosyllactose (2’FL), 2’,3-difucosyllactose (diFL), lacto-N-tetraose (LNT), 3’-sialyllactose (3’-SL), and 6’- sialyllactose (6’-SL).
  • the mixture of HMOs consists of 2’-fucosyllactose (2’FL), 2’,3- difucosyllactose (diFL), lacto-N-tetraose (LNT), 3’-sialyllactose (3’-SL), and 6’-sialyllactose (6’- SL).
  • the mixture of HMOs comprises at least one fucosylated oligosaccharide.
  • the at least one fucosylated oligosaccharide comprises of consists of 2’- fucosyllactose (2’FL), 2’,3-difucosyllactose (diFL), 3-fucosyllactose (3FL), lacto-N- fucopentaose-l (LNFP-I), lacto-N-fucopentaose-ll (LNFP-II), lacto-N-fucopentaose-lll (LNFP- III), lacto-N-fucopentaose-V (LNFP-V), lacto-neofucopentaose V (LNnFP-V), lacto-N- difucosylhexaose-l (LNDFH-1), lacto-N-neodifucosylhexaose (LNnDFH), monofucosyllacto-n- hexaose-lll (MFNL
  • the at least one fucosylated oligosaccharide comprises of consists of 2’-fucosyllactose (2’FL) and/or 2’, 3-difucosyllactose (diFL). In some embodiments, the at least one fucosylated oligosaccharide consists of 2’-fucosyl lactose (2’FL) and 2’, 3-difucosyllactose (diFL).
  • the at least one fucosylated oligosaccharide may be obtained by any suitable method.
  • 2’FL may be produced by biotechnological means using specific fucosyltransferases and/or fucosidases either through the use of enzyme-based fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes.
  • 2’FL may be produced by chemical synthesis from lactose and free fucose. diFL may be synthesized by enzymatic, biotechnological and/or chemical processes.
  • the mixture of HMOs comprises at least one N-acetylated oligosaccharide.
  • the at least one N-acetylated oligosaccharide comprises of consists of lacto-N- tetraose (LNT), lacto-N-neotetraose (LNnT), a N-acetyl-glucosamine, a N-acetyl- galactosamine, or any combination thereof.
  • the at least one N-acetylated oligosaccharide consists of lacto-N- tetraose (LNT).
  • the N-acetylated oligosaccharides may be obtained by any suitable method.
  • LNnT may be synthesised chemically by enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyltransferases.
  • LNnT may be prepared by chemical conversion of Keto-hexoses (e.g. fructose) either free or bound to an oligosaccharide (e.g. lactulose) into N-acetylhexosamine or an N-acetylhexosamine- containing oligosaccharide.
  • LNT may be synthesized by enzymatic, biotechnological and/or chemical processes.
  • the mixture of HMOs comprises at least one sialylated oligosaccharide.
  • the at least one sialylated oligosaccharide comprises of consists of 3’-sialyllactose (3’-SL), 6’-sialyllactose (6’-SL), syalyllacto-N-tetraose b (LSTb), syalyllacto-N-tetraose c (LSTc), disyallacto-N-tetraose (DSLNT), or any combination thereof.
  • the at least one sialylated oligosaccharide comprises or consists of 3’- sialyllactose (3’-SL) and/or 6’-sialyllactose (6’-SL). In some embodiments, the at least one sialylated oligosaccharide consists of 3’-sialyllactose (3’-SL) and 6’-sialyllactose (6’-SL).
  • the sialylated oligosaccharides may be obtained by any suitable method.
  • 3’- sialyllactose (3’-SL) and/or 6’-sialyllactose (6’-SL) may be isolated by chromatographic or filtration technology from a natural source such as animal milks.
  • they may be produced by biotechnological means using specific sialyltransferases or sialidases, neuraminidases, either by an enzyme based fermentation technology (recombinant or natural enzymes), by chemical synthesis or by a microbial fermentation technology.
  • microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes.
  • DP polymerisation
  • sialyllactoses may be produced by chemical synthesis from lactose and free sialic acid.
  • the mixture of HMOs may be administered in any suitable form.
  • the mixture of HMOs may be administered in the form of a nutritional composition, a medical food product for clinical nutrition, or a supplement.
  • the nutritional composition may be any suitable nutritional composition in which the mixture of HMOs can be incorporated, such as a nutritional composition in the form of a food or beverage product, a nutritional supplement, a nutraceutical composition, or a pharmaceutical composition.
  • the nutritional composition may be in solid (e.g. powder), liquid or semi-liquid form.
  • the nutritional composition is in a form suitable for feeding infants, such as an infant formula, a milk fortifier, or a supplement.
  • the nutritional composition can also be in a form for young children such as a yoghurt or a medical food.
  • the mixture of HMOs is administered in the form of an infant formula.
  • An infant formula can be a starter infant formula, a preterm infant formula, a milk fortifier, or a follow-up formula.
  • the mixture of HMOs is administered in the form of a starter infant formula.
  • a “starter infant formula” is intended for infants from birth as breast-milk substitute.
  • the mixture of HMOs is administered in the form of follow-up formula.
  • a “follow-up formula” or “follow-on formula” may be given from the sixth month onwards. It may constitute the principal liquid element in the progressively diversified diet of this category of person.
  • the mixture of HMOs is administered in the form of a preterm infant formula.
