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WO2024227720A1 - Composition nutritionnelle - Google Patents

Composition nutritionnelle Download PDF

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Publication number
WO2024227720A1
WO2024227720A1 PCT/EP2024/061696 EP2024061696W WO2024227720A1 WO 2024227720 A1 WO2024227720 A1 WO 2024227720A1 EP 2024061696 W EP2024061696 W EP 2024061696W WO 2024227720 A1 WO2024227720 A1 WO 2024227720A1
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WO
WIPO (PCT)
Prior art keywords
subject
nutritional composition
lnfp
bifidobacterium
protein
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/EP2024/061696
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English (en)
Inventor
Kieran James
Norbert Sprenger
Jean-Philippe Godin
Karine MEISSER REDEUIL
Peter Erdmann
Florac DE BRUYN
Hanne Lore Paula TYTGAT
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
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Publication date
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Priority to AU2024265200A priority Critical patent/AU2024265200A1/en
Publication of WO2024227720A1 publication Critical patent/WO2024227720A1/fr
Priority to MX2025012912A priority patent/MX2025012912A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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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
    • 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

Definitions

  • the present invention provides a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto-N-fucopentaose-l
  • LNFP-1 LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the invention also provides the use of the nutritional composition for increasing the levels of phenolic amino acid metabolites in the gastrointestinal tract of a subject or modulating the microbiota of a subject.
  • the present invention also provides applications of the nutritional composition in human health.
  • HMOs Human milk oligosaccharides
  • Infancy especially the first weeks, 3 months, 6 months or 12 months of life is a critical period for the establishment of a balanced gut microbiota. It is known that the modulation of the gut microbiota during infancy and early childhood can prospectively have a significant influence in the future health status of the body. For example, the gut microbiome can have an influence on the development of a strong immune system later in life, as well as normal growth, and even on the development of obesity later in life.
  • a healthy intestinal flora is an indicator of the health of an infant and an altered intestinal microbiota can be an indicator (and/or a cause) of abnormal health events such as diarrhea, under-absorption of nutrients, colic, altered sleep and/or altered growth and development. It is known that the mode of delivery can also affect the initial gut microbiota of infants: infants delivered by Caesarean section (C-section) have been shown to have a different gut microbiota compared to vaginally-delivered infants.
  • the gut microbiome and its evolution during the development of the infant or young child is, however, a fine balance between the presence and prevalence (amount) of many populations of gut bacteria.
  • Some gut bacteria are classified as “generally positive” while others are “generally negative” (or pathogenic) regarding their effect on the overall health of the infant.
  • Certain species of “generally positive” bacteria, such as bifidobacteria may be under- represented in infants fed conventional infant formula in comparison to breastfed infants. Similarly, some bacterial populations are considered pathogenic and should remain at a low prevalence in the gut microbiota.
  • Bifidobacterium longum subsp. infantis has been demonstrated to predominate in the gut microbiota of breastfed infants and to benefit the host by accelerating maturation of the immune response, balancing the immune system to suppress inflammation, improving intestinal barrier function, and increasing short-chain fatty acid (SCFA) production.
  • SCFA short-chain fatty acid
  • Bifidobacterium longum subsp. infantis has the ability to efficiently catabolise a wide array of HMO structures, in particular fucosylated HMO glycans.
  • fucosylated HMO glycans Among the commonly-occurring fucosylated HMO glycans in breastmilk is the pentasaccharide lacto-N-fucopentaose I (LNFP- I).
  • LNFP- I pentasaccharide lacto-N-fucopentaose I
  • Phenolic metabolites are increasingly being shown to provide biological benefits in humans.
  • PLA aromatic phenylalanine metabolite 3-phenyllactate
  • the hydroxylated PLA, 3-(4-hydroxyphenyllactate (HO-PLA), has been associated with innate immune (Zugasti et al., Nature Immunology, 2014, 15: 833-838) and antimicrobial (Pahalagedara et al., Metabolites, 2023, 13(2): 252) functions.
  • An isomer of PLA, 3-(4- hydroxyphenyl)propionate (HO-PPA) is also associated with antiviral (Hooda et al., Viruses, 2022, 14: 1778) and anti-inflammatory (Wei et al., FASEB J, 2020, 34: 16117-16128) activities.
  • Lactic Acid Bacteria including breastfeeding-associated Bifidobacteria such as B. longum subsp. infantis are known to convert the amino acids phenylalanine and tyrosine to (hydroxy-)phenyllactate, HO-PPA and HO-P-HO-PA (Smith and Macfarlane, 1996, Journal of Applied Bacteriology, 81 : 288-302). This is due to their expression of an aromatic lactate dehydrogenase (Laursen et al., 2021 , Nat Microbiol, 6: 1367-1382).
  • the present inventors have surprisingly found that the human milk oligosaccharide (HMO) lacto-N-fucopentaose-l (LNFP-I) increases the biosynthesis of phenolic amino acid metabolites (such as 3-phenyllactate (PLA), 3-(4-hydroxyphenyl)propionate (HO-PPA), 3-(4- hydroxyphenyl)lactate (HO-PLA), or 3-hydroxyphenyl-3-hydroxypropionate (HO-P-HO-PA)) by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • HMO human milk oligosaccharide
  • LNFP-I lacto-N-fucopentaose-l
  • the invention provides a nutritional composition comprising LNFP-I and a LNFP- 1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • LNFP-I a LNFP- 1 metabolizing Bifidobacterium
  • a LNFP- 1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp. infantis.
  • the infantis, and phenolic metabolites have been demonstrated to benefit the host and gut environment in multiple ways, including anti-microbial activities against pathogenic species, anti-oxidant, innate immune and anti-inflammatory effects.
  • the invention provides a way to increase the production of a metabolite (i.e. PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA) with known benefits such as anti-microbial, antioxidant, innate immune and anti-inflammatory effects in the intestine.
  • the nutritional composition of the invention would be expected to provide increased beneficial anti-microbial, anti-oxidant, innate immune and anti-inflammatory effects by increasing the production of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject fed the nutritional composition.
  • the invention provides a nutritional composition comprising lacto- N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. Infantis.
  • LNFP-I lacto- N-fucopentaose-l
  • LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. Infantis.
  • the LNFP-1 metabolizing Bifidobacterium is Bifidobacterium longum subsp. infantis.
  • the invention provides a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto-N-fucopentaose-l
  • Bifidobacterium longum subsp. infantis lacto-N-fucopentaose-l
  • the nutritional composition comprises lacto-N-fucopentaose-l (LNFP- I) and as a LNFP-1 metabolizing Bifidobacterium the strain Bifidobacterium longum subsp. Infantis LMG 11588 (also known as ATCC 17930).
  • the composition further comprises a protein source.
  • the protein source is an intact protein source.
  • the intact protein source comprises: a) skimmed milk and demineralized, caseino-glyco-macropeptide (CGMP)-reduced-whey; b) skimmed milk and CGMP-free whey, such as acid or native whey; or c) skimmed milk and alpha-lactalbumin-enriched whey protein.
  • the CGMP-free whey is demineralized CGMP-free whey, such as demineralized CGMP-free acid or native whey.
  • the protein source is a partially hydrolysed protein source.
  • the partially hydrolysed protein source comprises: a) CGMP-free whey protein isolate and demineralized sweet whey protein concentrate; or b) demineralized CGMP-reduced sweet whey and demineralized sweet whey.
  • LNFP-I is present in a total amount of from 25 mg/L to 5000 mg/L of the nutritional composition or of from 0.02-3.75 g/100g of the nutritional composition.
  • LNFP-I is the most abundant HMO in the nutritional composition.
  • LNFP-I is the most abundant fucosylated oligosaccharide in the nutritional composition.
  • the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing- up milk, a fortifier or a supplement.
  • the invention provides the use of a nutritional composition of the invention for increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject, and optionally for further increasing the levels of SCFA in the gastrointestinal tract of the subject, especially for further increasing the levels acetate and butyrate in the gastrointestinal tract of the subject.
  • the invention provides the use of a nutritional composition of the invention for modulating the microbiota of a subject.
  • modulating the microbiota of a subject comprises increasing the abundance of Bifidobacteriaceae and/or a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, in the gastrointestinal tract of the subject.
  • the subject is an infant, a young child or a child.
  • the invention provides a nutritional composition of the invention for use in: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject.
  • the composition is for use in: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject; by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject, and preferably by further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably by further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • the composition is increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject, and preferably is further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably is further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject, and thereby is: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject;
  • modulating the microbiota of a subject comprises increasing the abundance of Bifidobacteriaceae and/or a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, in the gastrointestinal tract of the subject.
  • the subject is an infant, a young child or a child.
  • the invention provides a combination comprising or consisting of lacto-N- fucopentaose-l (LNFP-I), a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, and in further aspects its uses and methods using it.
  • the invention provides a combination comprising or consisting of lacto-N- fucopentaose-l (LNFP-I) and Bifidobacterium longum subsp. infantis, and in further aspects its uses and methods using it.
  • LNFP-I lacto-N- fucopentaose-l
  • Bifidobacterium longum subsp. infantis and in further aspects its uses and methods using it.
  • the invention provides a combination comprising or consisting of lacto-N- fucopentaose-l (LNFP-I), and as a LNFP-1 metabolizing Bifidobacterium he strain Bifidobacterium longum subsp. infantis LMG 11588 (also known as ATCC 17930), and in further aspects its uses and methods using it.
  • LNFP-I lacto-N- fucopentaose-l
  • infantis LMG 11588 also known as ATCC 17930
  • LNFP-I is the most abundant HMO in the combination.
  • LNFP-I is the only HMO in the combination.
  • LNFP-I is the most abundant fucosylated oligosaccharide in the combination.
  • the invention provides a nutritional composition comprising the combination, its uses and methods using it.
  • the invention provides a nutritional composition comprising a combination, the combination comprising or consisting of lacto-N-fucopentaose-l (LNFP-I), the strain Bifidobacterium longum subsp. infantis LMG 11588 (also known as ATCC 17930), and in further aspects its uses and methods using it.
  • LNFP-I lacto-N-fucopentaose-l
  • the strain Bifidobacterium longum subsp. infantis LMG 11588 also known as ATCC 17930
  • the composition is for use in preventing and/or treating fungal, viral and/or bacterial infections in a subject.
  • the composition is for use in preventing and/or treating fungal infections in a subject.
  • the composition is for use in preventing and/or treating viral infections in a subject.
  • the composition is for use in preventing and/or treating bacterial infections in a subject.
  • the composition is for use in preventing and/or treating fungal, viral and bacterial infections in a subject.
  • the composition is for use in preventing and/or reducing inflammation in the intestine of a subject and/or promoting a healthy immune system in a subject.
  • the composition is for use in preventing and/or reducing inflammation in the intestine of a subject.
  • the composition is for use in promoting a healthy immune system in a subject.
  • the composition is for use in preventing and/or reducing inflammation in the intestine of a subject and/or promoting a healthy immune system in a subject.
  • FIG. 1 End of fermentation plate counts for B. infantis following incubation with the various ingredient combinations tested. Each bar represents mean values for three biological replicates per variant. Error bars represent standard deviation.
  • FIG. 1 End of fermentation levels of supernatant 3-(4-hydroxyphenyl)lactate (HO-PLA) or 3-hydroxyphenyl-3-hydroxy propionate (HO-P-HO-PA) following incubation with the various ingredient combinations tested, as detected by UHPLC-HRMS.
  • HO-PLA/ HO-P-HO-PA levels are given in pM concentration.
  • Each box plot represents the distribution of values for three biological replicates per variant. Parentheses represent T-values for each variant compared to the variant LNFP-I + WPG (HA); p ⁇ 0.05.
  • FIG. 3 End of fermentation levels of supernatant 3-phenyl lactate (PLA) or 3-(4- hydroxyphenyl)propionate (HO-PPA) following incubation with the various ingredient combinations tested, as detected by UHPLC-HRMS.
  • PLA/ HO-PPA levels are given in pM concentration.
  • Each box plot represents the distribution of values for three biological replicates per variant. Parentheses represent T-values for each variant compared to the variant LNFP-I + WPC (HA); p ⁇ 0.05.
  • Figure 4 Acetate, butyrate, and total SOFA produced microbially during the fecal fermentation of LNFP-I, Bifidobacterium longum subsp. infantis LMG11588 and WPC (HA) conducted using Cryptobiotix’s ex-vivo SIFR protocol. Adding LNFP-I increases acetate, butyrate, and total SCFA. The levels of SCFA is further boosted by the addition of Bifidobacterium longum subsp. infantis LMG 11588 and WPC (HA).
  • Figure 5 Butyrate and PLA produced microbially during the fecal fermentation of B. infantis LMG11588 and WPC (HA) conducted using Cryptobiotix’s ex-vivo SIFR protocol. A synergy between WPC (HA) and Bifidobacterium longum subsp. infantis LMG 11588 was observed even in the absence of LNFP-I.
  • Figure 6 Biomass growth with LNFP-I and Bifidobacterium longum subsp. infantis LMG11588 (NCC3039) compared to other HMOs. LNFP-I presents a unique diauxic shift. Experiments were conducted in triplicate, with the average being depicted.
  • subject refers to an infant, young child, child, an infant small for gestational age (SGA) or a preterm.
  • SGA gestational age
  • infant means a child under the age of 12 months.
  • young child means a child aged between one and three years, also called toddler.
  • child means a child aged between three and twelve years. Preferably, the term “child” means a child aged between three and six years.
  • preterm or premature subject means an infant or young child who was not born at term. Generally it refers to an infant or young child born prior 36 weeks of gestation.
  • SGA small for gestational age
  • SGA intrauterine growth restriction
  • low birth weight it should be understood as any body weight under 2500g at birth.
  • the expression "nutritional composition” means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and/or a protein source. In a particular embodiment the nutritional composition is a ready-to-drink composition such as a ready-to-drink formula. In a particular embodiment, the nutritional composition of the present invention is a "synthetic nutritional composition".
  • the expression “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 nutritional composition is not breast milk).
  • infant formula refers to a foodstuff intended for particular 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 “follow-up formula” or “follow-on formula”.
