WO2025242902A1 - Mélange d'oligosaccharides pour le développement cérébral - Google Patents

Mélange d'oligosaccharides pour le développement cérébral

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Publication number
WO2025242902A1
WO2025242902A1 PCT/EP2025/064367 EP2025064367W WO2025242902A1 WO 2025242902 A1 WO2025242902 A1 WO 2025242902A1 EP 2025064367 W EP2025064367 W EP 2025064367W WO 2025242902 A1 WO2025242902 A1 WO 2025242902A1
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WIPO (PCT)
Prior art keywords
social
nutritional composition
infant
hmos
bgos
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PCT/EP2025/064367
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English (en)
Inventor
Ingrid Brunhilde RENES
Cornelus Johannes Petrus Van Limpt
Jan Knol
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Nutricia NV
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Nutricia NV
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Publication of WO2025242902A1 publication Critical patent/WO2025242902A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; PREPARATION THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/20—Dietetic milk products not covered by groups A23C9/12 - A23C9/18
    • A23C9/203—Dietetic milk products not covered by groups A23C9/12 - A23C9/18 containing bifidus-active substances, e.g. lactulose; containing oligosaccharides
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/28—Oligosaccharides
    • A23V2250/284—Oligosaccharides, non digestible

Definitions

  • the invention relates to a nutritional composition for infants and young children for use in improving brain development.
  • Human milk contains substantial amounts of non-digestible carbohydrates, known as human milk oligosaccharides (HMOs). Mature human milk contains 5 to 15 g/l of HMOs. It is presumed that more than 200 structurally distinct oligosaccharides are present.
  • the building blocks of human milk oligosaccharides are the monosaccharides D-glucose (Glc), D-galactose (Gal), N-acetylglucosamine (GIcNAc), L-fucose (Fuc), and sialic acid (N-acetyl neuraminic acid (Neu5Ac).
  • Lactose forms the reducing end and can be elongated with N-acetyllactosamine repeat units (Galp1-3/4GlcNAc). Lactose, type 2 polylactosamine or type I Lacto-N-biose backbone structures can be sialylated at the terminal Gal in a2-3 and/or a2-6 linkages and/or fucosylated at the terminal Gal in a1-2, or on internal Glc or GIcNAc residues in a1-3, and/or a1-4 linkages.
  • HMOs in human milk improve the intestinal microbiota by stimulating bifidobacteria and other beneficial lactic acid producing bacteria and thereby inhibit the growth of potentially pathogenic bacteria. HMOs furthermore inhibit binding of pathogenic microorganisms to the infant's epithelial cell surface. HMOs have also been shown to improve neurodevelopment and cognition (Martin et al., 2016, Nutrients 8:279).
  • WO 2021/116236 discloses age staged nutritional compositions comprising a HMOs mix.
  • at least one of the nutritional compositions comprises a prebiotic, preferably the prebiotic comprises polydextrose, galacto-oligosaccharides, or a combination thereof.
  • WO 2018/215572 discloses a nutritional composition comprising a Human Milk Oligosaccharide (HMO) having an effect on the promoting, enhancement or improvement of the short-term memory of the subjects in infants and/or young children.
  • HMO Human Milk Oligosaccharide
  • the HMO may be 2FL, difucosyllactose (DFL) and/or lacto-N-tetraose LNT and/or lacto-N-neotetraose (LNnT) or combinations thereof.
  • WO 2020/001862 discloses a nutritional composition comprising human milk oligosaccharide (HMO) having an effect on a mammal to improve, enhance, promote or modulate a serotonergic function in the CNS, preferably in a human infant or a young child, preterm or term, between birth and 7 years.
  • HMO human milk oligosaccharide
  • the HMO may be 2FL, DFL and/or LNT and/or LNnT or combinations thereof.
  • WO 2020/001863 discloses a nutritional composition comprising human milk oligosaccharides (HMO) implicated in improving, enhancing, promoting, or modulating GABAergic function in the CNS, preferably in a human infant or a young child, preterm or term, between birth and 7 years.
  • HMO human milk oligosaccharides
  • the HMO may be 2FL, DFL and/or LNT and/or LNnT, or combinations thereof.
  • WO 2017/021476 discloses a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide for promoting or inducing a global gut microbiota that is closer to the one of infants fed exclusively with human breast milk, in comparison to infants fed with a conventional nutritional composition.
  • WO 2019/215289 discloses nutritional compositions that are useful for promoting beneficial bacteria in the gastrointestinal tract of a Caesarean-section (C-section)-delivered infant.
  • the nutritional composition can include a prebiotic composition comprising human milk oligosaccharides (HMO), milkfat globule membrane (MFGM), and galacto-oligosaccharides (GOS) and/or polydextrose (PDX).
  • HMO human milk oligosaccharides
  • MFGM milkfat globule membrane
  • PDX galacto-oligosaccharides
  • the inventors thus found that that a combination of bGOS, IcFOS and HMOs exerts beneficial effects on social recognition memory and social behaviour. It was also found that the adverse effects on brain development as a result of antibiotic treatment can be prevented and/or treated.
  • the present invention thus concerns compositions comprising non-digestible oligosaccharides (NDO), wherein the NDO comprise i) betagalacto-oligosaccharide (bGOS), ii) long chain fructo-oligosaccharide (IcFOS) and iii) human milk oligosaccharides (HMOs), wherein the HMOS comprise at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide for use in improving and/or ameliorating social recognition improving and/or ameliorating social behaviour and/or social behaviour development.