  • preterm infant formula as used herein may refer to an infant formula intended for a preterm infant.
  • the mixture of HMOs is administered in the form of a milk fortifier.
  • milk fortifier as used herein may refer to liquid or solid nutritional compositions suitable for mixing with infant formula.
  • the mixture of HMOs is administered at least in the form of a starter infant formula, and/or a follow-up formula. In some embodiments, the mixture of HMOs is administered at least in the form of a starter infant formula. In some embodiments, the mixture of HMOs is administered at least in the form of a starter infant formula and a follow-up formula.
  • the mixture of HMOs is administered in the form of a starter infant formula. In some embodiments, the mixture of HMOs is administered in the form of a starter infant formula and a follow-up formula.
  • the mixture of HMOs is administered in the form of a fortifier.
  • the fortifier can be a formula fortifier such as an infant formula fortifier.
  • the fortifier may be a particularly advantageous embodiment when the infant or young child is born preterm.
  • the mixture of HMOs is administered in the form of a supplement.
  • a “supplement” or “dietary supplement” may be used to complement the nutrition of a subject (it is typically used as such but it might also be added to any kind of compositions intended to be ingested by the subject).
  • composition When the composition is a supplement, it can be provided in the form of unit doses.
  • Supplements are typically present in the form of a liquid, a gel, a powder, a tablet, or a capsule.
  • Powder supplements typically encompass supplements to be dissolved in water or to be sprinkled on food or in a beverage. Such supplements are intended to provide additional nutrients and/or a health benefit to the subject consuming it.
  • a supplement can be used for providing nutrients and/or a health benefit to human beings, as well as to animals, as defined above.
  • Supplements include for example powder supplements to be added to breast milk, for example for premature or low birth weight infants.
  • the mixture of HMOs is administered in the form of a pharmaceutical product.
  • Pharmaceutical products include for example drops, syrups, powder, tablet or capsule products intended to treat or prevent an adverse medical condition in a subject in need thereof.
  • the mixture of HMOs is administered in the form of a nutraceutical product.
  • the mixture of HMOs may be administered in any dosage that is effective to promote Bifidobacterium in the gut microbiota of the infant or young child.
  • the effective dosage may vary depending on e.g. the weight and/or age of the infant.
  • the infant formula may be administered as normal (e.g. based on the weight of the infant or child) and suitable amounts of an individual HMO e.g. of 2’FL, diFL, LNT, 3’-SL, 6’-SL may be based on the amounts found in human breast milk produced for an infant or child of the same age, in particular by a nutritionally replete mother.
  • the amounts in the infant formula may vary depending on for example bioavailability of said HMOs from infant formula in comparison to human breastmilk.
  • the exemplary concentration of HMOs described herein may refer to the concentration after the composition has been reconstituted e.g. with water.
  • 2’FL, diFL, LNT, 3’-SL, 6’-SL in human breast milk may fall within the following ranges: 2’FL in an amount of about 0.5 to about 3 g/L (e.g. about 1.8 g/L); diFL in an amount of about 0.1 to about 0.5 g/L (e.g. about 0.26 g/L); LNT in an amount of about 0.05 to about 0.3 g/L (e.g. about 0.77 g/L); 3’SL in an amount of about 0.1 to about 0.4 g/L (e.g. about 0.22 g/L); and 6’SL in an amount of about 0.05 to about 0.75 g/L (e.g. about 0.47 g/L).
  • 2’FL in an amount of about 0.5 to about 3 g/L (e.g. about 1.8 g/L); diFL in an amount of about 0.1 to about 0.5 g/L (e.g. about 0.26 g/L); LNT in an amount of about
  • the mixture of HMOs (e.g. 2’FL, diFL, LNT, 3’-SL, and/or 6’-SL) is administered in a total amount of about 0.1 g/day to about 10 g/day.
  • the mixture of HMOs is administered in a total amount of about 0.5 g/day or more, about 1 .0 g/day or more, or about
  • the mixture of HMOs is administered in a total amount of about 5.0 g/day or less, 4.5 g/day or less, 4.0 g/day or less, 3.5 g/day or less, 3.0 g/day or less, or
  • the mixture of HMOs is administered in a total amount of from about 0.5 g/day to about 5.0 g/day, from about 1 .0 g/day to about 3.0 g/day, or from about 1.4 g/day to about 2.5 g/day.
  • the mixture of HMOs is administered in a total amount of from about 1 .2 g/day to about 1 .8 g/day (e.g. about 1.46 g/day) or from about 2.0 g/day to about 3.0 g/day (e.g. about 2.44 g/day). In some embodiments, the mixture of HMOs is administered in a total amount of from about 1.2 g/day to about 1.8 g/day. In some embodiments, the mixture of HMOs is administered in a total amount of about 1.46 g/day.
  • the mixture of HMOs when administered in the form of a starter infant formula the mixture of HMOs is administered in a total amount of from about 0.5 g/day to about 5.0 g/day, from about 1.0 g/day to about 3.0 g/day, or from about 1.5 g/day to about 2.5 g/day (e.g. about
  • the mixture of HMOs is administered in the form of a follow-up formula in a total amount of from about 0.1 g/day to about 2.0 g/day, from about 0.2 g/day to about 1.0 g/day, from about 0.3 g/day to about 0.7 g/day, or about 0.5 g/day.