  • follow-up formula or “follow-on formula” is given from the 6th month onwards and includes “growing-up milk”. It constitutes the principal liquid element in the progressively diversified diet of this category of person.
  • growing-up milk refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children.
  • baby food means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.
  • infant cereal composition 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 mixing with breast milk or infant formula.
  • weaning period means the period during which the mother's milk is substituted by other food in the diet of an infant or young child.
  • the "mother's milk” should be understood as the breast milk or the colostrum of the mother.
  • oligosaccharide is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).
  • HMO human milk oligosaccharide(s). These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g. pancreatic and/or brush border), indicating that they may display functions not directly related to their caloric value. It has especially been illustrated that 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 terminal positions at the non-reducing ends.
  • the HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g.
  • HMOs fucosylated oligosaccharides
  • N-acetylated oligosaccharides the fucosylated oligosaccharides
  • sialylated oligosaccharides Some examples of HMOs are the fucosylated oligosaccharides, the N-acetylated oligosaccharides and/or the sialylated oligosaccharides.
  • a "fucosylated oligosaccharide” is an oligosaccharide having a fucose residue. It has a neutral nature.
  • Some examples are LNFP-I (lacto-N-fucopentaose I), 2’-FL (2' fucosyllactose), 3-FL (3-fucosyl lactose). Lacto-N-fucopentaose I may be referred to as LNFP-1 or LNFP-I.
  • fucosylated oligosaccharides comprising an alpha-1, 2-fucosyl- epitope encompass fucosylated oligosaccharides with a certain homology of form since they contain an alpha-1 , 2'-fucosyl-epitope, therefore a certain homology of function can be expected.
  • 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. Suitable examples are LNT (lacto- N-tetraose), para-lacto-N-neohexaose (para-LNnH), LNnT (lacto-N-neotetraose) and any combinations thereof.
  • 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.
  • a "sialylated oligosaccharide” is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue.
  • sialyllactose consists of lactose at the reducing terminus and one sialic acid residue at the non-reducing end via an alpha-2,3 binding or alpha-2,6 binding, resulting in 3'-SL and 6'-SL, respectively.
  • a "precursor of HMO” is a key compound that intervenes in the manufacture of HMO, such as sialic acid and/or fucose.
  • GOS means “Galacto-oligosaccharide”.
  • Galacto-oligosaccharides (GOS) as used herein typically consist of p-linked galactose moieties with galactose or glucose at the reducing end.
  • Such GOS contains p-(1— >2), p-(1— >3), p-(1— >4), or p-(1— >6) linked galactose moieties and may have a degree of polymerization (DP) of 3-8 galactose units.
  • DP degree of polymerization
  • GOS is therefore preferably referred to as oligosaccharide(s) comprising at least three galactose units, more preferably as oligosaccharide(s) comprising at least four galactose units, preferably having a degree of polymerization (DP) of 3-8 galactose units.
  • the nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form.
  • the amount of the various ingredients e.g. the oligosaccharides
  • infants/young children fed exclusively with human breast milk can be used interchangeably. They refer to infants or young children fed with a great majority (i.e. at least 90%, or at least 95%, or at least 99%) or all (100%) of nutrients and/or energy originating from human breast milk.
  • conventional nutritional composition refers to standard synthetic nutritional compositions such as infant formula, follow-up milks or growing-up milks already found in the market.
  • microbial microflora
  • microbiota microbiota
  • microbiota in the gut can be used interchangeably.
  • gut microbiota dysbiosis refers to microbial imbalance in the gut.
  • preventing and/or treating gut microbiota dysbiosis encompasses one or several of the following:
  • preventing or “prevention” it is meant avoiding that a physical state, a condition or their consequences occurs and/or decreasing its incidence (i.e. reduction of the frequency).
  • treating or “treatment” it is meant a decrease of the duration and/or of the severity of a physical state, a condition or their consequences (e.g. a decrease or elimination of symptoms of the condition).
  • the prevention and/or the treatment of a physical state, a condition or their consequences can occur during the treatment (i.e. during the administration of the composition of the present invention, either immediately after the start of the administration or some time after, e.g. some days or weeks after the start). But it can also encompass the prevention and/or the treatment later in life.
  • the term “later in life” encompasses the effect after the termination of the intervention or treatment.
  • the effect “later in life” can be from 1 week to several months, or even years, for example from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to 6 months or from 2 to 12 months.
  • the effect “later in life” can be from 12 months to 12 years, such as from 2 years to 10 years, or from 4 years to 5 years, after the administration of the composition.
  • 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).
  • probiotic means microbial cell preparations 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 are generally bacteria or yeasts.
  • Short Chain fatty acids are especially produced by microbial fermentation of dietary fibres in the intestine.
  • increasing SCFA production means that the amount of systemic and/or colonic SCFA, is higher in an individual fed with the nutritional composition according to the present invention in comparison with a standard.
  • the SCFA production may be measured by techniques known by the skilled person such as by Gas-Liquid Chromatography.
  • the “Average Nucleotide Identity (ANI)” is a measure of nucleotide-level genomic similarity between the coding regions of two genomes. Average Nucleotide Identity can be assessed as describe here: Yoon SH, Ha SM, Lim J, Kwon S, Chun J. A large-scale evaluation of algorithms to calculate average nucleotide identity. Antonie Van Leeuwenhoek. 2017 Oct;110(10): 1281- 1286.
  • the strain Bifidobacterium longum subsp. infantis LMG 11588 also known as ATCC 17930
  • longum subsp. infantis LMG 11588 can be found in PATRIC (https://www.patricbrc.org), genome ID 1678.111.
  • the Bifidobacterium longum subsp. infantis strain does not harbour potentially transferable antibiotic resistances.
  • the ANI of the shared genes between two strains is known to be a robust means to compare genetic relatedness among strains.
  • Strains with ANI values of at least about 96% can be considered to belong to the same species (Konstantinidis and Tiedje, 2005, Proc Natl Acad Sci USA, 102(7):2567-72; and Goris et al., 2007, Int Syst Evol Microbiol. 57(Pt 1 ):81 -91), while AN I values of at least about 99% indicate that the bacterial genomes belong to the same strain.
  • 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., 2017, Antonie van Leeuwenhoek 110:1281-1286); ANI Calculator, JSpecies (Richter and Rossello-Mora, 2009, Proc Natl Acad Sci USA 106:19126-19131); and JSpeciesWS (Richter et al., 2016, Bioinformatics 32:929-931). Other methods for determining the ANI of two genomes are known in the art (Konstantinidis, K. T.
  • LNFP-1 metabolizing Bifidobacterium or “LNFP-1 metabolizing Bifidobacteria species” is defined as a Bifidobacterium species or a strain thereof possessing the capacity to hydrolyze alpha 1-2 bound fucose, respectively harbors an 1 ,2-a- L-fucosidase belonging to the glycoside hydrolase 95 (GH95, see Katayama et al., 2004, J. Bacteriol. 186, 4885-4893).
  • composition of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs.
  • the present inventors have surprisingly found that the combination of LNFP-I and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis increases the production of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis. That this specific combination increases the production of PLA by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp.
  • the invention provides a nutritional composition comprising lacto- N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto- N-fucopentaose-l
  • LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the invention provides a combination comprising or consisting of LNFP-I and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the LNFP-1 metabolizing Bifidobacterium is Bifidobacterium longum subsp. infantis.
  • the invention provides a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto-N-fucopentaose-l
  • Bifidobacterium longum subsp. infantis lacto-N-fucopentaose-l
  • the invention provides a combination comprising or consisting of LNFP-I and Bifidobacterium longum subsp. infantis.
  • the combination consists of LNFP-I and Bifidobacterium longum subsp. infantis.
  • Bifidobacterium longum is a bacterium of the Bifidobacterium genus which is present in the human gastrointestinal tract.
  • B. infantis three previously distinct species of Bifidobacterium, B. infantis, B. longum, and B. suis, were unified into a single species named B. longum with the biotypes infantis, longum, and suis, respectively (Sakata, S., et al., 2002. International journal of systematic and evolutionary microbiology, 52(6), pp.1945-1951).
  • Bifidobacterium longum subsp. infantis strain Any suitable Bifidobacterium longum subsp. infantis strain may be used in the present invention. Such strains will be well-known to the skilled person. Suitable strains include Bifidobacterium longum subsp. infantis LMG 11588 (also known as Bifidobacterium longum subsp. infantis NCC3039 or Bifidobacterium longum subsp. infantis ATCC 17930) and Bifidobacterium longum subsp. infantis ATCC 15697 (also known as Bifidobacterium longum subsp. infantis NCC 3078), Rosell-33 (sold by Lallemand), m-63 (sold by Morinaga).
  • the Bifidobacterium longum subsp. infantis may be a strain having at least 99% (suitably, at least 99.9%) ANI to Bifidobacterium longum subsp. infantis strain known to
  • the Bifidobacterium longum subsp. infantis has at least 99% (suitably, at least 99.1 %, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. infantis LMG 11588 (also known as Bifidobacterium longum subsp. infantis NCC3039 or Bifidobacterium longum subsp. infantis ATCC 17930).
  • the Bifidobacterium longum subsp. infantis has at least 99.9% ANI to Bifidobacterium longum subsp. infantis LMG 11588.
  • Bifidobacterium longum subsp. infantis LMG 11588 is sold by the Belgian Coordinated Collections of Microorganisms (BCCM) under the LMG accession number LMG 11588.
  • Suitable LNFP-1 metabolizing Bifidobacteria species may be selected from the list consisting of: Bifidobacterium lactis, B. longum, Bifidobacterium breve, B. longum subsp. infantis, B. longum subsp. iuvenis, B. bifidum, B. pseudocatenulatum and B. kashiwanohense, and any combination thereof.
  • the LNFP-1 metabolizing Bifidobacteria species is Bifidobacterium lactis. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is B. longum. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is Bifidobacterium breve. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is B. longum subsp. infantis. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is B. longum subsp. iuvenis. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is B.
  • the LNFP-1 metabolizing Bifidobacteria species is B. pseudocatenulatum. In one embodiment, the LNFP-1 metabolizing Bifidobacteria species is B. kashiwanohense.
  • Suitable probiotic bacterial strains include Bifidobacterium animalis subsp. lactis CNCM 1-3446 deposited according to the Budapest Treaty on 7 th June 2005 at Collection Nationale Cultures De Microorganismes [French National Collection Of Microorganism Cultures] (CNCM), Institut Pasteur, 25 Rue Du Dondel Roux, F-75724 Paris Cedex 15 (France), or BL818 or Bifidobacterium animalis subsp. lactis sold inter alia by the Christian Hansen company of Denmark under the trademark Bb 12, also known as DSM- 15954, B. longum CNCM 1-2618 (B.
  • Bifidobacterium breve sold by Danisco under the trademark Bb-03 Bifidobacterium breve sold by Morinaga under the trade mark M-16V
  • Bifidobacterium breve sold by Morinaga under the trade mark B-3 Bifidobacterium breve sold by sold by Yakult under the trade mark BBG-01 and Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trademark R0070.
  • the Bifidobacterium longum subsp longum strain may be selected from Bifidobacterium longum subsp longum strain CNCM 1-2169, Bifidobacterium longum subsp longum strain CNCM 1-2171, Bifidobacterium longum subsp longum strain ATCC 15708, Bifidobacterium longum subsp longum strain DSM 20097, Bifidobacterium longum subsp longum strain NCIMB 8809, Bifidobacterium longum subsp longum strain CNCM 1-2618 (NCC 2705), Bifidobacterium longum subsp longum strain CNCM 1-2170, Bifidobacterium longum subsp longum strain ATCC 15707, or a combination thereof, in particular B. longum CNCM 1-2618 (NCC 2705).
  • the Bifidobacterium longum subsp. longum has at least 99% (suitably, at least 99.1 %, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%) ANI to Bifidobacterium longum subsp. longum NCC 2705 (also known as Bifidobacterium longum subsp. longum CNCM 1-2618).
  • the Bifidobacterium longum subsp. longum has at least 99.9% ANI to Bifidobacterium longum subsp. longum NCC 2705.
  • B. longum microorganisms belonging to this clade are referred to herein as Bifidobacterium longum transitional (B. longum transitional) and are also known in the art as B. longum subsp. iuvenis (see Modesto et al; International Journal of Systematic and Evolutionary Microbiology 73(10)).
  • NCC 5000, NCC 5001 , NCC 5002, NCC 5003 and NCC 5004 were deposited with the Collection exactly de cultures de micro-organisms (CNCM), Institute Pasteur (INSTITUT PASTEUR, 25 RUE DU DOCTEUR ROUX, F-75724 PARIS CEDEX 15, FRANCE) by SOCIETE DES PRODUITS NESTLE S.A according to Budapest Treaty on 11th of May 2021 receiving the deposit numbers CNCM I- 5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, respectively.
  • CNCM CollectionInstitut Pasteur
  • SOCIETE DES PRODUITS NESTLE S.A according to Budapest Treaty on 11th of May 2021 receiving the deposit numbers CNCM I- 5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, respectively.
  • a B. longum transitional microorganism has an ANI of at least 96% with at least one B. longum strain selected in the group consisting of CNCM I-5683, CNCM I- 5684, CNCM 1-5685, CNCM 1-5686, CNCM 1-5687, and CMCC-P0001 (ATCC BAA-2753), and any combination thereof.