  • the nutritional composition is particularly of benefit in an infant or young child, in particular in infants or young children at risk of impaired brain development, in particular infant born by
  • a composition comprising digestible carbohydrate, protein, lipid, and non-digestible oligosaccharides (NDO), wherein the NDO comprise i) betagalacto-oligosaccharide (bGOS), ii) long chain fructo- oligosaccharide (IcFOS) and iii) human milk oligosaccharides (HMOs), wherein the HMOS comprise at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide for use in improving and/or ameliorating social recognition improving and/or ameliorating social behaviour and/or social behaviour development in an infant or young child, wherein said composition is not human milk.
  • NDO non-digestible oligosaccharides
  • bGOS betagalacto-oligosaccharide
  • IcFOS long chain fructo- oligosaccharide
  • HMOs human milk oligosaccharides
  • the HMOS comprise at least one fucosy
  • composition for use according to the preceding embodiments wherein social recognition comprises social memory and social recognition memory.
  • Composition for use according to the preceding embodiments wherein improving and/or ameliorating social recognition, social behaviour and/or social behaviour development comprises improving corticolimbic signaling in the prefrontal cortex and/or amygdala; increasing and/or enhancing glutamate re-uptake and/or myelinization in the amygdala; improving blood brain barrier establishment; and/or improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex.
  • composition for use according to the preceding embodiments wherein the infant is an antibiotic treated infant wherein the adverse effects of antibiotic on social recognition and/or social behaviour; learning; and/or memory are prevented and/or treated.
  • Nutritional composition for use according to the preceding embodiments, wherein the composition comprises 2.5 to 20 wt% of non-digestible oligosaccharides consisting of i) bGOS, ii) IcFOS) and iii) HMOs, more preferably 2.5 to 15 wt%, even more preferably 3.0 to 10 wt%, most preferably 5.0 to 7.5 wt%, based on total dry weight of the composition, or when in liquid form, 0.35 to 2.5 wt% total NDO, more preferably 0.35 to 2.0 wt%, even more preferably 0.4 to 1.5 wt%, based on 100 ml of the composition.
  • non-digestible oligosaccharides consisting of i) bGOS, ii) IcFOS) and iii) HMOs, more preferably 2.5 to 15 wt%, even more preferably 3.0 to 10 wt%, most preferably 5.0 to 7.5 wt%, based on total
  • composition for use according to the preceding embodiments, wherein the HMOs comprise 35 to 55 wt% 2’-FL, 10 to 25 wt% 3-FL, 4 to 10 wt% 3’-SL and 5 to 30 wt% 6’-SL based on total HMO weight.
  • compositions for use according to any one of the preceding embodiments wherein the composition is a nutritional composition selected from an infant formula, a follow-on formula, or a growing up milk, preferably an infant formula.
  • the present invention concerns a nutritional composition for infants comprising a mixture of human milk oligosaccharides (HMOs), beta-galacto-oligosaccharides (bGOS) and long chain fructo-oligosaccharides (IcFOS).
  • HMOs human milk oligosaccharides
  • bGOS beta-galacto-oligosaccharides
  • IcFOS long chain fructo-oligosaccharides
  • the invention further pertains to a nutritional composition
  • a nutritional composition comprising digestible carbohydrate, protein, lipid, and non-digestible oligosaccharides (NDO), wherein the NDO comprise i) betagalactooligosaccharide (bGOS), ii) long chain fructo-oligosaccharide (IcFOS) and iii) human milk oligosaccharides (HMOs), wherein the HMOS comprise at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide for use in improving and/or ameliorating social recognition, wherein social recognition comprises social memory and/or social recognition memory; improving and/or ameliorating social behaviour and/or social behaviour development in an infant or young child.
  • the nutritional composition according to the invention is not human milk.
  • the use of the present invention is in a human subject, more preferably in a human young child of 1 , 2 or 3 year of age, or an infant of 0 up to 12 months of age, more preferably in a human young child of 1 or 2 year of age, or an infant of 0 up to 12 months of age, even more preferably an infant 0-12 months and most preferably an infant of 0-6 months.
  • the nutritional composition is advantageously for use in infants or young children, preferably for infant or young children that were born via C-section and/or treated with antibiotics, preferably infants treated with antibiotics.
  • prevention means “reducing the risk of (occurrence)” or “reducing the severity of’.
  • prevention of a certain condition also includes “treatment of a person at (increased) risk of said condition”.
  • infant is a child under the age of 12 months.
  • young child means a child aged between one and less than three years, also called toddler.
  • An "infant, young child or child born by C-section” means an infant, young child or child who was delivered by caesarean section. It means that the infant, young child, or child was not vaginally delivered.
  • the expression "nutritional composition” means a composition which nourishes a subject.
  • This nutritional composition is to be taken orally or parenterally, and it generally includes a lipid or fat source, a protein source and a carbohydrate source,
  • the nutritional composition of the invention is a synthetic nutritional composition, i.e. the nutritional composition is not human or animal’s milk.
  • composition of the present invention is a "synthetic nutritional composition".
  • synthetic nutritional composition means a mixture obtained by chemical and/or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic combination or synthetic composition is not breast milk).
  • infant formula refers to a foodstuff intended for nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91/321/EEC 2006/141/EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose).
  • infant formula encompasses both "starter infant formula” and “followup formula” or “follow-on formula”.
  • HMO human milk oligosaccharide(s).
  • HMOs are complex carbohydrates found in human breast milk ((Urashima et al.: Milk Oligosaccharides. Nova Science Publisher (2011); Chen Adv. Carbohydr. Chem. Biochem. 72, 113 (2015)). These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes.
  • Each human milk oligosaccharide is based on a combination of lactose and one or more of four monosaccharides (N-acetyl-D-glucosamine, D-galactose, sialic acid and/or L-fucose) to for an oligosaccharide.