  • the mixture of HMOs when administered in the form of a growing-up milk the mixture of HMOs is administered in a total amount of from about 0.05 g/day to about 0.5 g/day, from about 0.1 g/day to about 0.3 g/day, or about 0.2 g/day.
  • the mixture of HMOs is administered in the following proportions: (i) 2’FL in an amount of from about 55 wt% to about 60 wt% (e.g. about 58%); (ii) diFL in an amount of from about 5 wt% to about 7 wt% (e.g. about 6 wt%); (iii) LNT in an amount of from about 18 wt% to about 20 wt% (e.g. about 19 wt%); (iv) 3’-SL in an amount of from about 6 wt% to about 8 wt% (e.g. about 7 wt%); and (v) 6’-SL in an amount of from about 9 wt% to about 11 wt% (e.g. about 10 wt%), based on the total weight of HMOs.
  • 2’FL in an amount of from about 55 wt% to about 60 wt% (e.g. about 58%);
  • diFL in an amount of from about 5 wt%
  • a nutritional composition comprising the mixture of HMOs may comprise the mixture of HMOs in any suitable concentrations to provide an effective dosage.
  • the mixture of HMOs e.g. 2’FL, diFL, LNT, 3’-SL, and/or 6’-SL
  • the composition comprises the mixture of HMOs in a total amount of about 0.5 g/L or more, about 1 .0 g/L or more, or about 1 .5 g/L or more.
  • the composition comprises the mixture of HMOs in a total amount of about 5.0 g/L or less, 4.5 g/L or less, 4.0 g/L or less, 3.5 g/L or less, 3.0 g/L or less, or 2.5 g/L or less.
  • the composition comprises the mixture of HMOs in a total amount of from about 0.5 g/L to about 5.0 g/L, from about 1.0 g/L to about 3.0 g/L, from about 1.2 g/L to 3.0 g/L, or from about 1.5 g/L to about 2.5 g/L.
  • the composition comprises the mixture of HMOs in a total amount of from about 1 .2 g/L to about 1 .8 g/L (e.g. about 1 .5 g/L) or from about 2.0 g/L to about 3.0 g/L (e.g. about 2.5 g/L). In some embodiments, the composition comprises the mixture of HMOs in a total amount of from about 1.2 g/L to about 1.8 g/L.
  • the composition comprises the mixture of HMOs in a total amount of about 1.5 g/L.
  • a starter infant formula comprises a total amount of HMOs of from about 0.5 g/L to about 5.0 g/L, from about 1.0 g/L to about 3.0 g/L, from about 1.2 g/L to 3.0 g/L, or from about 1.5 g/L to about 2.5 g/L.
  • a follow-up formula comprises a total amount of HMOs of from about 0.1 g/L to about 2.0 g/L, from about 0.2 g/L to about 1.0 g/L, from about 0.3 g/L to about 0.8 g/L, from about 0.35 g/L to about 0.65 g/L, or about 0.5 g/L.
  • a growing-up milk comprises a total amount of HMOs of from about 0.1 g/L to about 1.0 g/L, from about 0.2 g/L to about 0.8 g/L, from about 0.28 g/L to about 0.52 g/L, from about 0.3 g/L to about 0.5 g/L, or about 0.4 g/L.
  • a starter infant formula comprises a total amount of HMOs of from about 0.5 g/L to about 1.5 g/L.
  • a starter infant formula comprises a total amount of HMOs of about 1.5 g/L.
  • the mixture of HMOs (e.g. in the form of a nutritional composition, such as an infant formula) comprises or consists of: (i) 2’FL in an amount of from about 50 wt% to about 65 wt%; (ii) diFL in an amount of from about 2 wt% to about 10 wt%; (iii) LNT in an amount of from about 15 wt% to about 25 wt%; (iv) 3’-SL in an amount of from about 4 wt% to about 10 wt%; and (v) 6’-SL in an amount of from about 5 wt% to about 15 wt%, based on the total weight of HMOs.
  • the mixture of HMOs (e.g. in the form of a nutritional composition, such as an infant formula) comprises or consists of: (i) 2’FL in an amount of from about 55 wt% to about 60 wt% (e.g. about 58%); (ii) diFL in an amount of from about 5 wt% to about 7 wt% (e.g. about 6 wt%); (iii) LNT in an amount of from about 18 wt% to about 20 wt% (e.g. about 19 wt%); (iv) 3’-SL in an amount of from about 6 wt% to about 8 wt% (e.g. about 7 wt%); and (v) 6’-SL in an amount of from about 9 wt% to about 11 wt% (e.g. about 10 wt%), based on the total weight of HMOs.
  • 2’FL in an amount of from about 55 wt% to about 60 wt% (e.g. about
  • the one or more fucosylated oligosaccharide may be present in a total amount of from about 0.1 g/L to about 4 g/L.
  • the one or more fucosylated oligosaccharide is present in amount of about 0.1 g/L to about 3.5 g/L, about 0.15 g/L to about 3 g/L, from about 0.2 g/L to about 2.5 g/L, from about 0.3 g/L to about 2 g/L, from about 0.4 g/L to about 2 g/L, or from about 0.5 g/L to about 2 g/L.
  • 2’FL is present in an amount of from about 0.5 g/L to about 3.0 g/L (e.g. about 0.87 g/L or about 1.45 g/L). In some embodiments, 2’FL is present in an amount of about 0.87 g/L.