  • a Bifidobacterium longum transitional microorganism has an ANI of about 96%, 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98%, 98.1 %, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.6 %, 98.7 %, 98.8 %, 98.9 %,
  • a Bifidobacterium longum transitional microorganism has an ANI of at least 96%, of at least 96.1%, of at least 96.2%, of at least 96.3%, of at least 96.4%, of at least 96.5%, of at least 96.6%, of at least 96.7%, of at least 96.8%, of at least 96.9%, of at least 97%, of at least 97.1 %, of at least 97.2%, of at least 97.3%, of at least 97.4%, of at least 97.5%, of at least 97.6%, of at least 97.7%, of at least 97.8%, of at least 97.9%, of at least 98%, of at least 98.1%, of at least 98.2%, of at least 98.3%, of at least 98.4%, of at least 98.5%, of at least 98.6%, of at least 98.6 %, of at least
  • a B. longum transitional microorganism has an Average Nucleotide Identity (ANI) of at least 98% with at least one B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • a B. longum transitional microorganism has an ANI of about 98% to 100% with at least one B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • a B. longum transitional microorganism has an Average Nucleotide Identity (ANI) of at least 98% with at least one B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • longum transitional microorganism has an ANI of at least 98%, 98.1 %, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.6 %, 98.7 %, 98.8 %, 98.9 %, 99 %, 99.1 %, 99.2 %, 99.3 %, 99.4 %, 99.5 %, 99.6 %, 99.7 %, 99.8 %, 99.9 %, or
  • B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • a B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • a B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • a B. longum strain selected in the group consisting of CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, and any combination thereof.
  • longum transitional microorganism has an ANI of at least 98.6%, of at least 98.6 %, of at least 98.7 %, of at least 98.8 %, of at least 98.9 %, of at least 99 %, of at least 99.1 %, of at least 99.2 %, of at least 99.3 %, of at least 99.4 %, of at least 99.5 %, of at least 99.6 %, of at least 99.7 %, of at least 99.8 %, of at least 99.9 % or of at least 100% with at least one B. longum strain selected in the group consisting of CNCM 1-5683, CNCM I- 5684, CNCM 1-5685, CNCM 1-5686 and CNCM 1-5687, and any combination thereof.
  • GenBank accession numbers for the 16S rRNA gene sequence and genome of Bifidobacterium longum subsp. iuvenis NCC 5000T are OP696622 (GenBank) and Ga0527908 (JGI), respectively.
  • a B. longum iuvenis microorganism for use in the present invention has an ANI of at least 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.6 %, 98.7 %, 98.8 %, 98.9 %, 99 %, 99.1 %, 99.2 %, 99.3 %, 99.4 %, 99.5 %, 99.6 %, 99.7 %, 99.8 %, 99.9 %, or 100 % compared to B. longum iuvenis NCC 5000.
  • a B. longum iuvenis microorganism for use in the present invention has an ANI of at least 98.6%, of at least
  • the Bifidobacterium longum transitional microorganism for use according to the invention has an Average Nucleotide Identity (ANI) of at least 98% with the B. longum transitional strain deposited under deposit number CNCM I-5942.
  • ANI Average Nucleotide Identity
  • the Bifidobacterium longum transitional microorganism for use according to the invention has an Average Nucleotide Identity (ANI) of at least 98% with CNCM I-5942.
  • ANI Average Nucleotide Identity
  • the B. longum transitional strain has an ANI of at least 98.1%, at least 98.2%, at least 98.3%, at least 98.4%, of at least 98.5%, of at least 98.6%, of at least 98.6 %, of at least 98.7 %, of at least 98.8 %, of at least 98.9 %, of at least 99 %, of at least 99.1 %, of at least 99.2 %, of at least 99.3 %, of at least 99.4 %, of at least 99.5 %, of at least 99.6 %, of at least 99.7 %, of at least 99.8 %, or of at least 99.9 % compared to the B. longum strain deposited with the CNCM under deposit number CNCM I-5942.
  • the B. longum transitional strain has an ANI of at least at least 99.0%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%, compared to the B. longum strain deposited with the CNCM under deposit number CNCM 1-5942.
  • the B. longum transitional strain has an ANI of at least 99.9% compared to the B. longum strain deposited with the CNCM under deposit number CNCM 1-5942.
  • the B. longum subsp. iuvenis may be B. longum subsp. iuvenis NCC 5025.
  • the B. longum transitional microorganism may be a Bifidobacterium longum transitional microorganism strain deposited with CNCM under deposit number CNCM 1-5942.
  • metagenomics methods may be used. Suitable metagenomics methods may be performed using shotgun sequencing data, for example. Suitable metogenomics methods are known in the art and include MetaPhlAn 3.0, for example (see Beghini et al.; eLife 2021 ;10: e65088; https://huttenhower.sph.harvard.edu/metaphlan).
  • Genome sequences for B. longum transitional strains NCC 5000 (CNCM I-5683), NCC 5001 (CNCM I-5684), NCC 5002 (CNCM I-5685), NCC 5003 (CNCM I-5686) and NCC 5004 (CNCM I-5687) are available via Joint Genome Project (JGI) Study number: Gs0156595 (https://qenome.iqi.doe.gov/portal/). Analysis project numbers and taxon numbers for each genome are as follows:
  • the B. longum transitional microorganism for use in the present invention is isolated from a human.
  • the nutritional composition according to the invention may contain from 10 3 to 10 12 cfu of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 10 1 ° cfu of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, per g of composition on a dry weight basis.
  • the LNFP-1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp.
  • infantis is administered to the subject in an amount of at least about 10 6 cfu/day, at least about 10 7 cfu/day, or at least about 10 8 cfu/day.
  • the LNFP-1 metabolizing Bifidobacterium for example the Bifidobacterium longum subsp. infantis, is administered to the subject in an amount of about 10 12 cfu/day or less, about 10 11 cfu/day or less, or about 1O 10 cfu/day or less.
  • the LNFP-1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp. infantis, is viable.
  • LNFP-I is present in a total amount of from 25 mg/L to 5000 mg/L of the nutritional composition or combination according to the invention or of from 0.02 g/100g to 4 g/100g of the nutritional composition or combination according to the invention.
  • LNFP-I is present in a total amount of from 50 mg/L to 2500 mg/L, for example from 60 mg/L to 2000 mg/L, for example from 80 mg/L to 1000 mg/L of the nutritional composition or combination according to the invention.
  • LNFP-I is present in a total amount of from 0.04 g/100g to 2 g/100g, for example from 0.05 g/100g to 1.6 g/100g, for example from 0.07 g/100g to 0.8 g/ 100g of the nutritional composition or combination (dry weight).
  • LNFP-I may be isolated by chromatography or filtration technology from a natural source such as animal milks.
  • the animal milk as used herein may be cow, sheep, goat, camel or buffalo milk.
  • the animal milk is cow’s milk.
  • the LNFP-I 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.
  • microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Single microbial cultures and/or mixed cultures may be used.
  • DP degree of polymerization
  • Suitable techniques for producing LNFP-I are known in the art (see, for example, Hu et al., Carbohydr Polym, 2022, 297: 120017 and Derya et al., J Biotechnol., 2020, 318: 31-38).
  • LNFP-I may be produced by chemical synthesis from lactose as initial acceptor substrate building an LNT backbone and free fucose as final donor substrate or by starting from LNT for example, produced by biotechnology or chemical synthesis, and using fucose. Fucosylated oligosaccharides are also available for example from DSM of the Netherlands or from Elicityl of France.
  • the composition further comprises a protein source.
  • the protein source has an optimized aminogram, for example enrichment in aromatic amino acids, an adapted protein profile, for example by mixing with casein, and/or adapted peptide profile for metabolic accessibility by Bifidobacterium species, for example by partial hydrolysis.
  • the term “protein source” refers to a source of amino acids.
  • the protein source comprises amino acids.
  • the protein source may comprise amino acids (e.g. free amino acids) or a salt thereof, oligopeptides, peptides, proteins, amino acid precursors or any combination thereof.
  • the protein source may comprise oligopeptides, peptides, proteins, or any combination thereof. More preferably, the protein source may comprise partially hydrolysed or hydrolysed oligopeptides, peptides, proteins, or any combination thereof.
  • free amino acids may refer to amino acid monomers, which are not part of an oligopeptide, peptide, or protein.
  • Amino acid salts may include any physiologically acceptable salt, such as hydrochloride, sodium, potassium, calcium, and magnesium salts.
  • the salt is a sodium or potassium salt.
  • the free amino acids are aromatic amino acid monomers, such as tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the free amino acids are phenylalanine and/or tyrosine monomers.
  • oligopeptides may refer to short chains of amino acid monomers (e.g. 2 to 20 amino acid monomers) linked via peptide bonds and can include dipeptides, tripeptides, tetrapeptides, and pentapeptides.
  • the oligopeptides may be enriched for one or more amino acids or consist solely of a single type of amino acid.
  • the oligopeptides may be enriched for one or more aromatic amino acids or consist solely of a single type of aromatic amino acid.
  • the aromatic amino acids are selected from tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the aromatic amino acids are phenylalanine and/or tyrosine.
  • peptides may refer to short chains of amino acid monomers (e.g. 20 to 50 amino acid monomers) linked via peptide bonds.
  • the peptides may be enriched for one or more amino acids or consist solely of a single type of amino acid.
  • the peptides may be enriched for one or more aromatic amino acids or consist solely of a single type of aromatic amino acid.
  • the aromatic amino acids are selected from tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the aromatic amino acids are phenylalanine and/or tyrosine.
  • polypeptide and “protein” are used herein interchangeably.
  • polypeptides and proteins may refer to long chains of amino acids (e.g. greater than about 50 amino acids).
  • the amino acids may be, partially, or entirely, in the form of proteins.
  • the polypeptides or proteins may be enriched for one or more amino acids or consist solely of a single type of amino acid.
  • the polypeptides or proteins may be enriched for one or more aromatic amino acids or consist solely of a single type of aromatic amino acid.
  • the aromatic amino acids are selected from tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the aromatic amino acids are phenylalanine and/or tyrosine.
  • the protein source has an optimized aminogram, i.e. the amino acid profile of the protein source has been changed to the desired profile.
  • the protein source may be enriched in aromatic amino acids.
  • the protein source may consist of aromatic amino acids.
  • the aromatic amino acids are selected from tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the aromatic amino acids are phenylalanine and/or tyrosine.
  • the protein source has an adapted protein profile and/or an adapted peptide profile for metabolic accessibility by Bifidobacterium species.
  • the protein source may have a structure or composition which avoids digestion of the amino acids by the subject and promotes availability of the amino acids for fermentation by Bifidobacterium species in the large intestine and/or colon of the subject.
  • the protein source has an adapted protein profile.
  • the protein source has an adapted peptide profile.
  • adapted protein profile may refer to the adaptation of the components provided in the protein source, i.e. to adapting the particular oligopeptide, peptide and/or protein components provided in the protein source.
  • adapted peptide profile may refer to the adaptation of the size distribution of the oligopeptides, peptides and proteins.
  • the peptide profile of the protein source may be adapted by partial hydrolysis and/or the protein profile of the protein source may be adapted by mixing with casein.
  • the present inventors have surprisingly found that partial hydrolysis of the protein source increases availability of the amino acids for fermentation by Bifidobacterium species (see Example).
  • TGF-P transforming growth factor beta
  • casein protects TGF-p from digestion by the subject (e.g. by the upper gastrointestinal tract of the subject) such that TGF-p can exert its effects in the large intestine.
  • aromatic amino acids within casein would be expected to avoid digestion of the amino acids by the subject and promote availability of the amino acids for fermentation by Bifidobacterium species in the large intestine and/or colon of the subject.
  • the protein source has an optimised aminogram and an adapted protein profile.
  • the protein source has an optimised aminogram and an adapted peptide profile.
  • the protein source has an optimised aminogram, and an adapted protein profile and an adapted peptide profile.
  • the protein can be in an amount of from 1.4 to 3 g per 100 kcal. In some embodiments, especially when the composition is intended for premature infants, the protein amount can be between 2.4 and 4 g/100kcal or more than 3.6 g/100kcal. In some other embodiments, the protein amount can be below 2.0 g per 100 kcal, e.g. between 1.8 to 2 g/100 kcal, or in an amount below 1.8 g per 100 kcal, such as between 1.4 to 1.8 g protein/IOOkcal.
  • the proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins.
  • intact is meant 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 means in the context of the present invention an oligopeptide, peptide or protein which has been hydrolysed or broken down into its component amino acids.
  • the oligopeptides, peptides or proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed oligopeptides, peptides or proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s milk allergy. If hydrolysed oligopeptides, peptides or 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.
  • the enzyme is a trypsin preparation.
  • the enzyme is porcine trypsin.
  • the enzymes are trypsin like or chymotrypsin like enzymes.
  • the proteins of the nutritional composition are hydrolysed, fully hydrolysed or partially hydrolysed.
  • the degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90.
  • the proteins of the nutritional composition are hydrolysed or partially hydrolysed.
  • the average molecular weight is 190 to 2500 Da, preferably 600 to 2000 Da, more preferably 800 to 1500 Da, even more preferably 1000 to 1400 Da, for example 1100 to 1200 Da.
  • At least 70% of the oligopeptides, peptides or proteins are hydrolysed, preferably at least 80% of the oligopeptides, peptides or proteins are hydrolysed, such as at least 85% of the oligopeptides, peptides or proteins are hydrolysed, even more preferably at least 90% of the oligopeptides, peptides or proteins are hydrolysed, such as at least 95% of the oligopeptides, peptides or proteins are hydrolysed, particularly at least 98% of the oligopeptides, peptides or proteins are hydrolysed. In a particular embodiment, 100% of the oligopeptides, peptides or proteins are hydrolysed.
  • suitable protein sources for use according to the invention include an intact protein source and a partially hydrolysed protein source.
  • Protein sources for use according to the invention may be animal milk, prepared from an animal milk or an animal milk fraction comprising free amino acids, oligopeptides, peptides or proteins.
  • Protein sources based on whey, casein and mixtures thereof may be used. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions. Protein sources of bovine, buffalo, goat and sheep origin, or mixtures thereof, may be used. For example, milk protein sources originating from different species may be mixed to provide the desired caseimwhey ratio. By way of further example, milk protein sources originating from different species may be mixed to provide the desired aminogram and/or bifidobacteria accessible peptide profile. Suitably, the desired aminogram may be one enriched in aromatic amino acids. Preferably, the aromatic amino acids are selected from tryptophan, tyrosine, phenylalanine or any combination thereof. Most preferably, the aromatic amino acids are phenylalanine and/or tyrosine.
  • the milk can be used as such (i.e. powder or liquid) as an ingredient, or these milk sources can be split into casein and whey according to the required application.