  • HMOs can be divided in neutral or non-acidic HMOs which can either be fucosylated or non-fucosylated, and acidic HMOs that have at least one sialyl residue in their structure.
  • lactose is not regarded as an HMO species.
  • HMOs can be manufactured by means known in the art.
  • a "fucosylated oligosaccharide” is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are 2'FL (2'-fucosyllactose), 3-FL (3- fucosyllactose), difucosyllactose (DFL), Lacto- difucotetraose (LDFT)), 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, difucosyilacto-N-neohexaose II and any combination thereof.
  • a "sialylated oligosaccharide” is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue. It has an acidic nature.
  • Some examples are 3-SL (3’sialyllactose) and 6'SL (6'sialyllactose).
  • N-acetylated oligosaccharide(s) encompasses both "N-acetyllactosamine” and “oligosaccharide(s) containing N-acetyl-lactosamine". They are neutral oligosaccharides having an N- acetyl-lactosamine residue. Suitable examples are LNT (lacto-N-tetraose), para-lacto-N-neohexaose (para- LNnH) and LNnT (lacto-N- neotetraose).
  • 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.
  • DP degree of polymerization
  • Social recognition as used herein comprises social recognition memory or social memory as used herein is an essential and basic component of social behaviour that is used to discriminate familiar and novel animals/humans.
  • the hippocampus, amygdala, and anterior cingulate cortex (ACC) are critical regions for the formation/consolidation of social recognition whereas the medial prefrontal cortex (mPFC) and amygdala are involved in the regulation of social behaviours such as social interaction and approach.
  • Social recognition can be assessed using a task in mice wherein an adult mouse is allowed to recognize a juvenile mouse through investigations of the juvenile mouse (Tanimizu et al. J Neurosci. 2017 Apr 12; 37(15): 4103— 4116.). The difference in social investigation times between the first and second exposures to a juvenile mouse reflects the familiarity of the two mice.
  • Social memory refers to an individual’s ability to remember information related to social interactions, group identities, and past experiences with other individuals within their social context. It encompasses the collective recollection of events, people, and shared experiences within a community or group.
  • Social recognition memory as used herein focuses on the ability to recognize and remember familiar individuals. It allows humans and animals to correctly respond to visitors in cooperative or competitive social situations. Examples include remembering a mating partner or recognizing threatening visitors to an animal’s habitat.
  • Both social memory and social recognition memory are part of a broader concept that encompasses both social memory and social recognition memory.
  • Social memory in turn encompasses the broader context of shared group experiences, while social recognition memory specifically focuses on remembering familiar individuals within a social group.
  • Social recognition includes both memory aspects and the ability to recognize unique characteristics in social interactions.
  • the nutritional composition comprises a mixture of human milk oligosaccharides (HMOs).
  • HMOs human milk oligosaccharides
  • human milk oligosaccharides or “HMO” as used herein refers to non-digestible oligosaccharides which are present in human breast milk.
  • the nutritional composition comprises a mixture of at least one fucosylated oligosaccharide and at least one sialyllacted oligosaccharide.
  • the nutrition composition comprises a mixture of at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide, wherein the HMO mixture preferably comprises 55 - 75 wt%, more preferably 60 - 70 wt% fucosylated HMOs based on weight of the HMOs.
  • the mixture of HMOs comprises 7.5 - 42.5 wt% sialylated HMOs, more preferably 9- 40 wt% sialylated HMOs based on weight of the HMOs.
  • the nutritional composition preferably comprises at least 2 types of HMO, more preferably at least 3 types of HMO, even more preferably at least 4 types of HMO.
  • the fucosylated oligosaccharide is 2’-fucosyllactose (2’-FL) or 3-fucosyllactose (3-FL), and preferably the mixture comprises both 2’-fucosyllactose and 3-fucosyllactose.
  • the sialylated oligosaccharide is 3'-sialyllactose (3’-SL) or 6'-sialyllactose (6’-SL), and preferably the mixture comprises both 3’-sialyllactose and 6’-sialyllactose.
  • the HMO is selected from 2’FL, 3-FL, DFL, 3’SL, 6’SL, and combinations thereof. More preferably the HMO is selected from 2’FL, 3-FL, 3’SL, 6’SL and combinations thereof.
  • the nutritional composition comprises at least 4 types of HMO, said 4 types of HMO being 2’FL, 3-FL, 3’SL, and 6’SL.
  • the HMOs comprises 35 to 55 wt% 2’-FL, 10 to 25 wt% 3-FL, 4 to 10 wt% 3’-SL and 5 to 30 wt% 6’-SL based on total HMO weight.
  • the sum of 2’-FL, 3-FL 3’-SL and 6’-SL is at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 90%, even more preferably 100% based on total HMO weight.
  • the nutritional composition comprises 5 types of HMO, said 5 types of HMO being 2’FL, 3-FL, LNT, 3’SL, and 6’SL. More preferably, the HMO comprises 42-62 wt.% 2’FL, 10- 16 wt.% 3-FL, 20-30 wt.% LNT, 3-5 wt.% 3’SL, and 4-6 wt.% 6’SL based on total HMO weight.
  • Suitable single HMO for the preparation of the nutritional composition are commercially available, for example from Kyowa Hakko Bio, Japan; Friesland Campina, The Netherlands; DSM/Firmenich, Denmark and Novonesis, Denmark. Otherwise, it is well within the reach of the skilled person to obtain HMO by isolation from suitable sources or by chemical synthesis using methods known in the art.
  • the composition When the nutritional composition is a powdered nutritional composition, the composition preferably comprises 300-4000 mg HMO per 100 g dry weight, more preferably 450-2000 mg HMO per 100 g dry weight.