  • the one or more N-acetylated oligosaccharide may be present in a total amount of about 0.05 g/L to about 1.0 g/L.
  • the one or more N-acetylated oligosaccharide is present in amount of about 0.1 g/L to about 0.5 g/L, or about 0.2 g/L to about 0.5 g/L.
  • LNT is present in an amount of from about 0.1 g/L to about 1.0 g/L (e.g. about 0.29 g/L or about 0.48 g/L). In some embodiments, LNT is present in an amount of about 0.29 g/L.
  • the one or more sialylated oligosaccharide may be present in a total amount of from about 0.05 g/L to about 1 g/L.
  • the one or more sialylated oligosaccharide is present in amount of about 0.05 g/L to about 0.5 g/L, or about 0.1 g/L to about 0.5 g/L.
  • 3’SL is present in an amount of from about 0.05 g/L to about 0.3 g/L (e.g. about 0.11 g/L or about 0.18 g/L).
  • 3’SL is present in an amount of about 0.11 g/L. In some embodiments, 6’SL is present in an amount of from about 0.05 g/L to about 0.5 g/L (e.g. about 0.14 g/L or about 0.24 g/L). In some embodiments, 6’SL is present in an amount of about 0.14 g/L.
  • the mixture of HMOs may comprise or consist of: (i) 2’FL in an amount of from about 0.5 g/L to about 3.0 g/L (e.g. about 0.87 g/L or about 1.45 g/L); (ii) diFL in an amount of from about 0.05 g/L to about 0.3 g/L (e.g. about 0.10 g/L or about 0.14 g/L); (iii) LNT in an amount of from about 0.1 g/L to about 1.0 g/L (e.g.
  • the mixture of HMOs (e.g. in the form of a nutritional composition, such as a starter infant formula) comprises or consists of: (i) 2’FL in an amount of from about 0.70 g/L to about 1 .05 g/L, preferably about 0.87 g/L; (ii) di FL in an amount of from about 0.05 g/L to about 0.11 g/L, preferably about 0.10 g/L; (iii) LNT in an amount of from about 0.23 g/L to about 0.36 g/L, preferably about 0.29 g/L; (iv) 3’-SL in an amount of from about 0.09 g/L to about 0.13 g/L, preferably about 0.11 g/L; and (v) 6’-SL in an amount of from about 0.12 g/L to about 0.17 g/L, preferably about 0.14 g/L.
  • 2’FL in an amount of from about 0.70 g/L to about 1 .05 g/L,
  • the mixture of HMOs (e.g. in the form of a nutritional composition, such as a starter infant formula) comprises or consists of: (i) 2’FL in an amount of from about 1.16 g/L to about 1.74 g/L, preferably about 1.45 g/L; (ii) diFL in an amount of from about 0.12 g/L to about 0.18 g/L, preferably about 0.14 g/L; (iii) LNT in an amount of from about 0.39 g/L to about 0.58 g/L, preferably about 0.48 g/L; (iv) 3’-SL in an amount of from about 0.14 g/L to about 0.21 g/L, preferably about 0.18 g/L; and (v) 6’-SL in an amount of from about 0.19 g/L to about 0.28 g/L, preferably about 0.24 g/L.
  • 2’FL in an amount of from about 1.16 g/L to about 1.74 g/L, preferably about 1.
  • the mixture of HMOs (e.g. in the form of a nutritional composition, such as a follow-up formula) comprises or consists of: (i) 2’FL in an amount of from about 0.19 g/L to about 0.34 g/L, preferably about 0.26 g/L; (ii) diFL in an amount of from about 0.03 g/L to about 0.05 g/L, preferably about 0.04 g/L; (iii) LNT in an amount of from about 0.06 g/L to about 0.11 g/L, preferably about 0.09 g/L; (iv) 3’-SL in an amount of from about 0.04 g/L to about 0.09 g/L, preferably about 0.06 g/L; and (v) 6’-SL in an amount of from about 0.03 g/L to about 0.06 g/L, preferably about 0.05 g/L.
  • the mixture of HMOs may be administered for any suitable period.
  • the HMOs may be administered until at least about 6 months after birth.
  • the HMOs may be administered until at least about 12 months after birth.
  • the HMOs may be administered until at least about 15 months after birth.
  • the mixture of HMOs may be administered at least from about 0 months to about 6 months after birth.
  • the mixture of HMOs is administered starting about 7 to about 21 days after birth.
  • the mixture of HMOs is administered until about 6 months to about 18 months after birth, until about 6 months to about 15 months after birth, or until about 6 months to about 12 months after birth.
  • the mixture of HMOs is administered starting about 7 to about 21 days after birth until about 15 months after birth, starting about 7 to about 21 days after birth until about 12 months after birth, starting about 7 to about 21 days after birth until about 9 months after birth, or starting about 7 to about 21 days after birth until about 6 months after birth.
  • a nutritional composition of the invention in addition to the mixture of HMOs, generally contains a protein source, a carbohydrate source and a lipid source.
  • a nutritional composition according to the invention, and especially an infant formula of the invention may contain a protein source.
  • the protein may be present in an amount of from about 1.5 to about 3.0 g/100kcal, from about 1.5 to about 2.5 g/100kcal, from about 1.6 to about 2.5 g/100kcal, or from about 1.6 to about 2.25 g/100kcal.