  • Caseins in the form of caseinates (Na, K, Ca), or in the form of micellar caseins originating from microfiltration processes may be used. Any suitable techniques which are known in the art for the preparation of such caseinates or micellar caseins may be used (see, for example, Carter et a/., J Dairy Sci., 2021 , 104 :2465-2479).
  • Whey proteins are typically obtained through processing of an animal milk.
  • sweet whey may be obtained by rennet coagulation of milk
  • acid whey may be obtained by acid precipitation from milk
  • native whey may be obtained by microfiltration of milk.
  • whey ingredients can be obtained with various demineralisation degrees, protein contents and nutritional qualities in respect to amino acid profiles as desired.
  • Whey proteins in the form of sweet whey, acid whey and native whey, or any derivatives thereof obtained after processing as described herein, may be used.
  • the sweet whey material for use according to the invention can be one of sweet whey obtained after separation of casein coagulated with rennet, a concentrate of sweet whey, a demineralized sweet whey, a demineralized concentrate of sweet whey, a concentrate of proteins of substantially lactose-free sweet whey obtained by ultrafiltration followed by diafiltration (ultrafiltration with washing), mother liquors of the crystallization of lactose from sweet whey, a permeate of ultrafiltration of a sweet whey, the product of hydrolysis - by a protease - of a native casein obtained by acid precipitation of skimmed milk with an inorganic acid or by biological acidification, obtained by microfiltration of a skimmed milk, or the product of hydrolysis of a caseinate by a protease.
  • the sweet whey has a solid content of about 6 to 30 wt. %.
  • the sweet whey has a solid content of about 6 to 30 wt. % after its decationisation.
  • sweet whey or a sweet whey protein concentrate may be further demineralized by electrodialysis, ion exchange, reverse osmosis, electrodeionisation or a combination of these procedures or other demineralization procedures known in the field (e.g. ultra- and/or nanofiltration).
  • the range of the protein content in the sweet whey for use according to the invention is between 5 and 90 wt. %, such as between 10 and 80 wt.%, or between 20 and 70 wt. %, or between 30 and 60 wt. %, or between 40 and 50 wt. %, such as 11 .5 wt.%.
  • the acid whey material for use according to the invention can be one of acid whey obtained after separation of casein coagulated with acid, a concentrate of acid whey, a demineralized acid whey, a demineralized concentrate of acid whey, a concentrate of proteins of substantially lactose-free acid whey obtained by ultrafiltration followed by diafiltration (ultrafiltration with washing), mother liquors of the crystallization of lactose from acid whey, a permeate of ultrafiltration of an acid whey, the product of hydrolysis - by a protease - of a native casein obtained by acid precipitation of skimmed milk with an inorganic acid or by biological acidification, obtained by microfiltration of a skimmed milk, or the product of hydrolysis of a caseinate by a protease.
  • the acid whey has a solid content of about 6 to 30 wt. %.
  • the acid whey has a solid content of about 6 to 30 wt. % after its decationisation.
  • acid whey or an acid whey protein concentrate may be further demineralized by electrodialysis, ion exchange, reverse osmosis, electrodeionisation or a combination of these procedures or other demineralization procedures known in the field (e.g. ultra- and/or nanofiltration).
  • the range of the protein content in the acid whey or native whey for use according to the invention is between 5 and 90 wt. %, such as between 10 and 80 wt.%, or between 20 and 70 wt. %, or between 30 and 60 wt. %, or between 40 and 50 wt. %, such as 11 .5 wt.%.
  • Casein glycomacropeptide or caseinoglycomacropeptide can be extracted from a dairy source such as sweet whey.
  • a dairy source such as sweet whey
  • Any suitable method known in the art for the extraction of CGMP from a dairy source such as sweet whey may be used in the practice of the present invention.
  • the method disclosed in WO2016/128254 A1 may be used. Examples 1-4 of WO2016/128254 A1 are thereby incorporated by reference.
  • CGMP is a phosphorylated and partially sialylated macropeptide which is formed by the action of a protease, for example rennet, on mammalian milk kappa-casein.
  • CGMP represents about 15 to 20% by weight of the proteins in sweet whey obtained after separation of casein during cheese manufacture.
  • a whey material (such as sweet whey) containing CGMP may be subjected to the extraction of CGMP.
  • a whey material (such as sweet whey) containing CGMP may be subjected to the extraction of CGMP to provide a protein material having a targeted tryptophan/threonine ratio, for example as described in EP 0 986 312 B1 , EP 3 256 001 B1 or EP 3 255 999 B1.
  • the resulting protein material following the extraction of CGMP from the starting whey material may be referred to as CGMP-reduced (acid, native or sweet) whey.
  • the treated liquid material that is obtained from the extraction of CGMP from a whey material has an amino acid profile which is enriched in aromatic amino acids such as Tryptophan (Trp) and reduced in Threonine (Thr).
  • a CGMP-reduced whey comprises at least an 85 % reduction in the amount of CGMP compared to the starting whey material.
  • the range of the protein content in the modified sweet whey (CGMP-reduced sweet whey) for use according to the invention is between 5 and 95 wt.%, between 10 and 80 wt.%, or between 20 and 70 wt. %, or between 30 and 60 wt. %, or between 40 and 50 wt. %, preferably 10 wt.%.
  • Alpha-lactalbumin enriched whey protein concentrate can be obtained, for example, by partial or complete removal of other major proteins like beta-lactoglobulin from milk. This leads to an increased ratio between alpha-lactalbumin and beta-lactoglobulin compared to the starting material, e.g. milk. Any suitable process for the preparation of alpha-lactalbumin enriched whey protein concentrate which is known in the art may be used.
  • Preferred protein sources for use according to the invention which have an optimised aminogram, an adapted protein profile and/or an adapted peptide profile include: a) skimmed milk and demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey; b) skimmed milk and CGMP-free acid or native whey; c) CGMP-free whey protein isolate and sweet whey protein concentrate; d) demineralized CGMP-reduced sweet whey and demineralized sweet whey; and e) skimmed milk and alpha-lactalbumin-enriched whey protein.
  • CGMP casein glycomacropeptide
  • skimmed milk in a) is optional.
  • sweet whey is used instead of native whey.
  • sweet whey is CGMP-reduced.
  • sweet whey protein concentrate is CGMP-reduced.
  • whey protein isolate in c) is CGMP-reduced.
  • the mixture of CGMP-free whey protein isolate and sweet whey protein concentrate in c) is partially or fully hydrolysed.
  • the mixture of CGMP-free whey protein isolate and sweet whey protein concentrate in c) is partially hydrolysed.
  • the mixture of CGMP-free whey protein isolate and sweet whey protein concentrate in c) is fully hydrolysed.
  • sweet whey in d) is not demineralized.
  • preferred protein sources for use according to the invention which have an optimised aminogram, an adapted protein profile and/or an adapted peptide profile include: a1) demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey and skimmed milk; a2) demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey; b1) skimmed milk and CGMP-free acid or native whey; b2) skimmed milk and CGMP-free acid or sweet whey; b3) skimmed milk and CGMP- reduced acid or native whey; b4) skimmed milk and CGMP-reduced acid or sweet whey; c1) CGMP-free whey protein isolate and sweet whey protein concentrate; c2) CGMP-free whey protein isolate and hydrolysed sweet whey protein concentrate; c3) CGMP-reduced whey protein isolate and sweet whey protein concentrate; c4) CGMP
  • Preferred protein sources for use according to the invention include: a) demineralized, caseino glycomacropeptide (CGMP)-reduced (at least 85% reduced) sweet whey, for example prepared according to the procedure described in EP 0 986 312 B1 , EP 3 256 001 B1 or EP 3 255 999 B1 ; b) CGMP-free acid whey; c) CGMP-free native whey; d) alpha-lactalbumin-enriched whey protein (alpha-lactalbumin content at least 28 g/100g protein of complete protein body); e) partially hydrolyzed 60-70% CGMP free (e.g., native or sweet whey protein) protein isolate and 30-40% sweet whey protein concentrate (WPG); f) partially hydrolyzed 80-85% CGMP free (e.g., native or sweet whey) or CGMP reduced (at least 85% reduced, protein content of 25-31 % of complete protein body) demineral
  • the protein source is an intact protein source.
  • the intact protein source comprises: a) skimmed milk and demineralized, caseino-glyco-macropeptide (CGMP)-reduced-whey; b) skimmed milk and CGMP-free whey, such as acid, sweet or native whey; or c) skimmed milk and alpha-lactalbumin-enriched whey protein.
  • CGMP caseino-glyco-macropeptide
  • the CGMP-free whey is demineralized CGMP-free whey, such as demineralized CGMP-free acid or native whey.
  • the protein source is a partially hydrolysed protein source.
  • the partially hydrolysed protein source comprises: a) CGMP-free whey protein isolate and demineralized sweet whey protein concentrate; or b) demineralized CGMP-reduced sweet whey and demineralized sweet whey.
  • the partially hydrolysed protein source comprises CGMP-free or CGMP-reduced whey protein isolate and demineralized sweet whey protein concentrate.
  • the protein source comprises or consists of skimmed milk and demineralized CGMP-reduced sweet whey.
  • the protein source comprises or consists of skimmed milk and CGMP- free whey, such as acid or native whey.
  • the protein source comprises or consists of skimmed milk and demineralized CGMP-free whey, such as acid or native whey.
  • the protein source comprises or consists of CGMP-free whey protein isolate and demineralized sweet whey protein concentrate. In one embodiment, the protein source comprises or consists of demineralized CGMP- reduced sweet whey and demineralized sweet whey. In one embodiment, the protein source comprises or consists of skimmed milk and alpha-lactalbumin-enriched whey protein.
  • the proteins are a combination of demineralized sweet whey and demineralized protein concentrate, such as MSWP80:DWP28.
  • the protein body when the protein body comprises hydrolysed or partially hydrolysed whey protein concentrate (WPG (HA)), the protein body also contains hydrolysed or partially hydrolysed whey protein isolate (WPI).
  • WPG hydrolysed or partially hydrolysed whey protein concentrate
  • WPI hydrolysed or partially hydrolysed whey protein isolate
  • the proteins are a mixture of hydrolysed or partially hydrolysed whey protein concentrate (WPG) and whey protein isolate (WPI).
  • WPG hydrolysed or partially hydrolysed whey protein concentrate
  • WPI whey protein isolate
  • the WPI is CGMP- free or CGMP-reduced.
  • the WPI is CGMP-free.
  • the WPC:WPI ratio (weightweight) is 90:10 to 10:90, preferably 60:40 to 10:90, more preferably 50:50 to 20:80, even more preferably 50:50 to 30:70, for example 40:60 to 30:70.
  • the WPC:WPI ratio (weightweight) is 37:63.
  • the proteins are a mixtures of WPG and WPI which has been hydrolysed or partially hydrolysed, also called WPG and WPI (HA), such as WPC87:WPI95 (HA), wherein 87 and 95 indicate the protein concentrations, the rest being mainly lactose, some minerals and butter fat as will established for the skilled person.
  • WPG and WPI WPG and WPI
  • HA WPC87:WPI95
  • the casein/whey ratio of the protein source may vary from 80/20 to 0/100.
  • the casein/whey ratio in nutritional compositions comprising an intact protein source is 30/70 to 40/60.
  • the ratio may be from 40/60 to 60/40; in growing-up milks the ratio may be from 50/50 to 80/20.
  • the casein/whey ratio in nutritional compositions comprising a partially hydrolysed protein source (such as pre-term formulas) may be from 20/80 to 40/60.
  • the casein/whey ratio in a nutritional composition comprising a partially hydrolysed protein source is 0/100.
  • the mixture of skimmed milk and demineralized CGMP-reduced sweet whey is provided with a casein/whey ratio from about 20/80 to about 60/40, preferably of about 20/80.
  • the mixture of skimmed milk and demineralized CGMP-reduced sweet whey comprises 10.1 wt.% of skimmed milk and 16.1 wt.% demineralized CGMP-reduced sweet whey (on dry matter basis).
  • the remainder of the mixture is comprised mainly of lactose and lipids.
  • the mixture of skimmed milk and (demineralized) CGMP-free acid whey comprises 10.1 wt.% of skimmed milk and 7.7 wt.% (demineralized) CGMP-free acid whey (dry matter).
  • the remainder of the mixture is comprised mainly of lactose and lipids.
  • the mixture of skimmed milk and demineralized CGMP-free native whey comprises 10.1 wt.% of skimmed milk and 7.7 wt.% demineralized CGMP-free native whey (dry matter).
  • the remainder of the mixture is comprised mainly of lactose and lipids.
  • the mixture of whey protein isolate CGMP-free and sweet whey protein concentrate comprises CGMP-free whey protein isolate:sweet whey protein concentrate at a ratio of 63:37 on protein basis (dry matter).
  • the mixture of demineralized CGMP-reduced sweet whey and demineralized sweet whey comprises demineralized CGMP-reduced sweet whey:demineralized sweet whey at a ratio of 83:17 on protein basis (dry matter).
  • the skimmed milk comprises at least 34 wt.% protein (dry matter), preferably at least 38 wt.% protein, more preferably at least 44 wt.% protein, such as 44 wt.% to 52 wt.% protein, for example 48 wt.% protein (dry matter).
  • the demineralized CGMP-reduced sweet whey comprises at least 76 wt.% protein (dry matter), preferably at least 80 wt.% protein, more preferably at least 86 wt.% protein, such as 86 wt.% to 94 wt.% protein, for example 90 wt.% protein (dry matter).
  • the (demineralized) CGMP-free native whey comprises at least 27.5 wt.% protein (dry matter), preferably at least 32 wt.% protein, more preferably at least 38 wt.% protein, such as 38 wt.% to 46 wt.% protein, for example 42 wt.% protein (dry matter).
  • the CGMP- free whey protein isolate comprises at least 95 wt.% protein (dry matter; such as at least 96 wt.%, at least 97 wt.%, at least 98 wt.% protein (dry matter)) and the sweet whey protein concentrate comprises at least 87 wt.% protein (MSWP87) (dry matter), preferably at least 91 wt.% protein, more preferably at least 95 wt.% protein, such as 95 wt.% to 98 wt.% protein, for example 96 wt.% protein (dry matter).