  • the composition When the nutritional composition is a ready-to-drink liquid nutritional composition, the composition preferably comprises 20-400 mg HMO per 100 ml, more preferably 30-300 mg HMO per 100 ml and most preferably 40-250 mg HMO per 100 ml HMO.
  • the nutritional composition When expressed in amounts based on calories, preferably the nutritional composition comprises 30-600 mg HMO per 100 kcal, more preferably 45-450 mg HMO per 100 kcal and most preferably 60-375 mg HMO per 100 kcal.
  • the nutritional composition preferably provides 40-600 mg HMO per serving, more preferably 50-500 mg HMO per serving. In terms of doses, the nutritional composition preferably provides a total daily dose of 0.1-10 g HMO, more preferably a total daily dose of 0.2-7 g HMO and most preferably a daily dose of 0.4-4 g HMO.
  • the nutritional composition comprises beta-galacto-oligosaccharide (bGOS) and long chain fructooligosaccharide (IcFOS).
  • bGOS and IcFOS are both non-digestible oligosaccharides [NDO] which act as a prebiotic.
  • Non-digestible oligosaccharides are oligosaccharides that are nondigested in the stomach or small intestine and reach the colon intact.
  • Maltodextrin, lactose and monomers such as galactose, fucose, and sialic acid are not considered non-digestible oligosaccharides, i.e. they are considered digestible carbohydrates.
  • GOS are non-digestible oligosaccharides preferably having the formula ([galactose]n-glucose; wherein n is an integer ranging from 2 to 10, i.e. 2, 3, 4, 5, 6, ....,10;), wherein the galactose units are preferably in majority linked together via a beta linkage.
  • bGOS are for example sold under the trademark VivinalTM GOS (Borculo Domo Ingredients, Netherlands).
  • Other suitable sources are OligomateTM (Yakult, Japan).
  • the present GOS have an average degree of polymerization (DP) ranging from 1 to 10, more preferably ranging from 2 to 8. In an embodiment the GOS has an average DP of 3 to 7.
  • the GOS comprise mainly beta-1 ,4 linkages and/or beta-1 ,6 linkages between the galactose units, more preferably predominantly beta-1 ,4 linkages.
  • the GOS comprise at least 80 % beta-1 ,4 and beta-1 ,6 linkages based on total linkages.
  • the bGOS is preferably transgalacto-oligosaccharide.
  • a suitable bGOS is commercially available, for example VivinalOGOS (FrieslandCampina DOMO).
  • bGOS is short chain galactooligosaccharide (bGOS) with an average degree of polymerization (DP) in the range of 1 to 10, more preferably in the range of 2 to 8.
  • DP average degree of polymerization
  • the GOS has an average DP of 3 to 7.
  • the present nutritional composition comprises long chain fructo-oligosaccharides (IcFOS).
  • IcFOS is commercially available, for example RaftilinOHP (Orafti).
  • IcFOS is long chain fructo-oligosaccharide (IcFOS) with an average DP in the range of 10-100, more preferably in the range of 20 to 60.
  • a suitable long chain FOS is RaftilinOHP (Orafti).
  • the weight ratio of bGOS to IcFOS ranges from 100:1 to 1 :10, more preferably from 20:1 to 1 :1 , even more preferably from 7:1 to 10:1 , and most preferably the weight ratio is 9:1 .
  • these weight ratios apply to bGOS and IcFOS.
  • the weight ratio of bGOS and IcFOS combined to HMO ranges from 20:1 to 1 :10, more preferably from 15:1 to 1 :5 and most preferably from 10:1 to 1 :1 .
  • the nutritional composition comprises 80 mg to 2 g of bGOS and IcFOS per 100 ml, more preferably 150 mg to 1 .5 g, most preferably 300 mg to 1 g of bGOS and IcFOS per 100 ml.
  • the nutritional composition comprises 120 mg to 3 g of bGOS and IcFOS per 100 kcal, more preferably 225 mg to 2.25 g, most preferably 450 mg to 1.5 g of bGOS and IcFOS per 100 kcal.
  • the nutritional composition preferably comprises 0.25-20 wt.%, more preferably 0.5-10 wt.%, and most preferably 1 .5-7.5 wt.% of bGOS and IcFOS.
  • the nutritional composition preferably comprises a mixture of non-digestible oligosaccharides consisting of HMOs as well as bGOS and IcFOS. Such a mixture may beneficially improve development of social recognition, social behaviour, and cognition.
  • the nutritional composition does not comprise other non-digestible oligosaccharides [NDO] than the mixture of HMOs, bGOS and IcFOS according to the invention.
  • NDO non-digestible oligosaccharides
  • the NDO in the nutritional composition according to the invention consists of at least 90 wt%, more preferably 95 wt% even more preferably at least 98 wt% of the NDO consisting of a mixture of bGOS-lcFOS and HMOs according to the invention.
  • the NDOs in the nutritional composition comprising the combination of bGOS-lcFOS and HMOs according to the invention consist of at least 90 wt%, more preferably 95 wt% even more preferably at least 98 wt% of the NDS according to the invention.
  • the NDO in the nutritional composition consists of the mixture of bGOS-lcFOS and HMOs according to the invention.
  • the total weight ratio of both the mixture of HMOs and the bGOS having a DP between 2 and 8 (DP 2-8) to IcFOS have an average DP of 10 to 100 is from 1/99 to 99/1 , more preferably from 1/19 to 19/1 , more preferably from 1/1 to 19/1 , more preferably from 2/1 to 15/1 , more preferably from 5/1 to 12/1 , even more preferably from 8/1 to 10/1 , even more preferably in a ratio of about 9/1 .
  • a nutritional composition that comprises bGOS, IcFOS and the mixture of HMOs and wherein the total ratio of HMO and bGOS to IcFOS is about 9:1 .