  • the protein amount is present in an amount of about 2.0 g g/100kcal or less, e.g. from about 1.8 to about 2.0 g/100kcal, or about 1.9 g/100kcal.
  • Protein sources based on, for example, whey, casein and mixtures thereof may be used as well as plant based protein sources, for example, based on soy.
  • the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.
  • the protein source is whey predominant (i.e. more than 50% of proteins are coming from whey proteins, such as 60% or more or 70% or more).
  • the proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins.
  • the term "intact" in the context of the present invention may mean that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered.
  • hydrolysed in the context of the present invention may mean proteins which have been hydrolysed or broken down into its component amino acids.
  • the proteins may be either fully or partially hydrolysed. If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art.
  • whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process.
  • the proteins of the composition are hydrolysed, fully hydrolysed or partially hydrolysed.
  • the degree of hydrolysis (DH) of the protein can be between 2 and 20, or between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90. At least 70%, 80%, 85%, 90%, 95% or 97% of the proteins may be hydrolysed. In a particular embodiment, 100% of the proteins are hydrolysed.
  • a nutritional composition according to the present invention may contain a carbohydrate source.
  • a carbohydrate source any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates for infant formula is lactose.
  • the carbohydrate may be in an amount of from about 8 to about 15 g/100kcal or from about 9 to about 14 g/100kcal. In some embodiments, the carbohydrate is present in an amount of from about 10 to about 13 g/100kcal, or about 11.1 g/100kcal.
  • a nutritional composition according to the present invention may contain lipids and essential fatty acids.
  • lipids include palm olein, high oleic sunflower oil, high oleic safflower oil, canola oil, fish oil, coconut oil, bovine milk fat, and combinations thereof.
  • essential fatty acids include linoleic acid (LA), a-linolenic acid (ALA).
  • Compositions of the invention may further contain gangliosides monosialoganglioside-3 (GM3) and disialogangliosides 3 (GD3), and combinations thereof.
  • the lipid may be in an amount of from about 3.0 to about 8.0 g/100kcal, from about 4.0 to about 6.0 g/100kcal, or from about 4.5 to about 5.5 g/100kcal. In some embodiments, the lipid is present in an amount of from about 5.0 to about 5.5 g/100kcal, or about 5.3 g/100kcal.
  • a nutritional composition of the invention 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 composition of the invention include vitamin A, vitamin B1 , vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K1 , vitamin K2, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine.
  • a nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and diglycerides, and the like.
  • a nutritional composition of the invention may have an energy density of from about 60 to about 72 kcal per 100 mL or about 67 kcal per 100 mL
  • compositions according to the present invention may be prepared by any known or otherwise suitable manner.
  • a nutritional composition e.g. an infant formula
  • a source of protein e.g. a carbohydrate source and a lipid source in appropriate proportions.
  • emulsifiers may be included at this stage.
  • Vitamins and minerals may be added at this stage, but may also be added later to avoid thermal degradation.
  • Water preferably water which has been subjected to reverse osmosis or deionized water, may then be added and mixed in to form a liquid mixture.
  • the temperature of mixing is preferably room temperature, but may also be higher.
  • the liquid mixture may then be thermally treated to reduce bacterial loads.
  • the mixture may then be homogenized.
  • the homogenized mixture may be dried in a suitable drying apparatus, such as a spray drier or freeze drier and converted into powder.
  • Processes used in the manufacture of formulae for infants and young children are based on the concept that the products must be nutritionally adequate and microbiologically safe to consume. Thus, steps that eliminate or restrict microbiological growth are central to production processes.
  • the processing technology generally involves the preservation of an oil-in-water (o/w) emulsion by dehydration in the case of powder products or, sterilization in the case of ready-to-feed or concentrated liquid products.
  • Powdered infant formula may be produced using various processes, such as dry blending dehydrated ingredients to constitute a uniform formula or hydrating and wet-mixing a mixture of macro-ingredients, such as fat, protein and carbohydrate ingredients and then evaporating and spray drying the resultant mixture.
  • a combination of the two processes described above may be used where a base powder is first produced by wet-mixing and spray drying all or some of the macro-ingredients and then dry blending the remaining ingredients, including carbohydrate, minerals and vitamins and other micronutrients, to create a final formula.
  • Liquid formulae are available in a ready-to-feed format or as a concentrated liquid, which requires dilution, normally 1 :1 , with water.
  • the manufacturing processes used for these products are similar to those used in the manufacture of recombined milk.
  • the homogenized mixture may be filled into suitable containers, preferably aseptically.
  • the liquid composition may also be retorted in the container, suitable apparatus for carrying out the filling and retorting of this nature is commercially available.
  • the invention further provides a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism for use according to the present invention.
  • the bifidogenic prebiotic and a Bifidobacterium microorganism may be administered separately, simultaneously or sequentially.
  • the bifidogenic prebiotic and a Bifidobacterium microorganism may be administered in a combined composition.
  • a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism may be referred to as a “synbiotic”.
  • each may be selected such that the Bifidobacterium microorganism is capable of metabolising the bifidogenic prebiotic provided in the combination.
  • the combinations of the invention are not limited to requiring that the Bifidobacterium microorganism is capable of metabolizing the bifidogenic prebiotic provided in the combination. As such, any combinations Bifidobacterium microorganism(s) and bifidogenic prebiotic disclosed herein are encompassed by the invention.