  • the demineralized CGMP- reduced sweet whey comprises at least 28 wt.% protein (modified sweet whey protein concentrate 28, MSWP28) and the demineralized sweet whey comprises at least 28 wt.% protein (demineralized sweet whey 28, DWP28) (dry matter).
  • the demineralized CGMP-reduced sweet whey comprises at least 80 wt.% protein (modified sweet whey protein concentrate 80, MSWP80) and the demineralized sweet whey comprises at least 80 wt.% protein (demineralized sweet whey 80, DWP80) (dry matter).
  • the alpha-lactalbumin-enriched whey protein comprises at least 68 wt.% protein (dry matter), preferably at least 72 wt.% protein, more preferably at least 78 wt.% protein, such as 78 wt.% to 86 wt.%, for example 82 wt.% (dry matter).
  • Suitable acid whey protein concentrates for use in the invention with 28% protein include aDWP28, sold by Paras of India, acid whey protein concentrate 80 (A WPG 80, LAC 7009) sold by Fonterra of New Zealand.
  • Suitable native whey protein concentrates for use in the invention include native whey 28 (nDWP28) sold by Euroserum of France, native whey protein concentrate 80 (nWPC 80) sold by Leprino of the USA, and native whey protein isolate with 95% protein (Pronative 95) sold by Lactalis of France.
  • Suitable demineralized CGMP-free acid whey protein sources for use in the invention include WPC 80 Lac7009 sold by Fonterra of New Zealand.
  • Suitable demineralized CGMP-free native whey protein sources for use in the invention include Native Whey 28 sold by Euroserum of France.
  • Suitable CGMP-free whey protein isolates for use in the invention include BiPro 9500 sold by Agropur of the USA.
  • Suitable sweet whey protein concentrates for use in the invention include whey protein concentrate 80 (WPC80) sold by Leprino of the USA and whey protein concentrate 87 (WPC87) sold by Milei of Germany or Lacprodan DI-8590 sold by Aria Foods of Denmark.
  • Suitable demineralized sweet whey protein for use in the invention include demineralized Whey 90 (DM90) or DWP3 sold by Euroserum of France, as well as demineralized whey protein powder/liquid 28 (DWP28) sold by Euroserum of France, Lactalis of France and Friesland Campina of the Netherlands.
  • Suitable alpha-lactalbumin-enriched whey protein for use in the invention include the HilmarTM 8800 alpha-lactalbumin enriched whey protein concentrate sold by Hilmar of the USA.
  • Suitable CGMP-reduced sweet whey protein for use according to the invention include modified sweet whey liquid and powder (CGMP reduced more than 85%) sold by Nestle of Switzerland, modified sweet whey powder and liquid 16% protein content sold by Nestle of Switzerland, modified sweet whey powder and liquid 28% protein content MSWP28 sold by Euroserum of France and Leprino of the USA, modified sweet whey protein concentrate with 80% proteins (MSWP 80) sold by Leprino of the USA, and modified sweet whey protein isolate (WPI) like for example Bipro (WPI95) sold by Agropure of the USA.
  • modified sweet whey liquid and powder CGMP reduced more than 85%
  • modified sweet whey powder and liquid 16% protein content sold by Nestle of Switzerland
  • modified sweet whey powder and liquid 28% protein content MSWP28 sold by Euroserum of France and Leprino of the USA
  • modified sweet whey protein concentrate with 80% proteins MSWP 80
  • WPI modified sweet whey protein isolate
  • PLA and HO-PPA are putative metabolites of phenylalanine which may be produced by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the protein source for use in the invention is phenylalanine-rich.
  • the protein source comprises phenylalanine or a salt thereof.
  • the protein source comprises from about 0.25 g to about 1.0 g of phenylalanine per 100 g of total powder (nutritional composition, dry matter).
  • the protein source comprises from about 0.4 g to about 0.7 g of phenylalanine per 100 g of total powder, such as from about 0.52 g to about 0.59 g of phenylalanine per 100 g of total powder.
  • the protein source comprises about 0.56 g of phenylalanine per 100 g of total powder.
  • metabolites are further derived from tryptophan.
  • the protein source comprises tryptophan or a salt thereof.
  • the protein source comprises from about 1.8 g to about 3.1 g of tryptophan per 100 g of total powder (nutritional composition, dry matter).
  • the protein source comprises from about 2 g to about 3 g of tryptophan per 100 g of total powder, such as from about 2.25 g to about 2.75 g of tryptophan per 100 g of total powder.
  • the protein source comprises about 2.48 g of tryptophan per 100 g of total powder.
  • HO-PPA, HO-PLA and/or HO-P-HO-PA are putative metabolites of tyrosine which may be produced by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the protein source for use in the invention is tyrosine-rich.
  • the protein source comprises tyrosine or a salt thereof.
  • the protein source comprises from about 0.15 g to about 0.9 g of tyrosine per 100 g of total powder (nutritional composition, dry matter).
  • the protein source comprises from about 0.2 g to about 0.6 g of tyrosine per 100 g of total powder, such as from about 0.35 g to about 0.45 g of tyrosine per 100 g of total powder.
  • the protein source comprises about 0.40 g of tyrosine per 100 g of total powder.
  • the protein source may comprise tryptophan, phenylalanine and/or tyrosine in any suitable form, for example in the form of a free amino acid, salt (e.g. hydrochloride, sodium, potassium, calcium, and magnesium salts), oligopeptide, polypeptide, or protein.
  • salt e.g. hydrochloride, sodium, potassium, calcium, and magnesium salts
  • oligopeptide polypeptide, or protein.
  • 3-Phenyllactate is a phenolic acid synthesized during phenylalanine and central carbon metabolism of LAB and other bacterial species such as Bifidobacterium longum subsp. infantis). Specifically, PLA is likely produced from phenylpyruvate via the action of lactate dehydrogenase. PLA is an important broad-spectrum antimicrobial compound that inhibits the growth of undesirable microbes through multifaceted actions.
  • the chemical structure of 3- phenyllactic acid is:
  • 3-(4-hydroxyphenyl)propionate also known as desaminotyrosine or phloretic acid, is likely produced from tyrosine.
  • HO-PPA 3-(4-hydroxyphenyl)propionate
  • 3-(4-hydroxyphenyl)lactate (HO-PLA) is likely produced from the breakdown of tyrosine.
  • the chemical structure of 3-(4-hydroxyphenyl)lactic acid is: 3-hydroxyphenyl-3-hydroxypropionate (HO-P-HO-PA) is likely produced from tyrosine.
  • the chemical structure of 3-hydroxyphenyl-3-hydroxypropionic acid is:
  • the protein sources for use in the invention are hydrolyzed at a degree of hydrolysis (DH) of from 7 to 11 %, preferably of from 8.3 to 10.8%, as determined using Assay 1 (described below).
  • DH degree of hydrolysis
  • the protein source for use in the invention are hydrolysed to an average molecular weight of from 941 to 1284 Da (with 3 sigma), preferably to an average molecular weight of 1112 Da or 1155 Da.
  • Protein Molecular Weights (MW) are determined by size exclusion chromatography with a specific post-column labelling and a fluorescence detection based on a calibration curve established with known MW of commercial proteins as described below.
  • the DH is defined as the percentage of peptides bonds cleaved through hydrolysis which is assessed on pure individual protein (Nielsen et al., 2001 , J. Food Sci. , 66: 642-646).
  • the DH is expressed by equation (1), wherein h represents the number of hydrolyzed peptide bonds in the protein hydrolysate and h tot represents the total number of peptide bonds in the protein source material available for hydrolysis. 100 (1) ' '
  • Equation (1) can be sub-divided into the following subsections:
  • h tot The derivation of h tot is described in detail in the publication from Nielsen et al. (supra). Based on these published data for h tot a value of 8.8 mmole/g protein is reported for whey protein.
  • AN free amino nitrogen groups
  • E- amino groups are determined by reaction with trinitrobenzenesulfonic acid [TNBS] based on the procedure described by Adler-Nissen (Adler- Nissen, 1979, J Agric Food Chem, 27:1256-62).
  • TNBS trinitrobenzenesulfonic acid
  • This method is a spectrophotometric assay of the chromophore specifically formed by the reaction of TNBS with free amino groups.
  • the reaction takes place in slightly alkaline conditions.
  • the reaction products are measured at an absorbance of 340 nm.
  • the total nitrogen content (TN) is determined via the Kjeldahl method (Kjeldahl, J., 1883, Zeitschrift fur analytician Chemie, 22: 366-383).
  • MWD molecular weight distribution
  • SEC size exclusion chromatography
  • Superdex 30 Increase column preferably using a Superdex 30 Increase column (Cytiva) with UV detection.
  • a complete description of the method used for determination of MWD characterization is described by Johns P.W. et al. and Bourdeau et al. (Johns P.W. et al., 2011 , Food Chemistry, 125, 1041-1050; and Bourdeau et al., 2021 , Nutrients, 13: 3011).
  • the elution time axis is calibrated (cubic fitting) using the following 17 standard proteins, peptides and free amino acids: (1) serum albumin (bovine, MW -66’354), (2) ovalbumin (chicken, MW -42’750), (3) carbonic anhydrase (bovine, MW -28’964), (4) beta-lactoglobulin (bovine, MW -18’264), (5) alpha-lactalbumin (bovine, MW -14’168), (6) ubiquitin (bovine, MW -8’564), (7) insulin (bovine, MW -5’733), (8) vasoactive intestinal peptide (VIP, mouse, MW -3’325), (9) dynorphin A (porcine, MW -2’147), (10) substance P (horse, MW -1’347), (11) angiotensin II (human,
  • the mass range was calibrated with a mix of 8 reference compounds (beta- lactoglobulin: 18’264 Dalton (Da); ubiquitin: 8’564 Da; insulin B-chain: 3’494 Da; substance P: 1’347 Da; bradykinin: 1’060 Da; Glye: 360 Da; Giya: 189 Da; His (representing an average amino acid): 110 Da) and cubic fitting.
  • 8 reference compounds beta- lactoglobulin: 18’264 Dalton (Da); ubiquitin: 8’564 Da; insulin B-chain: 3’494 Da; substance P: 1’347 Da; bradykinin: 1’060 Da; Glye: 360 Da; Giya: 189 Da; His (representing an average amino acid): 110 Da) and cubic fitting.
  • the nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, a supplement, a pet food, or a pet food supplement.
  • the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age.
  • the nutritional composition of the invention is an infant formula.
  • the combination according to the invention can be for example formulated as an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, a supplement, a pet food, or a pet food supplement.
  • a fortifier such as a human milk fortifier, a supplement, a pet food, or a pet food supplement.
  • the nutritional composition or combination of the present invention is a fortifier.
  • the fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on/follow-up formula fortifier.
  • the nutritional composition or combination When the nutritional composition or combination is a supplement, it can be provided in the form of unit doses. In such cases it is particularly useful to define the amount of oligosaccharides and probiotics in terms of daily dose to be administered to the infant, young child or child.
  • the nutritional composition or combination when it is a supplement, it may comprise LNFP-I, a galactose source and a LNFP-1 metabolizing Bifidobacterium, for example B. infantis, and no other additional nutrient on top of the excipients necessary to obtain a stable nutritional composition.
  • the nutritional composition or combination of the present invention can be in solid (e.g. powder), liquid or gelatinous form.
  • the nutritional composition or combination is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g/100 mL (5 to 75% (w/v)).
  • the supplement when the supplement is in powder form, it may comprise a carrier. It is however preferred that the supplement is devoid of a carrier.
  • the components are preferably dissolved or suspended in water acidified with citrate.
  • the nutritional composition or the combination according to the invention is a hypoallergenic composition.
  • the composition or combination according to the invention is a hypoallergenic nutritional composition.
  • the nutritional composition or combination according to the invention may be prepared in any suitable manner.
  • a composition will now be described by way of example.
  • a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture.
  • the oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.
  • the liquid mixture is then homogenised, for example in two stages.
  • the liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger. Then, the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling. The liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and minerals. The pH and solids content of the homogenised mixture are conveniently adjusted at this point.
  • the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder.
  • the powder should have a moisture content of less than about 5% by weight.
  • the oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, along with the probiotic strain(s), and the mixture is spray-dried or freeze-dried.
  • the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted.
  • the composition or combination of the invention may be a supplement.
  • the supplement may be in the form of tablets, capsules, pastilles or a liquid for example.
  • the supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents.
  • protective hydrocolloids such as gums, proteins, modified starches
  • binders film forming agents
  • encapsulating agents/materials, wall/shell materials such as binders, film forming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings,
  • the supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • conventional pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatine of any origin, vegetable gums, lignin-sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.
  • the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA.
  • the present inventors have surprisingly found that a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis has the ability to efficiently catabolise LNFP- I.
  • the composition or combination of the present invention will increase the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of a subject administered the composition or combination of the invention.
  • the invention provides the use of a nutritional composition or combination of the invention for modulating the microbiota of a subject.
  • the invention provides a method of modulating the microbiota of a subject, the method comprising administering the nutritional composition of the invention or combination of the invention to the subject.
  • modulating the microbiota of a subject comprises increasing the abundance of Bifidobacteriaceae and/or a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the relative abundance of a LNFP-1 metabolizing Bifidobacterium for example Bifidobacteriaceae and/or Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject is increased.
  • the abundance of Bifidobacteriaceae and/or a LNFP-1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp. infantis (or relative abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacteriaceae and/or a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis) is increased in a subject using a nutritional composition or combination according to the invention when compared to a corresponding nutritional composition which does not comprise LNFP-1.
  • the present inventors have surprisingly found that the combination of LNFP-I increases the production of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA by a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the invention provides the use of a nutritional composition or combination of the invention for increasing the levels of PLA, HO-PPA, HO-PLA and/or HO- P-HO-PA in the gastrointestinal tract of a subject, and preferably for further increasing the levels of SOFA in the gastrointestinal tract of the subject, more preferably for further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • the invention provides a method of increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject, the method comprising administering the nutritional composition of the invention or combination of the invention to the subject.
  • the levels of PLA are increased.
  • the levels of HO-PPA are increased.