  • the weight ratio of bGOS and IcFOS to HMO ranges from 20 to 1 , more preferably ranges from 10 to 1 , more preferably ranges from 5 to 1 , even more preferably ranges from 2 to 1.
  • a nutritional composition according to the present invention comprises 2.5 to 20 wt% total NDO, more preferably 2.5 to 15 wt%, even more preferably 3.0 to 10 wt%, most preferably 5.0 to 7.5 wt%, based on total dry weight of the composition, i.e., the total wt% of both the mixture of HMO, bGOS and IcFOS.
  • the nutritional composition according to the invention preferably comprises 0.35 to 2.5 wt% total NDO, more preferably 0.35 to 2.0 wt%, even more preferably 0.4 to 1.5 wt%, based on 100 ml of the composition.
  • the nutritional composition comprises digestible carbohydrate.
  • the digestible carbohydrate preferably provides 30 to 80% of the total calories of the nutritional composition.
  • the digestible carbohydrate provides 40 to 60% of the total calories.
  • the nutritional composition preferably comprises of 5 to 20 g of digestible carbohydrate per 100 kcal, more preferably 7.5 to 15 g.
  • the nutritional composition preferably comprises 3 to 30 g digestible carbohydrate per 100 ml, more preferably 6 to 20 g, even more preferably 7 to 10 g per 100 ml.
  • the nutritional composition preferably comprises 20 to 80 wt.%, more preferably 40 to 65 wt.% digestible carbohydrate.
  • Preferred digestible carbohydrate sources are lactose, glucose, sucrose, fructose, galactose, maltose, starch, and maltodextrin.
  • Lactose is the main digestible carbohydrate present in human milk. Lactose advantageously has a low glycaemic index.
  • the nutritional composition preferably comprises lactose.
  • the nutritional composition preferably comprises digestible carbohydrate, wherein at least 35 wt.%, more preferably at least 50 wt.%, more preferably at least 75 wt.%, and most preferably at least 95 wt.% of the digestible carbohydrate is lactose. Based on dry weight the nutritional composition preferably comprises at least 25 wt.% lactose, preferably at least 40 wt.%.
  • the nutritional composition comprises protein.
  • the protein preferably provides 5 to 15% of the total calories, more preferably 6 to 12% of the total calories.
  • protein is present in the nutritional composition below 3.5 gram per 100 kcal, more preferably between 1.8 and 2.1 g protein per 100 kcal, and most preferably between 1.85 and 2.0 g protein per 100 kcal.
  • the protein concentration in a nutritional composition is determined by the sum of protein, peptides, and free amino acids.
  • the amount of protein can be calculated according to the amount of nitrogen multiplied by 6.25.
  • the nutritional composition preferably comprises less than 12 wt.% protein, more preferably between 9.6 and 12 wt.%, most preferably between 10 and 11 wt.% protein.
  • the nutritional composition preferably comprises less than 1.5 g protein per 100 ml, more preferably between 1 .2 and 1 .5 g, even more preferably between 1 .25 and 1 .35 g protein per 100 ml.
  • the source of the protein is preferably selected in such a way that the minimum requirements for essential amino acid content are met, and satisfactory growth is ensured.
  • protein sources based on cows' milk proteins such as whey, casein, and mixtures thereof and proteins based on soy, potato or pea are preferred.
  • the protein source is preferably based on acid whey, sweet whey, whey protein isolate, or mixtures thereof.
  • the nutritional composition comprises at least 3 wt.% casein based on dry weight.
  • the nutritional composition comprises lipid.
  • lipid refers to one or more selected from the group consisting of triglycerides, polar lipids (such as phospholipids, cholesterol, glycolipids, sphingomyelin), free fatty acids, monoglycerides and diglycerides.
  • the lipid provides preferably 30 to 60% of the total calories of the nutritional composition. More preferably the nutritional composition comprises lipid providing 35 to 55% of the total calories, even more preferably the nutritional composition comprises lipids providing 40 to 50% of the total calories.
  • the lipids are preferably present in an amount of 4 to 6 g per 100 kcal.
  • the nutritional composition preferably comprises 2.1 to 6.5 g lipids per 100 ml, more preferably 3.0 to 4.0 g per 100 ml. Based on dry weight, the nutritional composition preferably comprises 10 to 50 wt.%, more preferably 12.5 to 40 wt.% lipids, even more preferably 19 to 30 wt.% lipids.
  • the lipid preferably comprises vegetable lipid.
  • the presence of vegetable lipids advantageously enables an optimal fatty acid profile, high in polyunsaturated fatty acids and/or more reminiscent to human milk fat.
  • Lipid from mammalian milk alone, e.g., cow’s milk do not provide an optimal fatty acid profile.
  • the amount of essential fatty acids is too low in mammalian milk.
  • LC-PUFA such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), preferably docosahexaenoic acid is present.
  • the nutritional composition comprises at least one, preferably at least two vegetable lipid sources selected from the group consisting of linseed oil (flaxseed oil), rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), sunflower oil, high oleic sunflower oil, safflower oil, high oleic safflower oil, olive oil, coconut oil, palm oil and palm kernel oil.
  • Suitable sources for providing DHA and ARA are fish oil, marine oil and microbial oils known in the art.
  • the nutritional composition is preferably selected from infant formula, follow-on formula, and young child formula. More preferably, the nutritional composition is an infant formula or a follow-on formula. Most preferably, the nutritional composition is an infant formula.
  • infant formula or “follow-on formula” or “young child formula” refers to compositions that are artificially made or that are synthetic This means that the composition that is administered is not human milk. It also means that the composition that is administered is not native cow’s milk or native milk from another mammal.