  • the composition comprises one or more glycan substrates as described herein.
  • the composition may comprise between 10 3 to 10 12 cfu of probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 1O 10 cfu of probiotic strain per g of composition on a dry weight basis mixed with a mixture of HMOs as defined herein.
  • the present invention provides a method of promoting butyrate-producing bacteria in the gut microbiota of an infant or young child comprising administering a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 5 years of age.
  • the present invention provides a method of treating and/or preventing an allergy and/or allergic sensitization in an infant or young child by promoting butyrate-producing bacteria in the gut microbiota of the infant or young child; comprising administering a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to the infant prior to about 12 months of age; and administration of bifidogenic prebiotic, Bifidobacterium microorganism or a combination promotes butyrate-producing bacteria in the gut microbiota of the infant or young child between about 1 and 5 years of age.
  • the present invention relates to the use of a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to promote butyrate-producing bacteria in the gut microbiota of the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate- producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 5 years of age.
  • the Bifidobacterium microorganism may be a Bifidobacterium microorganism as described herein.
  • the prebiotic may be a prebiotic as described herein.
  • the combination of a Bifidobacterium microorganism and a prebiotic may be provided in any form as described herein.
  • the combination may be provided in a composition as described herein.
  • a bifidogenic prebiotic for use in promoting butyrate-producing bacteria in the gut microbiome of an infant or young child; wherein the bifidogenic prebiotic is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • a Bifidobacterium microorganism for use in promoting butyrate-producing bacteria in the gut microbiome of an infant or young child; wherein the Bifidobacterium is administered to the infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • HMOs human milk oligosaccharides
  • HMOs comprise or consist of a mixture of 2’-fucosyllactose (2’FL), 2’,3-difucosyllactose (diFL), lacto-N-tetraose (LNT), 3’-sialyllactose (3’-SL), and 6’-sialyllactose (6’-SL).
  • a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism for use in treating and/or preventing an allergy and/or allergic sensitization in an infant or young child by promoting butyrate- producing bacteria in the gut microbiome of the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age. 23.
  • a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to promote butyrate-producing bacteria in the gut microbiome of the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiota of the infant or young child between about 1 and 5 years of age.
  • a method of promoting butyrate-producing bacteria in the gut microbiome of an infant or young child comprising administering a bifidogenic prebiotic, a Bifidobacterium microorganism or a combination of a bifidogenic prebiotic and a Bifidobacterium microorganism to the infant or young child; wherein the bifidogenic prebiotic, Bifidobacterium microorganism or a combination is administered to an infant prior to about 12 months of age; and the butyrate-producing bacteria are promoted in the gut microbiome of the infant or young child between about 1 and 5 years of age.
  • Table 1 Infant-type Bifidobacterium spp. (B) was defined according to Laursen et al. (Nature Microbiology volume 6, pagesl 367-1382 (2021)): Table 2: Butyrate producers (P) were defined according to Louis & Flynt (FEMS Microbiol Lett
  • GLMM Linear Mixed Model
  • Bifidobacterium infantis was shown to be the main factor driving the longitudinal association with butyrate producers.
  • HMOs human milk oligosaccharides
  • the standard starter infant was a bovine milk-based whey predominant term infant formula with 67 kcal/100 mL reconstituted formula, consisting of 1.9 g intact protein (70% whey/30% casein)/100 kcal, 11.1 g carbohydrates/100 kcal, and 5.3 g lipids/100 kcal.
  • the concentration of individual HMOs in TG1 and TG2 starter infant formula is shown in Table 3 below.
  • the standard follow-up formula was a bovine milk-based whey predominant term infant formula with 67 kcal/100 mL reconstituted formula, consisting of 2 g intact protein (50% whey/50% casein)/100 kcal, 12.4 g carbohydrates/100 kcal, and 4.7 g lipids/100 kcal.
  • the concentration of total HMOs in TG1 and TG2 follow-up formula was 0.5 g/L of the same blend as the starter infant formula.
  • the standard growing-up milk was a bovine milk-based growing-up milk with 67 kcal/100 mL reconstituted formula, consisting of 2.25 g intact protein (40% whey/60% casein)/100 kcal, 12.6 g carbohydrates/100 kcal, and 4.5 g lipids/100 kcal.
  • the concentration of total HMOs in TG1 and TG2 growing-up milk was 0.4 g/L of the same blend as the starter infant formula.
  • Fecal samples collected at enrolment, 3, 6, 12, and 15 months of age were used for profiling.
  • the infant-type Bifidobacterium were taken as defined in Laursen et al, Nature Microbiology 2021. It included the sum of abundances of B. longum subspp., B. breve, B. bifidum, and B. scardovii. However, B. scardovii was not detected in the gene catalog used to profile the microbiome data from this trial (Bosheva et al. Front Nutr. 2022; 9:920362); the rest of the species were detected and present in the data.
  • Butyrate molecule was measured as part of the organic acids estimated from fecal samples collected in this trial (Bosheva et al.; as above).
  • data transformation cube root
  • V3 refers to 3 months (this visit is after start of the intervention)
  • V7 is at 12 months
  • V8 is at 15 months.