  • the levels of HO-PLA are increased.
  • the levels of HO-P-HO-PA are increased.
  • the biosynthesis of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA by the LNFP-1 metabolizing Bifidobacterium, for example the Bifidobacterium longum subsp. infantis in the subject is increased from 1.1 to 20-fold, such as by 1.2 to 11-fold, preferably by 4-fold to 11- fold.
  • infantis in the subject is increased by at least 1.1 -fold, such as by 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold or 20-fold.
  • the base-2 logarithm of the ratio between the value of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA for the combination or composition according to the invention and the value of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA for a corresponding nutritional composition which does not comprise LNFP-1 is increased by from 0.2 to 5, suitably from 0.25 to 3.8.
  • the amount of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA secreted i.e. PLA, HO-PPA, HO- PLA and/or HO-P-HO-PA biosynthesis
  • a LNFP-1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject may be measured by methods known in the art.
  • the amount of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in fresh fecal samples from an infant, young child or child fed the combination or nutritional composition according to the invention may be compared to samples from an infant, young child or child not exposed to a combination or nutritional composition according to the invention (Laursen et al., 2021 , Nat Microbiol, 6: 1367-1382).
  • the levels of SCFA in the gastrointestinal tract of the subject is increased.
  • the levels of acetate and butyrate in the gastrointestinal tract of the subject is increased.
  • the level of butyrate in the gastrointestinal tract of the subject is increased.
  • the levels of PLA and SCFA are increased.
  • the levels of PLA, acetate and butyrate are increased.
  • the levels of PLA and/or HO-PPA, HO-PLA and/or HO-P-HO-PA and acetate and butyrate are increased.
  • the levels of PLA and/or HO-PPA and/or HO-PLA and/or HO-P-HO- PA and butyrate are increased.
  • Bifidobacterium is one of the main genera of commensal bacteria present in the human gastrointestinal tract and its presence has been related to health benefits in several studies (Hidalgo-Cantabrana, C., et al., 2017. Microbiology spectrum, 5(3), pp.5-3). As described above, the use of probiotics, including Bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well-documented (Tojo, R., et al., 2014. World journal of gastroenterology: WJG, 20(41), p.15163).
  • SCFAs have a well-known role in immune protection against infection and regulation.
  • SCFAs have been shown to promote host antibody responses (Kim et al., 2016, Cell Host & Microbe, 20(2): 202-214), protect against respiratory infections such as respiratory syncytial virus infection (Antunes et al., 2019, Nat Commun 10: 3273; and Dogra et al., Microorganisms, 2021 , 9: 1939), enhance antimicrobial function of macrophages (and thereby boost the host defence against infections) (Schulthess et al., 2019, Immunity, 50(2): 432-445; and Machado et al., 2022, Front.
  • the SCFA butyrate has been shown to provide various health benefits and especially to protect against obesity, insulin resistance, diabetes, to be involved in adipogenesis, in food intake, in the prevention of non-alcoholic fatty liver disease or of cardiometabolic related conditions like development of atherosclerosis, in the prevention/treatment of inflammation, infections, allergies, in the gut maturation, the gut brain axis connection, the colonic healing especially in case of colitis and to have anti-cancer effects (Lin et al., Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-lndependent Mechanisms, 2012 ; Aguilar et al, "Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing N FKB activation", 2015 ; Endo et al, "Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gutliver axis", 2013 ; Goverse et al
  • Phenolic metabolites are increasingly being shown to provide biological benefits in humans.
  • PLA aromatic phenylalanine metabolite 3-phenyllactate
  • PLA has been added as a supplement to poultry and pig feed in the livestock industry and been shown to exert its anti-microbial effects in vivo, for example in weaning or growing pigs (Chaudhari and Gokhale, 2016, J Bacteriol Mycol Open Access, 2:121-125; and Wanmeng Mu et al., 2012, Appl Microbiol Biotechnol, 95: 1155-1163).
  • PLA has shown anti-pathogenic properties in the large intestine of chicks fed PLA-supplemented with chick feed diets (Chaudhari and Gokhale, 2016, J Bacteriol Mycol Open Access, 2:121-125; and Wanmeng Mu et al., 2012, Appl Microbiol Biotechnol, 95: 1155-1163).
  • PLA supplementation in the diet would be expected to exert the same effects in humans, e.g. infants.
  • an isomer of PLA, 3-(4-hydroxyphenyl)propionate (HO-PPA) is also associated with anti-viral activities, showing inhibition of replication of Hepatitis E virus (Hooda et al., Viruses, 2022, 14: 1778).
  • HO-PPA has also shown anti-inflammatory activities (Wei et al., FASEB J, 2020, 34: 16117-16128).
  • supplementation with HO-PPA provided antiinflammatory effects and promoted maintenance of local and systemic immune homeostasis, which in turn protected intestinal barrier integrity, in mice. It is known that intestinal barrier dysfunction and systemic inflammation lead to the development of obesity.
  • HO-PPA could be useful in the prevention or treatment of obesity.
  • HO-PPA has been shown to have an anti-inflammatory effect in the gastrointestinal tract as well as to promote immune homeostasis, which is known to reduce the risk of developing allergies, asthma, and other inflammatory diseases later in life as well as reducing the risk of developing obesity (Wei et al., FASEB J, 2020, 34: 16117-16128).
  • the composition or combination of the invention is therefore particularly advantageous for promoting a healthy immune system in a subject and preventing and/or reducing inflammation in the intestine of a subject.
  • hydroxylated PLA 3-(4-hydroxyphenyl)lactate (HO-PLA)
  • HO-PLA 3-(4-hydroxyphenyl)lactate
  • the use of the combination or composition of the invention which enhances the growth of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis and/or increases the levels of SCFA and/or increases the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject would be expected to have the same effects as the administration of the probiotics or SCFAs or PLA, HO-PPA, HO-PLA and HO-P-HO-PA discussed above.
  • the present invention provides the combination or nutritional composition of the invention for use as a medicament.
  • the present invention provides the use of the combination or nutritional composition of the invention for the manufacture of a medicament.
  • the invention provides a nutritional composition of the invention for use in: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject.
  • the nutritional composition according to the invention is for use in preventing and/or treating fungal, viral and/or bacterial infections in a subject. In one embodiment, the nutritional composition according to the invention is for use in preventing and/or reducing inflammation in the intestine of a subject. In one embodiment, the nutritional composition according to the invention is for use in promoting a healthy immune system in a subject. In one embodiment, the nutritional composition according to the invention is for use in preventing and/or treating microbiota dysbiosis in a subject. In one embodiment, the nutritional composition according to the invention is for use in modulating the microbiota of a subject. In one embodiment, the nutritional composition according to the invention is for use in preventing and/or treating obesity in a subject. Preferably, preventing obesity in a subject refers to the prevention of obesity later in life.
  • the invention provides a method of preventing and/or treating fungal, viral and/or bacterial infections in a subject, preventing and/or reducing inflammation in the intestine of a subject, promoting a healthy immune system in a subject; preventing and/or treating obesity in a subject; preventing and/or treating microbiota dysbiosis in a subject and/or modulating the microbiota of a subject, the method comprising administering the nutritional composition of the invention to the subject.
  • the composition of the invention exerts the above beneficial health effects by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject.
  • the levels of PLA, HO-PPA, HO-PLA and/or HO- P-HO-PA in the subject may be increased as described herein above.
  • modulating the microbiota of a subject comprises increasing the abundance of Bifidobacteriaceae and/or the a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • Bifidobacteriaceae and/or Bifidobacterium longum subsp. infantis may be increased as described herein above.
  • the composition according to the invention may also be for use in promoting healthy growth, promoting a healthy gut function, and/or preventing and/or treating allergy in a subject.
  • the combination or nutritional composition of the invention may prevent or treat an infection or a disease by increasing the levels of SCFA in the gastrointestinal tract and systemic levels of SCFA of the subject.
  • the increased systemic levels of SCFA in the subject facilitates the exertion of the effects of the combination or nutritional composition of the invention beyond the gastrointestinal tract (e.g. in the lungs).
  • the combination or nutritional composition of the invention may prevent or treat an infection or a disease by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject, and preferably by further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably by further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • the combination or nutritional composition of the invention may prevent or treat an infection or a disease by enhancing the growth of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • a LNFP-1 metabolizing Bifidobacterium for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the combination or composition of the invention may be used to treat or prevent disorders associated with decreased numbers of Bifidobacteria in the gut (see e.g. Riviere, A., et al., 2016. Frontiers in microbiology, 7, p.979).
  • the invention provides the combination or composition of the invention for use in treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut.
  • the invention provides for use of the combination or composition of the invention for the manufacture of a medicament for treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut.
  • the invention provides a method of treating and/or preventing a disorder associated with decreased numbers of Bifidobacteria in the gut in a subject, comprising administering the combination or composition of the invention to the subject.
  • the disorder associated with decreased numbers of Bifidobacteria in the gut in a subject may be selected from: a gastrointestinal disease, obesity, an allergic disease, and regressive autism.
  • the beneficial health benefits provided by the composition of the invention can be short term and/or long term effects.
  • the effect may be immediate with the administration of the composition of the present invention, or later in life, i.e. after the administration of the composition, e.g. from 1 week to several months or years, for example from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to 6 months, from 2 to 12 months, or from 6 months to 12 years, such as from 2 years to 10 years, from 4 years to 5 years, after said administration.
  • composition of the invention is, in particular, effective for use in the treatment and/or prevention of a bacterial infection in a subject.
  • composition of the invention is also effective for use in reducing the risk of contracting a bacterial infection in a subject and/or for use in reducing the symptoms associated with a bacterial infection in subject.
  • the composition of the invention is for use in the prevention of a bacterial infection in a subject.
  • the bacterial infection may be a gastrointestinal infection or a respiratory tract infection.
  • the gastrointestinal infection may be an intestinal infection or a stomach infection.
  • Salmonella spp. e.g. Salmonella enterica
  • Clostridium difficile e.g. Clostridium difficile toxin A/B
  • Campylobacter e.g. E. coli 0157.
  • the symptoms most often associated with the bacterial infection, and which may be reduced by the composition of the invention, are irritation in the lungs, congestion in the lungs, excessive mucus production, fever, cough, wheezing, breathlessness, abdominal cramps, diarrhoea or vomiting.
  • the symptoms are abdominal cramps, diarrhoea or vomiting.
  • composition of the invention is, in particular, effective for use in the treatment and/or prevention of a fungal infection in a subject.
  • composition of the invention is also effective for use in reducing the risk of contracting a fungal infection in a subject and/or for use in reducing the symptoms associated with a fungal infection in subject.
  • the composition of the invention is for use in the prevention of a fungal infection in a subject.
  • Colonization by Candida species is reported to be the most important predictor of the development of invasive fungal disease in preterm neonates, and the enteric reservoir is a major site of colonization.
  • the administration of the combination or composition of the invention is expected to reduce the colonisation due to the anti-microbial effects of PLA produced by the composition of the invention.
  • the symptoms most often associated with the fungal infection, and which may be reduced by the composition of the invention, are irritation in the lungs, congestion in the lungs, excessive mucus production, fever, cough, wheezing, breathlessness, abdominal cramps, diarrhoea or vomiting.
  • the symptoms are irritation in the lungs, congestion in the lungs, excessive mucus production, fever, cough, wheezing, breathlessness.
  • composition of the invention is, in particular, effective for use in the treatment and/or prevention of a viral infection in a subject.
  • composition of the invention is also effective for use in reducing the risk of contracting a viral infection in a subject and/or for use in reducing the symptoms associated with a viral infection in subject.
  • the viral infection may be a viral gastrointestinal infection or a viral respiratory tract infection.
  • the viral gastrointestinal infection may be a viral intestinal infection or a viral stomach infection.
  • the viral infection is a viral respiratory tract infection.
  • the viral respiratory tract infection may be a viral infection in the upper respiratory tract or in the lower respiratory tract.
  • the viral respiratory tract infection is caused by respiratory syncytial virus (RSV).
  • RSV respiratory syncytial virus
  • the disease associated with the viral infection will typically be common cold, influenza (flu), bronchitis, bronchiolitis, pneumonia, sore throat (pharyngitis), sinusitis, non-allergic rhinitis, severe acute respiratory syndrome (SARS), viral croup, otitis media, meningitis or diarrhoea.
  • the disease associated with the respiratory tract infection is common cold, influenza (flu), bronchitis, bronchiolitis, pneumonia, sore throat (pharyngitis), sinusitis, non-allergic rhinitis, severe acute respiratory syndrome (SARS), viral croup or otitis media.
  • influenza flu
  • bronchitis bronchiolitis
  • pneumonia sore throat (pharyngitis)
  • sinusitis non-allergic rhinitis
  • SARS severe acute respiratory syndrome
  • viral croup or otitis media Most often, the disease associated with the viral respiratory tract infection is common cold, influenza (flu), bronchitis, bronchiolitis or pneumonia.
  • the composition of the invention is for use in treating and/or preventing a disease associated with a viral respiratory tract infection selected from the group consisting of common cold, influenza (flu), bronchitis, bronchiolitis and pneumonia.
  • a disease associated with a viral respiratory tract infection selected from the group consisting of common cold, influenza (flu), bronchitis, bronchiolitis and pneumonia.
  • the disease associated with the respiratory tract infection is selected from the group consisting of bronchiolitis and pneumonia, in particular bronchiolitis and pneumonia caused by RSV.
  • the disease associated with the respiratory tract infection is bronchiolitis, in particular bronchiolitis caused by RSV.
  • the symptoms most often associated with the viral infection, and which may be reduced by the composition of the invention, are irritation in the lungs, congestion in the lungs, excessive mucus production, fever, cough, wheezing, breathlessness, abdominal cramps, diarrhoea or vomiting.
  • the above-mentioned infections may be caused by a variety of different viruses, including respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus such as influenza virus A (IVA) and/or influenza virus B (IVB), rhinovirus (RV), adenovirus (ADV), metapneumovirus (MPV), bocavirus (BoV), coronavirus (CoV), myxovirus, herpesvirus, enterovirus (EV), parachovirus (PeV) or a combination thereof.