  • infant formula refers to nutritional compositions, artificially made, intended for infants of 0 to about 4 to 6 months of age and are intended as a substitute for human milk. Typically, infant formulae are suitable to be used as sole source of nutrition. Such formulae are also known as starter formula. Formula for infants starting for 4 to 6 months of life to 12 months of life are intended to be supplementary feedings to infants that start weaning on other foods.
  • Such formulae are also known as follow-on formulae.
  • Infant formulae and follow-on formulae are subject to strict regulations, for example the EU regulations no. 609/2013 and no. 2016/127.
  • young child formulae refer to nutritional compositions, artificially made, intended for infants of 12 months to 36 months, which are intended to be supplementary feedings to infants.
  • Such formulae are also known as growing-up milks.
  • the nutritional composition is preferably an infant formula or follow-on formula and preferably comprises 3 to 7 g lipid/100 kcal, preferably 4 to 6 g lipid/100 kcal, more preferably 4.5 to 5.5 g lipid/100 kcal, preferably comprises 1 .7 to 5 g protein/100 kcal, more preferably 1 .8 to 3.5 g protein/100 kcal, even more preferably 1.8 to 2.1 g protein/100 kcal, most preferably 1 .8 to 2.0 g protein/100 kcal and preferably comprises 5 to 20 g digestible carbohydrate/100 kcal, more preferably 6 to 16 g digestible carbohydrate/100 kcal, and most preferably 10 to 15 g digestible carbohydrate/100 kcal.
  • Non-digestible oligosaccharides have a caloric density of 2 kcal/g and preferably make up 0.4 to 7% of total calories of the nutritional compositions according to the invention.
  • the nutritional composition is an infant formula or follow-on formula and when in a ready-to-drink format has an energy density of 60 kcal to 75 kcal/100 ml, more preferably 60 to 70 kcal/100 ml. This density ensures an optimal balance between hydration and caloric intake.
  • the nutritional composition is a powder.
  • the nutritional composition is in a powdered form, which can be reconstituted with water or other food grade aqueous liquid, to form a ready- to drink liquid, or is in a liquid concentrate form that should be diluted with water to a ready-to-drink liquid.
  • compositions according to the invention comprising HMO, bGOS and IcFOS are preferably used for providing nutrition to an infant or young child, preferably an infant.
  • the HMO in the composition according to the invention comprises at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide.
  • the present composition can advantageously be applied as a complete nutrition for infants.
  • the nutritional composition comprising the HMO, bGOS, IcFOS mixture is a first infant formula for the first 6 months of life, wherein the formula comprises the HMO, bGOS, IcFOS mixture according to the invention and wherein the HMO in the nutritional composition according to the invention comprises at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide.
  • the nutritional composition of the present invention is provided to a human subject during the first 3 years of life.
  • the nutritional composition is used in a method or for use for providing nutrition to a human subject in the first 12 months of life, optionally the first 3 years of life.
  • the nutritional composition according to the invention is for use in providing nutrition to an infant, preferably infants exposed to antibiotics and/or infants born by C-section, preferably directly after birth and up to 12 months of age.
  • the nutritional composition is administered in the first 12 months of life.
  • the nutritional composition is preferably administered in the first 12 months of life, more preferably in the first 6 months of life, more preferably in the first 3 months of life, most preferably in the first month of life.
  • the composition is administered to C-section infants starting at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth.
  • the composition is administered to infants treated with antibiotics starting at least in the first two weeks after treatment, preferably within the first week after treatment, more preferably at least within 5 days after treatment, even more preferably at least within 3 days after treatment, even more preferably at least within 2 days after treatment, most preferably at the same day as antibiotics treatment is started.
  • the invention further concerns the nutritional composition for use in therapy.
  • said nutritional composition according to the invention for therapeutic use is administered to an infant or young child, preferably an infant, more preferably to a C-section born infant and/or antibiotic treated infant, even more preferably an antibiotic treated infant.
  • the present invention aims to promote social recognition comprising social memory and/or social recognition memory, social behaviour and/or social behaviour development in infants, preferably C-section born infants and/or antibiotic treated infants, even more preferably antibiotic treated infants. These infants are at risk of impaired social recognition, social behaviour and/or impaired development of social recognition and/or social behaviour.
  • the invention further pertains to the nutritional composition for use in restoring and/or alleviating the effects on brain development in infants, preferably C-section born infants and/or antibiotic treated infants, even more preferably antibiotic treated infants.
  • the nutritional composition of the present invention is preferably suitable for use of, or in a method of providing nutrition to infants suffering from or at risk of impaired social recognition, impaired social memory and/or social recognition memory, impaired social behaviour and/or social behaviour development.
  • the invention further pertains to nutritional compositions according to the invention comprising HMO, bGOS and IcFOS for therapeutic use in improving and/or ameliorating social recognition improving and/or ameliorating social recognition comprising improving and/or ameliorating social memory or social recognition memory improving and/or ameliorating social behaviour and/or social behaviour development.
  • the therapeutic use in improving and/or ameliorating social recognition, social behaviour and/or social behaviour development comprises improving corticolimbic signalling in the prefrontal cortex and/or amygdala; increasing and/or enhancing glutamate re-uptake and/or myelinisation in the amygdala; improving blood brain barrier establishment; and/or improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex.
  • the use further pertains to improved central nervous system development (CNS) and blood brain barrier (BBB) establishment.
  • CNS central nervous system development
  • BBB blood brain barrier
  • the nutritional composition is for use in improving and/or ameliorating social recognition, improving and/or ameliorating social memory or social recognition memory, improving and/or ameliorating social behaviour and/or social behaviour development and/or improving in an infant, more preferably to a C-section born infant and/or antibiotic treated infant, even more preferably an antibiotic treated infant.