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Abstract

La présente invention concerne un prébiotique bifidogène destiné à être utilisé dans la stimulation de bactéries productrices de butyrate dans le microbiome intestinal d'un nourrisson ou d'un jeune enfant ; le prébiotique bifidogène étant administré au nourrisson avant environ 12 mois d'âge ; et les bactéries productrices de butyrate étant stimulées dans le microbiome intestinal du nourrisson ou du jeune enfant entre environ 1 et 5 ans.
PCT/EP2025/051052 2024-03-13 2025-01-16 Stimulation de bactéries productrices de butyrate dans le microbiome intestinal Pending WO2025190540A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012158517A1 (fr) * 2011-05-13 2012-11-22 Glycosyn LLC Utilisation de 2'-fucosyllactose, 3-fucosyllactose et lactodifucotétraose purifiés en tant que prébiotiques
WO2017129640A1 (fr) * 2016-01-26 2017-08-03 Nestec S.A. Compositions comprenant des oligosaccharides de lait humain destinées à être utilisées chez des nourrissons ou des jeunes enfants pour prévenir ou traiter des allergies
WO2018206434A1 (fr) * 2017-05-09 2018-11-15 Nestec S.A. Production synergique de butyrate associée à la complexité d'un mélange de hmo pour une utilisation chez des nourrissons ou de jeunes enfants à des fins sanitaires
WO2020127642A1 (fr) * 2018-12-21 2020-06-25 Société des Produits Nestlé S.A. Butyrate alimentaire pour le traitement ou la prévention d'un trouble allergique
WO2022036225A1 (fr) * 2020-08-14 2022-02-17 Prolacta Bioscience, Inc. Compositions d'oligosaccharide de lait humain destinées à être utilisées avec des bactériothérapies
WO2022161865A1 (fr) * 2021-01-29 2022-08-04 Societe Des Produits Nestle S.A. Mélange de hmo et de bifidobactéries
WO2023281099A1 (fr) * 2021-07-09 2023-01-12 Société des Produits Nestlé S.A. Utilisations d'un micro-organisme de transition de bifidobacterium longum
WO2024008851A1 (fr) * 2022-07-08 2024-01-11 Société des Produits Nestlé S.A. Utilisations d'un micro-organisme transitoire bifidobacterium longum
WO2024227719A1 (fr) * 2023-04-28 2024-11-07 Société des Produits Nestlé S.A. Composition nutritionnelle
WO2024227720A1 (fr) * 2023-04-28 2024-11-07 Société des Produits Nestlé S.A. Composition nutritionnelle
WO2025008277A1 (fr) * 2023-07-06 2025-01-09 Societe Des Produits Nestle S.A. Combinaison pour la gestion alimentaire de la santé intestinale

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012158517A1 (fr) * 2011-05-13 2012-11-22 Glycosyn LLC Utilisation de 2'-fucosyllactose, 3-fucosyllactose et lactodifucotétraose purifiés en tant que prébiotiques
WO2017129640A1 (fr) * 2016-01-26 2017-08-03 Nestec S.A. Compositions comprenant des oligosaccharides de lait humain destinées à être utilisées chez des nourrissons ou des jeunes enfants pour prévenir ou traiter des allergies
WO2018206434A1 (fr) * 2017-05-09 2018-11-15 Nestec S.A. Production synergique de butyrate associée à la complexité d'un mélange de hmo pour une utilisation chez des nourrissons ou de jeunes enfants à des fins sanitaires
WO2020127642A1 (fr) * 2018-12-21 2020-06-25 Société des Produits Nestlé S.A. Butyrate alimentaire pour le traitement ou la prévention d'un trouble allergique
WO2022036225A1 (fr) * 2020-08-14 2022-02-17 Prolacta Bioscience, Inc. Compositions d'oligosaccharide de lait humain destinées à être utilisées avec des bactériothérapies
WO2022161865A1 (fr) * 2021-01-29 2022-08-04 Societe Des Produits Nestle S.A. Mélange de hmo et de bifidobactéries
WO2023281099A1 (fr) * 2021-07-09 2023-01-12 Société des Produits Nestlé S.A. Utilisations d'un micro-organisme de transition de bifidobacterium longum
WO2024008851A1 (fr) * 2022-07-08 2024-01-11 Société des Produits Nestlé S.A. Utilisations d'un micro-organisme transitoire bifidobacterium longum
WO2024227719A1 (fr) * 2023-04-28 2024-11-07 Société des Produits Nestlé S.A. Composition nutritionnelle
WO2024227720A1 (fr) * 2023-04-28 2024-11-07 Société des Produits Nestlé S.A. Composition nutritionnelle
WO2025008277A1 (fr) * 2023-07-06 2025-01-09 Societe Des Produits Nestle S.A. Combinaison pour la gestion alimentaire de la santé intestinale