  • RSV respiratory syncytial virus
  • PAV parainfluenza virus
  • influenza virus such as influenza virus A (IVA) and/or influenza virus B (IVB)
  • influenza virus such as influenza virus A (IVA) and/or influenza virus B (IVB)
  • influenza virus such as influenza virus A (IVA) and/or influenza virus B (IVB)
  • influenza virus such as influenza virus A (IVA) and/or influenza virus B (IVB)
  • influenza virus such as influenza
  • composition of the invention is particularly effective in treating, preventing, reducing the risk of contracting and/or reducing the symptoms of a viral infections caused by respiratory syncytial virus (RSV).
  • composition of the invention is particularly preferred for use in treating, preventing, reducing the risk of contracting and/or reducing the symptoms of bronchiolitis caused by respiratory syncytial virus (RSV) or pneumonia caused by respiratory syncytial virus (RSV).
  • composition of the invention is also suitable for use in preventing or reducing the risk of developing pulmonary diseases, in particular chronic obstructive pulmonary disease, in a mammal, such as a human.
  • composition of the invention is also effective for use in preventing or reducing the risk of a bacterial co-infection and/or a bacterial secondary infection associated with respiratory viral infection in a mammal, in particular a human.
  • Pathogenic bacteria typically involved in co-infections or secondary infections include Staphylococcus aureus, Streptococcus pneumoniae and/or Haemophilus influenza.
  • composition of the invention is useful for treating and/or preventing viral infections, in particular respiratory tract infection in a human of any age.
  • the human to be treated with the composition of the invention may be selected from the group consisting of 0 to ⁇ 1 year (infants), 1 to ⁇ 3 years (young children) and 3 to ⁇ 5 years (children).
  • the composition of the invention is also effective for use in preventing or reducing the risk of allergen sensitisation and/or developing an allergic respiratory tract disease in a mammal, such as a human.
  • allergic respiratory tract diseases include asthma and recurrent wheeze, in particular asthma.
  • the composition of the invention is preferably administered to a human having an age from 0 to ⁇ 3 years, preferably from 0 to 2 years, more preferably from 0 to ⁇ 1 year, such as from 0 to 6 months.
  • This prevents or reduces the risk of developing an allergic respiratory tract disease when said human has reached an age of 3 years or more, preferably from 3 to 12 years, more preferably from 3 to 10 years, even more preferably from 3 to 8, most preferably from 3 to 6 years, in particular from 3 to 5 years or from 3 to 4 years.
  • Phenolic metabolites such as HO-PPA have been shown to have an anti-inflammatory effect in the gastrointestinal tract and to promote immune homeostasis, which is known to reduce the risk of developing allergies, asthma, and other inflammatory diseases later in life as well as reducing the risk of developing obesity (Wei et al., FASEB J, 2020, 34: 16117-16128; Meng et a!., 2020, Pediatr.
  • the composition or combination of the invention is for use in preventing and/or reducing intestinal inflammation in a subject.
  • the prevention or reduction of inflammation in the intestine of a subject may be determined using methods known in the art (see, for example, Wei et al., FASEB J, 2020, 34: 16117- 16128; Henrick et al., 2021 , Cell, 184: 3884-3898; and Laursen et al., Nat Microbiol., 2021 , 6: 1367-1382).
  • composition of the infant gut microbiome is critical to immunological development, particularly during the first 3 months of life, when differences in gut microbial composition are most influential in impacting the developing immune system.
  • Bifidobacterium longum subsp. infantis has been demonstrated to predominate in the gut microbiota of breastfed infants and to benefit the host by accelerating maturation of the immune response and balancing the immune system to suppress inflammation.
  • Reduced abundance of Bifidobacterium species in infants and young children has been correlated to chronic diseases, including asthma and obesity, as well as to increased incidence of allergic and autoimmune diseases later in life.
  • the anti-inflammatory effects of Bifidobacterium longum subsp. infantis may at least in part be effected by the production of PLA, HO-PPA, HO-PLA and HO-P-HO-PA.
  • composition or combination of the present invention increases the levels of PLA, HO- PPA, HO-PLA and HO-P-HO-PA and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of a subject.
  • the composition or combination of the invention is for use in promoting a healthy immune system in a subject.
  • promoting a healthy immune system in a subject comprises promoting immune homeostasis and/or preventing and/or reducing inflammation.
  • the promotion of immune homeostasis in a subject may be determined using methods known in the art (see, for example, Wei et al., FASEB J, 2020, 34: 16117-16128).
  • the subject is a mammal, such as a human.
  • the nutritional composition or combination according to the invention is for use in infants, young children or children.
  • the subject is an infant. In one embodiment, the subject is a young child. In one embodiment, the subject is a child.
  • the nutritional composition according to the invention is for use in infants or young children. It is particularly adapted for infants under 6 months of age.
  • the infants, young children or children may be born term or preterm.
  • the nutritional composition or combination of the invention is for use in infants, young children or children that were born preterm.
  • Preterm infants may be at increased risk of poor nutrient utilization, impaired lean body mass growth, fat accumulation in the visceral area and metabolic disease later in life.
  • the nutritional composition or combination of the invention is for use in preterm infants.
  • the subject is an infant or a young child that was born small for gestational age or low birth weight.
  • Infants or young children with low birth weight may or may not be preterm, and similarly, infants or young children who are small for gestational age may or may not be preterm.
  • the nutritional composition of the present invention may also be used in an infant or a young child that was born by C-section or that was vaginally delivered. All infants and young children can benefit from the invention as all of them are or can be, at a certain age, susceptible to acquiring an unbalanced intestinal/gut microbiota.
  • the nutritional composition in for use infants or young children having a fragile or unbalanced microbiota or dysbiosis of microbiota, such as preterm infants, infants born by Caesarean-section, infants born small for gestational age or with low birth weight, hospitalized infants/young children, infants/young children treated or having been treated by antibiotics and/or infants/young children suffering or having suffered from gut infection and/or gut inflammation.
  • composition of the invention may be even more beneficial to infants born with possibly impaired gut microbiota or fragile infants/young children (such as prematurely born infants and/or infants born by C-section). It is also foreseen that the composition of the invention may be even more beneficial to infants/young children exhibiting intestinal disorders (such as diarrhea, infections or colic), especially after birth, for example, during the first 4 weeks after birth.
  • intestinal disorders such as diarrhea, infections or colic
  • the infants born prematurely or born by caesarean section or born small for gestational age or with low birth weight, or exhibiting unbalanced or abnormal gut microbiota or suffering or having suffered from gut infection and/or gut inflammation are targeted by the composition of the present invention, and especially when the infants are 0-6 months of age.
  • younger infants benefit even more from the composition of the invention, especially when the infants have (or are at risk of having) an unbalanced intestinal microbiota and/or have a fragile health condition (as exemplified by the conditions cited above).
  • the nutritional composition can be administered (or given or fed) at an age and for a period that depends on the needs.
  • the infants oryoung children are 0-36 months of age, such as 0-12 months or 0-6 months of age. It is foreseen that the composition of the invention may be even more beneficial to infants just after birth (0-4 weeks or 0-8 weeks) as their intestinal tract may be more fragile.
  • the mammal to be treated is preferably a human being, but the mammal may also be nonhuman mammal, such as a non-human mammal selected from the group consisting of pig, cow, horse, dog, cat, goat, sheep and rabbit.
  • the subject is a juvenile animal, preferably wherein the animal is a pet.
  • a pet may be a mammal such as dogs or cats, or rodents such as mice, rats, and guinea pigs, rabbits, etc.
  • the pet is a small dog breed.
  • the term “juvenile” may refer to an individual that has not yet reached adulthood.
  • the nutritional composition or combination according to the invention can be for use before and/or during the weaning period.
  • the nutritional composition or combination according to the invention is for use in a subject at risk and/or in need.
  • the subject at risk and/or in need may be bottle-fed and/or formula-fed.
  • the composition or combination of the invention is given to the subject as a supplementary composition to the mother's milk.
  • the subject receives the mother's milk during at least the first 2 weeks, first 1 , 2, 4, or 6 months.
  • the nutritional composition or combination of the invention is given to the subject after such period of mother's nutrition, or is given together with such period of mother's milk nutrition.
  • the composition or combination is given to the subject as the sole or primary nutritional composition during at least one period of time, e.g. after the 1 st , 2 nd or 4 th month of life, during at least 1 , 2, 4 or 6 months.
  • the nutritional composition of the invention is a complete nutritional composition (fulfilling all or most of the nutritional needs of the subject).
  • the nutrition composition or combination of the invention is a supplement or a fortifier intended for example to supplement human milk or to supplement an infant formula or a follow- on formula.
  • the nutritional composition or combination according to the present invention may also comprise other types of oligosaccharide(s), polysaccharides and/or a fiber(s) and/or a precursor(s) thereof.
  • the other oligosaccharide and/or fiber and/or precursor thereof may be selected from the list comprising human milk oligosaccharides (HMOs), galactooligosaccharides (GOS), fructo-oligosaccharides (FOS), xylooligosaccharides (XOS), cello- oligosaccharides (COS), arabinoxylans, arabinans, xylans, inulin, polydextrose, beta-glucans, pectins and any combination thereof and any derived preparations thereof (e.g. partial hydrolysis). They may be in an amount between 0 and 10% by weight of composition.
  • the nutritional composition or the combination can also contain at least one BMO (bovine milk derived oligosaccharide).
  • Additional HMOs which may be included in the nutritional composition or combination according to the present invention may be selected from the group consisting of 2’-FL (2’- fucosyl lactose), 3-FL (3- fucosyllactose), Lacto-difucotetraose (LDFT), 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- hexaose II, para-lacto-N-neohexaose (para-LNnH), LNT (lacto-N-n
  • the nutritional composition or combination according to the invention comprises at least one additional HMO.
  • the nutritional composition or combination according to the present invention is devoid of any further HMOs.
  • LNFP-I may be the sole HMO in the nutritional composition or combination of the invention.
  • LNFP-I may be the predominant HMO in the nutritional composition or combination of the invention.
  • “predominant HMO” is meant that LNFP-I is present in a greater amount than any other HMO in the composition or combination of the invention.
  • LNFP-I is the most abundant HMO in the nutritional composition or combination according to the invention.
  • LNFP-I is the only HMO in the nutritional composition or combination according to the invention.
  • LNFP-I is the most abundant fucosylated oligosaccharide in the nutritional composition or combination according to the invention.
  • the nutritional composition or combination according to the invention comprises only fucosylated HMOs. In some embodiments, the nutritional composition or combination according to the invention does not comprise N-acetylated HMOs.
  • the nutritional composition of the present invention can further comprise at least one probiotic (or probiotic strain), such as at least one probiotic bacterial strain.
  • the combination of the present invention can further comprise at least one further probiotic (or probiotic strain), such as at least one further probiotic bacterial strain.
  • the probiotic microorganisms most commonly used are principally bacteria and/or yeasts of the following genera: Lactobacillus spp., Lacticaseibacillus spp, Limosilactobacillus spp, Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.
  • the probiotic is a probiotic bacterial strain. In some specific embodiments, it is particularly Lactobacilli.
  • Suitable probiotic bacterial strains include Lactobacillus rhamnosus ATCC 53103 available from Valio Oy of Finland under the trademark LGG, Lactobacillus rhamnosus CGMCC 1 .3724, Lactobacillus paracasei CNCM 1-2116, Lactobacillus johnsonii CNCM 1-1225, Streptococcus salivarius DSM 13084 sold by BLIS Technologies Limited of New Zealand under the designation KI2.
  • the nutritional composition or combination according to the invention may contain from 10e3 to 10e12 cfu of the at least one (further) probiotic strain, more preferably between 10e7 and 10e12 cfu such as between 10e8 and 10e10 cfu of probiotic strain per g of composition on a dry weight basis.
  • the probiotics are viable. In another embodiment, the probiotics are nonreplicating or inactivated. There may be both viable probiotics and inactivated probiotics in some other embodiments. Probiotic components and metabolites can also be added.
  • the nutritional composition according to the invention may contain an additional protein source.
  • Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy (for example soy protein isolate from Gushen Biological Techn. Group Co. Ltd) and/or rice (for example HyprolRice Advance from Kerry of Ireland).
  • soy for example soy protein isolate from Gushen Biological Techn. Group Co. Ltd
  • rice for example HyprolRice Advance from Kerry of Ireland
  • the additional 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 additional protein source is casein, skim milk, or whole milk.
  • a typical recipe may combine skim milk with the protein source as described herein above to reach the desired casein:whey ratio.
  • the nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula.
  • 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 is lactose.
  • the nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula.
  • the lipid source may be any lipid or fat which is suitable for use in infant formulae.
  • Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil.
  • the essential fatty acids linoleic and a-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils.
  • the fat source may have a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15: 1 ; for example about 8: 1 to about 10: 1.
  • the 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 B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population.
  • the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and di-glycerides, and the like.
  • the nutritional composition of the invention may also contain other substances which may have a beneficial effect such as lactoferrin, nucleotides, nucleosides, and the like.
  • the nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.
  • B. infantis (LMG11588) fermentations were prepared in the presence of a selection of various carbohydrate sources and protein bodies.
  • a standard growth medium was used for all variants, as described in Table 1 below.
  • WPG hydrolysed whey protein concentrate
  • Table 3 Starting concentrations of each protein body were calculated, as shown in Table 3 below.
  • Table 3 Starting concentrations of each protein body within the modified medium formulations
  • the modified medium contained 0% or 0.5% carbohydrate source, and was supplemented with 42.13 g(dry matter)/L of protein body.
  • the carbohydrate source consisted of LNFP-I or 2’-FL. A control with no added carbohydrate source was also included.
  • the protein source was either skim milk powder (MSK), whey concentrate powder (MSWP80), partially hydrolysed whey concentrate (WPC HA), or a combination of MSK (15.53g/L) and MSWP80 (26.6g/L).
  • MSK skim milk powder
  • MSWP80 whey concentrate powder
  • WPC HA partially hydrolysed whey concentrate
  • a control with no added protein body was also included.
  • the arms and variants of this experiment are shown in Table 4 below.