  • the nutritional composition is for use in countering and/or improving and/or ameliorating antibiotic- induced changes in brain and behaviour.
  • the nutritional composition is for use in restoring and/or alleviating adverse effects on brain development in infants, preferably C-section born infants and/or antibiotic treated infants, even more preferably antibiotic treated infants.
  • the nutritional composition is for use in restoring and/or alleviating the adverse effects of an antibiotic on social recognition, social behaviour, learning, memory and/or CNS development.
  • Restoring and/or alleviating adverse effects on brain development in said infants comprises improving corticolimbic signalling in the prefrontal cortex and/or amygdala, increasing and/or enhancing glutamate reuptake and/or myelinisation in the amygdala, improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex.
  • the nutritional composition is for use in improving and/or ameliorating social recognition, improving and/or ameliorating social memory or social recognition memory, improving and/or ameliorating social behaviour and/or social behaviour development in an infant, preferably an infant at risk of autism spectrum disorder.
  • the invention can also be worded as the use of HMO, bGOS and IcFOS, wherein the HMO comprises at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide in the manufacture of a nutritional composition for improving and/or ameliorating social recognition, for improving and/or ameliorating social memory or social recognition memory, improving and/or ameliorating social behaviour and/or social behaviour development in an infant.
  • HMO comprises at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide in the manufacture of a nutritional composition for improving and/or ameliorating social recognition, for improving and/or ameliorating social memory or social recognition memory, improving and/or ameliorating social behaviour and/or social behaviour development in an infant.
  • the use further pertains to improving corticolimbic signalling in the prefrontal cortex and/or amygdala, increasing and/or enhancing glutamate re-uptake and/or myelinisation in the amygdala; improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex in said infant.
  • the use in the manufacture of a nutritional composition further pertains to restoring and/or alleviating the adverse effects of an antibiotic treatment on social recognition, social behaviour, learning, memory and/or CNS development.
  • Restoring and/or alleviating adverse effects on brain development in said infants comprises improving corticolimbic signalling in the prefrontal cortex and/or amygdala, increasing and/or enhancing glutamate re-uptake and/or myelinisation in the amygdala, improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex.
  • the invention concerns a method for improving and/or ameliorating social recognition, improving and/or ameliorating social memory or social recognition memory, social behaviour and/or social behaviour development in an infant in infants at risk of or suffering from impaired social recognition comprising impaired social memory and/or impaired social recognition memory, improving and/or ameliorating social behaviour and/or social behaviour development comprising administering to the infant a nutritional composition comprising HMO, bGOS and IcFOS and wherein the HMO comprises at least one fucosylated oligosaccharide and at least one sialylated oligosaccharide.
  • the method thus further pertains to restoring and/or alleviating the adverse effects of an antibiotic on social recognition, social behaviour, learning, memory and/or CNS development.
  • Restoring and/or alleviating adverse effects on brain development in said infants comprises improving corticolimbic signalling in the prefrontal cortex and/or amygdala, increasing and/or enhancing glutamate re-uptake and/or myelinisation in the amygdala, improving myelination, axonal growth and/or synapse formation in the amygdala and/or prefrontal cortex.
  • Figure 2 The effect of HMOs, GOS/FOS, and HMOs+GOS/FOS on restoration or gene expression in pathways relevant to learning or memory and CNS development in P23 amygdala in response to ABX- treatment is shown.
  • Figure 3 The effect of HMOs, GOS/FOS, and HMOs+GOS/FOS on restoration or gene expression in pathways relevant to learning or memory and CNS development in P23 prefrontal cortex (PFC) in response to ABX-treatment.
  • NIH Swiss (HSD:NIHS) female and male breeder mice were purchased at 8 weeks old from Envigo, UK. After they were acclimated in the animal unit for 1 week in 33x15x13cm white cages with environmental enrichment (bedding, nesting material, cylindrical tube) and access to tap water and chow food ad libitum at 26 degrees Celsius in a 12-hour light, 12-hour dark cycle. Animals were bred for the first time (primiparous), with plug defining the beginning of gestation and the moment of separation of females from the male breeders into their own cage. After separation, the males were sacrificed. Approximately 20 days after plug detection offspring was produced.
  • the offspring in each cage was administered either a broadspectrum antibiotics (ABX) mixture (ampicillin: 0.2mg/g, gentamicin: 0.2mg/g, vancomycin: 0.1 mg/g and imipenem: 0.05mg/g) or tap water (Vehicle) via gavage from postnatal day 3 (P3) to P7.
  • ABX broadspectrum antibiotics
  • a mixture of HMOs 39 wt% 2’-FL, 3-FL, 10 wt% 3’-SL and 28 wt% 6’-SL) or bGOS (GOS sirup Vivinal) /IcFOS (inulin HP) at a 9:1 weight ratio or a combination of HMOs+bGOS/lcFOS consisting of 2.02 parts bGOS and IcFOS and 1.28 parts of the mixture of HMOs (such that the the bGOS, IcFOS, HMO mixture had a 9:1 weight ratio of short chain to long chain oiligosaccharides) was provided to the offspring by oral administration from postnatal day 3 (P3) until P20.
  • P3 postnatal day 3
  • the three-chamber social interaction test is widely used to evaluate social behaviour as previously described by Desbonnet et al. 2014.
  • animals were placed in a 36x19x30cm rectangular light grey apparatus divided into three chambers (left and right chambers: 13x19x30cm each], and a smaller centre chamber: 9x19x30cm), small circular openings allowed easy access to all compartments.