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
BEGHINI ET AL., ELIFE, vol. 10, 2021, pages 65088, Retrieved from the Internet <URL:https://huttenhower.sph.harvard.edu/metaphlan>
BERG, G. ET AL., MICROBIOME, vol. 8, no. 1, 2020, pages 1 - 22
BOSHEVA ET AL., FRONT NUTR., vol. 9, 2022, pages 920362
CHAN ET AL.: "Defining bacterial species in the genomic era: insights from the genus Acinetobacter", BMC. MICROBIOL., vol. 12, 2012, XP021134905, DOI: 10.1186/1471-2180-12-302
CLARK, M. J.MILLION, R. P, NATURE REVIEWS, DRUG DISCOVERY, vol. 8, 2009, pages 271 - 272
DEPNER ET AL., NAT MED., vol. 26, no. 11, November 2020 (2020-11-01), pages 1766 - 1775
DONKOR, GENES, vol. 4, no. 4, 2013, pages 556 - 572
EWASCHUK JB ET AL., AM J PHYSIOL GASTROINTEST LIVER PHYSIOL., vol. 295, no. 5, November 2008 (2008-11-01), pages 1025 - 34
FAZLOLLAHI ET AL., ALLERGY, vol. 73, no. 7, July 2018 (2018-07-01), pages 1515 - 1524
GALAZZO ET AL., GASTROENTEROLOGY, vol. 158, no. 6, May 2020 (2020-05-01), pages 1584 - 1596
GIBSON GRROBERFROID MB: "Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics", J NUTR., vol. 125, 1995, pages 1401 - 12
GORIS ET AL., INT SYST EVOL MICROBIOL., vol. 57, no. 1, 2007, pages 81 - 91
GORIS ET AL.: "DNA-DNA hybridization values and their relationship to whole-genome sequence similarities", INT. J. SYST. EVOL. MICROBIOL., vol. 57, 2007, pages 81 - 91
HEYMAN M., EUR. J. GASTROENTEROL. HEPATOL., vol. 17, pages 1279 - 1285
HODGKINSON ET AL., CLIN NUTR., vol. 42, no. 2, February 2023 (2023-02-01), pages 61 - 75
HOSKINSON ET AL., NAT COMMUN., vol. 14, no. 1, 29 August 2023 (2023-08-29), pages 4785
HUSSAIN M. ET AL., J. ALLERGY CLIN. IMMUNOL., 2019
KIM ET AL.: "Towards a taxonomic coherence between average nucleotide identity and 16S rRNA gene sequence similarity for species demarcation of prokaryotes", INT. J. SYST. EVOL. MICR., vol. 64, 2014, pages 346 - 351, XP055877627, DOI: 10.1099/ijs.0.059774-0
KONSTANTINIDIS, K. T.TIEDJE, J. M., PROC. NATL. ACAD. SCI. U.S.A., vol. 102, 2005, pages 2567 - 2572
KONSTANTINIDISTIEDJE, PROC NATL ACAD SCI USA, vol. 102, no. 7, 2005, pages 2567 - 72
LAURSEN ET AL., NATURE MICROBIOLOGY, 2021
LOUISFLINT, APPL ENVIRON MICROB, vol. 73, no. 2009-2012, 2007
LOUISFLINT, FEMS MICROBIOL LETT, vol. 294, no. 1, 2009, pages 1 - 8
LOUISFLINT, FEMS MICROBIOLOGY LETTERS, vol. 294, no. 1, 2009, pages 1 - 8
NOVICHKOV ET AL., BIOINFORMATICS, vol. 32, no. 15, 2016, pages 2380 - 23811
ODENWALD M., NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, vol. 9, no. 14, 2017, pages 21
OSTBLOM, E. ET AL., CLINICAL AND EXPERIMENTAL ALLERGY, vol. 38, no. 8, 2008, pages 1325 - 1332
POMÉS, A. ET AL., MOLECULAR IMMUNOLOGY, 2018
RADAUER, C. ET AL., ALLERGY, vol. 69, no. 4, 2014, pages 413 - 419
RICHTER ET AL.: "Shifting the genomic gold standard for the prokaryotic species definition", P NATL ACAD SCI USA, vol. 106, 2009, pages 19126 - 19131
RICHTERROSSELLO-MORA, PROC NATL ACAD SCI USA, vol. 106, 2009, pages 19126 - 19131
SALMINEN SOUWEHAND ABENNO Y ET AL.: "Probiotics: how should they be defined", TRENDS FOOD SCI. TECHNOL., vol. 10, 1999, pages 107 - 10, XP055150446
SASAKI ET AL., ALLERGY, vol. 77, no. 12, 2 August 2022 (2022-08-02), pages 3629 - 3640
SEGERMAN, FRONT. CELL. INFECT. MICROBIOL., vol. 10, 2020
TULYEU J, MICROORGANISMS, vol. 7, no. 10, 16 October 2019 (2019-10-16)
VARGHESE ET AL., NUCLEIC ACIDS RESEARCH, vol. 43, no. 14, 2015, pages 6761 - 6771
VENTURA , M. T ET AL., DIG. DIS. SCI., vol. 38, 2006, pages 732 - 736
WAYNE ET AL.: "Report of the Ad-Hoc-Committee on Reconciliation of Approaches to Bacterial Systematics", INT J SYST BACTERIOL, vol. 37, 1987, pages 463 - 464
WOPEREIS ET AL., J ALLERGY CLIN IMMUNOL., vol. 141, no. 4, April 2018 (2018-04-01), pages 1334 - 1342
YANG ET AL., NAT COMMUN., vol. 11, no. 1, 8 September 2020 (2020-09-08), pages 4457
YIP ET AL., FRONT IMMUNOL., vol. 12, 15 February 2021 (2021-02-15), pages 628453
YOON ET AL., ANTONIE VAN LEEUWENHOEK, vol. 110, 2017, pages 1281 - 1286
ZEUNER ET AL., MOLECULES, vol. 24, no. 11, 2019, pages 2033

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