  • B. infantis (LMG11588) was inoculated to the modified growth medium at a titre of 2.0E+07 cfu/mL and incubated as a 12-hour static anaerobic monoculture fermentation at 37°C.
  • each fermentate was centrifuged for 15 minutes at 4,500 rpm, to produce cell-free supernatant. This supernatant was aliquoted into a separate vessel and stored at - 20°C for the metabolite analysis.
  • Amino acids and acetylated amino acids such as arginine (ARG) (polyamine precursor), tryptophan (TRP), acetyl glutamate (AcGLU) and acetyl lysine (AcLYS).
  • ARG arginine
  • TRP tryptophan
  • AcGLU acetyl glutamate
  • AcLYS acetyl lysine
  • Aromatic compounds such as indole acetate (IAA), indole lactate (ILA), hydroxy phenyl acetate, phenyl acetate, imidazole acetate, indole propionate (I PA), 3- phenyllactate (PLA), hydroxy phenyl propionate (HO-PPA), phenyl propionate, imidazole propionate and hydroxy phenyl lactate (HO-PLA) and hydroxy-phenyl- hydroxy-propionate (HO-P-HO-PA)
  • Samples were produced and collected in Eppendorf tubes. Samples were stored at -80°C until day of analysis after each experimental trial performed.
  • Bacterial media samples were stored at -80°C until the analysis day.
  • samples were thawed at room temperature for at least 1 h, vortexed for homogenization (10 sec) and centrifuged at 12500 g for 10 min at 4 °C in a Thermo Heraeus Fresco 17 centrifuge.
  • An aliquot of 150 pL was taken into an Eppendorf tube and followed by addition of 600 pL of pure methanol.
  • the mixture was vortexed for 10 min at 1500 rpm and left to stand for 5 min at room temperature to allow any precipitation.
  • the samples were centrifuged at 12500 rpm for 10 min at 4 °C in a Thermo Heraeus Fresco 17 centrifuge.
  • the supernatant (720 pL) was transferred into a 96-well plate and evaporated under a stream of gaseous nitrogen flow at room temperature during about 1.5 h.
  • Dried extracts were reconstituted in 135 iL of pure MeOH with in addition, 15 pL of internal standard (ISTD) mix (at a concentration of 125 iM in pure MeOH) to make up a final volume of 150 pL.
  • the samples were vortexed for 10 min at 1500 rpm. Extracts were then transferred into Eppendorf tubes for a centrifugation cycle (12500 rpm for 10 min at 4 °C). Finally, they were transferred into appropriate vial prior to injection.
  • LNFP-I + 8. infantis LMG11588 + WPC (HA)
  • the study was designed this way to overcome inter-individual biological variability between donors and their microbiota compositions.
  • Donors were 3-month-old infants ( ⁇ 3 weeks) exclusively fed with formulae without HMO/probiotics.
  • the exclusion criteria were antibiotic use in 30 days before sample delivery for the study and previous NEC or gut surgery. This resulted in the enrolment of 6 specific test subjects with an average age of 3.1 ( ⁇ 0.5) months. Intestinal absorption and colonic incubation conditions were then conducted using Cryptobiotix’s proprietary “ex-vivo SIFR” protocols (cf. Van den Abbeele et al. Frontiers Microbiol. 2023).
  • LNFP-I was dosed at a final concentration of 0.03 g/L WPC (HA) was added at a final concentration of 42.13 g dry matter/L.
  • B. infantis was dosed at a concentration of 5 x 107 CFLI/mL.
  • Colonic incubations were carried out for 24-hours, with sampling at 0 and 24 hours for SCFA levels by HPLC.
  • Microbially-produced acetate, butyrate, and total SCFA concentrations were quantified in liquid after 24 h incubation as described in Van den Abbeele et al., 2023.
  • the study was designed this way to overcome inter-individual biological variability between donors and their microbiota compositions.
  • Donors were 3-month-old infants ( ⁇ 3 weeks) exclusively fed with formulae without HMO/probiotics.
  • the exclusion criteria were antibiotic use in 30 days before sample delivery for the study and previous NEC or gut surgery. This resulted in the enrolment of 6 specific test subjects with an average age of 3.1 ( ⁇ 0.5) months. Intestinal absorption and colonic incubation conditions were then conducted using Cryptobiotix’s proprietary “ex-vivo SIFR” protocols (cf. Van den Abbeele et al. Frontiers Microbiol. 2023).
  • Colonic incubations were carried out for 24-hours, with sampling at 0 and 24 hours for SCFA levels by HPLC and 3-phenyllactic acid PLA by LC-MS.
  • PHA Microbially-produced
  • butyrate were quantified in liquid after 24 h incubation as described in Van den Abbeele et al., 2023.
  • infantis LMG 11588 were jointly present. Synergy is apparent as the concentrations in which WPC (HA) and B. infantis LMG 11588 were jointly present (rightmost bar) is higher than the summed WPC (HA) only and B. infantis LMG 11588 only condition (middle bar). Individual contributions in the latter condition are shown by coloring them (black for B. infantis LMG 11588 only condition and white for WPC (HA) only condition).
  • B. infantis LMG11588 was grown in anaerobic conditions in minimal medium MRS API with 0.25% Glucose overnight. After 16h growth, this overnight culture was used to inoculate B. infantis LMG11588 at OD 0.05 in MRS API medium supplemented with 0.25% of below listed carbon sources in a total volume of 1200 pL.
  • Bifidobacterium longum subsp. infantis (B. infantis) has the ability to efficiently catabolise a wide array of HMO structures, in particular fucosylated HMO glycans.
  • fucosylated HMO glycans Among the commonly- occurring fucosylated HMO glycans in breastmilk is LNFP-I.
  • LNFP-I fucosylated HMO glycans in breastmilk
  • LNFP-I fucosylated HMO glycans in breastmilk
  • the combination of B. infantis and LNFP-I can significantly elevate levels of the compound PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA, compared to any combination of two of these components, or individually.
  • the levels of PLA are significantly higher when LNFP-I is used rather than 2’-FL (2.385 pM).
  • protein bodies containing higher starting levels of phenylalanine and tyrosine also enabled the greater production of PLA, HO- PPA, HO-PLA and/or HO-P-HO-PA.
  • protein bodies containing an optimised aminogram enabled the greater production of these phenolic metabolites.
  • These protein bodies had an adapted protein profile and/or an adapted peptide profile.
  • the combination of B. infantis and LNFP-I and a phenylalanine-rich and/or tyrosinerich protein body can significantly elevate levels of the compound(s) PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA, compared to any combination of two of these components, or individually.
  • the Cryptobiotix study carried out demonstrated the effect of the combination of LNFP-I with Bifidobacterium longum subsp. infantis LMG 11588 and WPC(HA) on boosting a microbial derived metabolites that is linked with immune benefits.
  • Adding LNFP-I increases acetate, butyrate, and total SCFA.
  • the levels of SCFA is further boosted by the addition of Bifidobacterium longum subsp. infantis LMG 11588 and WPG (HA) ( Figure 4).
  • WPG WPG
  • Bifidobacterium longum subsp. infantis LMG 11588 WPG
  • PPA phenyllactic acid
  • SCFA SCFA
  • the inventors also performed in vitro growth assays in which B. infantis LMG11588 was inoculated in the presence of several carbon sources.
  • the biomass gain was continuously monitored as a measure of if and how the different carbon sources could support the growth of B. infantis LMG11588 over the course of 48 hours.
  • no carbon source was added (no substrate)
  • no growth was observed, whilst the addition of the simple sugar glucose or the less complex HMO LNT resulted in exponential growth that started to stagnate after 10 hours.
  • B. infantis LMG11588 can utilize LNFP-I to grow, and after an adaptation period, a diauxic growth is observed, sselling that B. infantis is able to utilize LNFP-I as a sole carbon source to ensure increase of biomass (Figure 6).
  • a combination comprising or consisting of lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis, or a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto-N-fucopentaose-l
  • LNFP-1 lacto-N-fucopentaose-l
  • a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • the protein source comprises: a) skimmed milk and demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey; b) skimmed milk and CGMP-free acid or native whey; c) CGMP-free whey protein isolate and sweet whey protein concentrate; d) demineralized CGMP-reduced sweet whey and demineralized sweet whey; or e) skimmed milk and alpha-lactalbumin-enriched whey protein.
  • CGMP glycomacropeptide
  • the protein source is an intact protein source comprising: a) skimmed milk and demineralized, caseino-glyco-macropeptide (CGMP)-reduced-whey; b) skimmed milk and CGMP-free whey, such as acid or native whey; or c) skimmed milk and alpha-lactalbumin-enriched whey protein.
  • CGMP caseino-glyco-macropeptide
  • the protein source is a partially hydrolysed protein source comprising: a) CGMP-free whey protein isolate and demineralized sweet whey protein concentrate; or b) demineralized CGMP-reduced sweet whey and demineralized sweet whey.
  • the protein source comprises: a) skimmed milk and demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey; b) CGMP-free whey protein isolate and sweet whey protein concentrate; or c) demineralized CGMP-reduced sweet whey and demineralized sweet whey.
  • CGMP glycomacropeptide
  • the protein source is an intact protein source comprising skimmed milk and demineralized, caseino-glyco-macropeptide (CGMP)-reduced-whey.
  • CGMP caseino-glyco-macropeptide
  • the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.
  • a combination or a nutritional composition as defined in any one of the preceding paras for increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject, and preferably for further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably for further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject. 18.
  • modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • a method of increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of a subject comprising administering a combination or a nutritional composition as defined in any one of paras 1 to 16 to the subject.
  • a method of modulating the microbiota of a subject comprising administering a combination or a nutritional composition as defined in any one of paras 1 to 16 to the subject.
  • modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the combination or the nutritional composition for use according to para 25 or para 26, wherein modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the subject is an infant, a young child or a child.
  • composition is for use in preventing and/or treating fungal, viral and/or bacterial infections in a subject.
  • a nutritional composition as defined in any one of paras 1 to 16 for the manufacture of a medicament for: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject.
  • a combination or a nutritional composition according to para 31 , wherein the medicament is for: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject; by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject, and preferably by further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably by further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • the use of the combination or the nutritional composition according to para 31 or para 32, wherein modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the method is for: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject; by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject, and preferably by further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably by further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • a combination comprising or consisting of lacto-N-fucopentaose-l (LNFP-I) and the strain Bifidobacterium longum subsp. Infantis LMG 11588.
  • a nutritional composition comprising a combination according to any of paras 1 to 16 or 41.
  • a nutritional composition comprising lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • LNFP-I lacto-N-fucopentaose-l
  • LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis.
  • composition according to para 1 , wherein the composition further comprises a protein source.
  • the protein source comprises at least one selected in the group consisting of a) skimmed milk and demineralized, casein glycomacropeptide (CGMP)-reduced sweet whey; b) skimmed milk and CGMP-free acid or native whey; c) CGMP-free whey protein isolate and sweet whey protein concentrate; d) demineralized CGMP-reduced sweet whey and demineralized sweet whey; and e) skimmed milk and alpha-lactalbumin-enriched whey protein; or any mixture thereof.
  • CGMP glycomacropeptide
  • the nutritional composition according to any one of the preceding paras wherein the nutritional composition is an infant formula, a starter infant formula, a follow-on or follow-up infant formula, a baby food, an infant cereal composition, a growing-up milk, a fortifier or a supplement.
  • a nutritional composition as defined in any one of the preceding paras for increasing the levels of 3-phenyllactate (PLA), 3-(4-hydroxyphenyl)lactate (HO-PLA), 3-(4- hydroxyphenyl)propionate (HO-PPA), and/or 3-hydroxyphenyl-3-hydroxypropionate (HO-P- HO-PA) in the gastrointestinal tract of a subject, and preferably for further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably for further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject. 7. Use of a nutritional composition as defined in any one of paras 1 to 5 for modulating the microbiota of a subject.
  • modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • composition for use according to para 9, wherein the composition is for use in: i) preventing and/or treating fungal, viral and/or bacterial infections in a subject; ii) preventing and/or reducing inflammation in the intestine of a subject ii) promoting a healthy immune system in a subject; iii) preventing and/or treating obesity in a subject; iv) preventing and/or treating microbiota dysbiosis in a subject; and/or v) modulating the microbiota of a subject; by increasing the levels of PLA, HO-PPA, HO-PLA and/or HO-P-HO-PA in the gastrointestinal tract of the subject, and preferably by further increasing the levels of SCFA in the gastrointestinal tract of the subject, more preferably by further increasing the levels acetate and butyrate, in the gastrointestinal tract of the subject.
  • the nutritional composition for use according to para 9 or para 10, wherein modulating the microbiota of a subject comprises increasing the abundance of a LNFP-1 metabolizing Bifidobacterium, for example Bifidobacterium longum subsp. infantis in the gastrointestinal tract of the subject.
  • the nutritional composition for use according to any one of paras 9 to 11 wherein the composition is for use in preventing and/or treating fungal, viral and/or bacterial infections in a subject.
  • the nutritional composition for use according to any one of paras 9 to 11 wherein the composition is for use in preventing and/or reducing inflammation in the intestine of a subject and/or promoting a healthy immune system in a subject.
  • a combination comprising or consisting of lacto-N-fucopentaose-l (LNFP-I) and a LNFP-1 metabolizing Bifidobacterium, for example the Bifidobacterium longum subsp. infantis, wherein Bifidobacterium longum subsp. Infantis is preferably the strain LMG 11588 (also known as ATCC 17930).

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Abstract

La présente invention concerne une combinaison comprenant ou consistant en du lacto-N-fucopentaose-I (LNFP-I) et en un Bifidobacterium métabolisant LNFP-1, par exemple Bifidobacterium longum subsp. infantis, ou une composition nutritionnelle comprenant du lacto-N-fucopentaose-I (LNFP-I) et un Bifidobacterium métabolisant LNFP-1, par exemple Bifidobacterium longum subsp. infantis.
PCT/EP2024/061696 2023-04-28 2024-04-26 Composition nutritionnelle Pending WO2024227720A1 (fr)

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