  • Social novelty recognition was assessed where the experimental animal is allowed to interact with a familiar or novel conspecific animal under a wired mesh (circular, 9cm diameter). All animals were age- and sex-matched; each chamber was cleaned and lined with fresh bedding between trials. Interaction time were recorded by a video camera mounted above the apparatus.
  • the three chambers social interaction test was used to assess the social behaviour in juvenile mice.
  • RNA from dissected P23 amygdala and prefrontal cortex was isolated with the mirVana RNA isolation kit (Invitrogen) and maintained at -80°C until further processing.
  • Paired-end sequence reads were generated using the Illumina NovaSeq 6000.
  • the sequences generated with the NovaSeq 6000 were performed under accreditation according to the scope of BaseClear B.V. (L457; NEN-EN-ISO/IEC 17025).
  • FASTQ read sequence files were generated using bcl2fastq version 2.20 (Illumina). Initial quality assessment was based on data passing the Illumina Chastity filtering. Subsequently, reads containing PhiX control signal were removed using an in-house filtering protocol.
  • RNAseq data was handled in R (v 4.3.1).
  • Gene transcription tables were filtered based on prevalence (50% threshold) and subsequently CLR-transformed, using the same 2/3 pseudocount imputation to deal with zeroes as described in Lubbe et al., 2021 .
  • Targeted enrichment analysis was performed by pre-defining GO terms of interest (astrocyte differentiation G0:0048708, CNS development G0:0007417, cytokine production G0:0001816, ensheathment of neurons G0:0007272, establishment of BBB G0:0060856, fatty acid catabolism G0:0009062, fucose metabolism G0:0006004, ganglioside metabolism G0:0001573, gliogenesis G0:0042063, glutamate metabolism G0:0006536, glutamate reuptake GO:0051935, learning and memory G0:0007611 , myelin sheath G0:0043209, myelination G0:0042552, neurogenesis G0:0022008, neuron projection morphogenesis G0:0048812, oligodendrocyte differentiation G0:0048709, response to AVP GO:1904117, SCFAs biosynthesis G0:0051790, structural constituent of myelin sheath G0:0019911).
  • Enrichment was assessed using hypergeometric tests (e.g., phyperQ in the R stats package) on the subset of genes that were found to be restored on the p ⁇ 0.05 level.
  • Figures were generated in R with ggplot2 (version 3.4.4). Data analysis of non-omics data
  • HMOs and/or GOS/FOS ameliorated the social behaviour deficits in juveniles induced by early-life antibiotic treatment.
  • HMOs and/or GOS/FOS restored pathways involved in myelination, CNS development and learning and memory in the juvenile amygdala.
  • the amygdala is a brain area relevant for social behaviour, as it is the brain centre for emotional processing (Garrido Zinn et al., 2016; Tanimizu et al., 2017).
  • Pathway enrichment analysis revealed that pathways involved in learning and memory, CNS development, glutamate re-uptake and establishment of blood brain barrier (BBB) were significantly enriched in animals that received any of the three treatments compared to ABX-treated animals ( Figure 2).
  • BBB blood brain barrier
  • ganglioside metabolism which is also relevant for myelination, was significantly enriched by GOS/FOS and HMOs+bGOS/lcFOS but not HMOs alone.
  • Other pathways of interest that were significantly enriched for any of the prebiotic treatments were neurogenesis, neuron projection morphogenesis and response to vasopressin (Figure 2).
  • HMOs and GOS/FOS restored pathways involved in CNS development and learning and memory in the juvenile PFC.
  • the PFC is an area implicated in social recognition memory, social motivation, decision making and is crucial brain area for social behaviour.
  • pathway enrichment analysis revealed a common pathway that was significantly enriched in both amygdala and PFC termed ‘Learning and Memory’ in response to HMOs+GOS/FOS treatment compared with ABX in juvenile male mice.
  • Previous studies have unmasked links between multiple brain areas implicated in social behaviour and connections between amygdala and prefrontal cortex (PFC) are crucial for social recognition memory (Felix-Ortiz et al., 2016). This conservation of pathways relevant for brain development and learning and memory in both PFC and amygdala might be linked with the enhanced social recognition memory in the animals that received the combination of HMOs+bGOS/lcFOS.
  • the social brain which includes PFC and amygdala, is going through outstanding transformations from childhood all the way to adolescence.
  • the macrostructural changes in the PFC correspond to neurodevelopmental mechanisms at the microstructural level with myelination, axonal growth and synaptic refinement taking a central role during this period.
  • Pathways relevant to neuron projection development and myelination were significantly enriched in the amygdala of the juvenile offspring in response to HMOs, GOS/FOS or HMOs+bGOS/lcFOS. Therefore, changes in gene expression patterns in amygdala and PFC may underly the improvement of social behaviour in prebiotic-treated juvenile mice compared with ABX-treated controls.
  • this example highlights the power of dietary manipulations in early life to counter the effects of antibiotics-induced changes in brain and behaviour. Specifically, it was found that HMOs, bGOS/lcFOS and HMOs+bGOS/lcFOS supplementation in early life has positive effects on the social brain. Overall, the data suggests that the combination of HMOs+bGOS/lcFOS beneficially reverts the adverse effects of antibiotic exposure on the developing brain, particularly improving social recognition memory and social behaviour which is supported by gene expression patterns associated with the establishment of the relevant connections therefore.

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Abstract

L'invention concerne une composition nutritionnelle comprenant des oligosaccharides non digestibles pour nourrissons et/ou jeunes enfants. L'invention concerne en outre l'utilisation de ladite composition nutritionnelle pour améliorer la fonction cérébrale, en particulier la reconnaissance sociale.
PCT/EP2025/064367 2024-05-24 2025-05-23 Mélange d'oligosaccharides pour le développement cérébral Pending WO2025242902A1 (fr)

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