[go: up one dir, main page]

WO2025008277A1 - Combinaison pour la gestion alimentaire de la santé intestinale - Google Patents

Combinaison pour la gestion alimentaire de la santé intestinale Download PDF

Info

Publication number
WO2025008277A1
WO2025008277A1 PCT/EP2024/068245 EP2024068245W WO2025008277A1 WO 2025008277 A1 WO2025008277 A1 WO 2025008277A1 EP 2024068245 W EP2024068245 W EP 2024068245W WO 2025008277 A1 WO2025008277 A1 WO 2025008277A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination
composition
nutritional composition
consumed
use according
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/EP2024/068245
Other languages
English (en)
Inventor
Sophie Hélène NUTTEN
Ralf HEINE
Laurent Favre
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Nestle SA
Original Assignee
Societe des Produits Nestle SA
Nestle SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Publication of WO2025008277A1 publication Critical patent/WO2025008277A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to compositions, particularly a nutritional composition, and methods for the dietary management of gut health; for example in an infant.
  • Nutritional compositions for infants and young children are often sold as powders to be reconstituted with water or in some instances as ready to drink or concentrated liquid compositions. Those compositions are intended to cover most or all of the nutritional needs of the infants or young children.
  • infant formula manufacturers have therefore made many attempts to induce nutritional health effects close to or similar to the benefits of human breast milk.
  • many studies have shown that infant formula do not induce the identical effects on the body compared to human breast milk.
  • infants fed infant formula and infants fed human-breast milk (HBM) can exhibit a different intestinal (gut) microbiota.
  • HMOs human milk oligosaccharides
  • Mammalian milk contains at least 130 of these complex oligosaccharides (Urashima et al, Milk Oligosaccharides, Nova Biomedical Books, New York, 2011 , ISBN: 978-1-61122-831-1).
  • microbiota the resident community of microbes
  • the microbiota the resident community of microbes
  • the host can suffer consequences.
  • Recent research has implicated intestinal microbiota imbalances in individual disorders as diverse as cancer, obesity, inflammatory bowel disease, psoriasis, asthma, and possibly even autism.
  • the modulation of the gut microbiota during infancy can prospectively have a significant influence in the future health status of the body.
  • 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 or allergy later in life.
  • the present inventors have surprisingly found that a combination of lactose and specific combinations of human milk oligosaccharides (HMO) synergistically promote beneficial effects for infant gut health, for example by reducing levels of branched chain fatty acids (BCFA).
  • BCFA that are indicative of proteolytic fermentation by the gut microbiota and are associated with the formation of metabolites such as phenol and indole that exert detrimental health effects.
  • Compositions that reduce and/or limit BCFA production may thus have beneficial effects on infant gut health.
  • the present invention provides a combination comprising lactose and human milk oligosaccharides (HMOs) 2'-fucosyllactose (2’-FL), lacto-ZV-neotetraose (LNnT), 3’-fucosyllactose (3'-FL), at least one of 3’-sialyllactose (3’-SL) or 6’-sialyllactose (6’-SL), and optionally lacto-ZV-tetraose (LNT) for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • HMOs human milk oligosaccharides
  • LNnT lacto-ZV-neotetraose
  • LNT lacto-ZV-tetraose
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3'-FL, LNT, 3’-SL, and 6’-SL for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optionally LNT for use in the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optional LNT for use in the dietary management of at least one pathogen, preferably a pathogenic bacteria, in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’- SL, 6’-SL, and LNT for use in in the dietary management of at least one pathogen, preferably a pathogenic bacteria, in a subject.
  • the invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optionally LNT for use in the reduction of BCFA in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the reduction of BCFA in a subject.
  • SIFR® technology platform for 4 HMO blends (M2, M4.1 , M4.2, M6), lactose (L) and combinations thereof (M2+L, M4.1+L, M4.2+L, M6+L) as compared to a no substrate control (NSC). Samples were collected after 6h, 24h and 48h of simulated colonic incubations.
  • PCA Principal component analysis
  • the PCA was calculated based on the (centred) average abundance across the 12 CMPA infants of the 100 most abundant operational taxonomic units (OTUs) as quantified via 16S rRNA sequencing combined with flow cytometry (cells/mL), both at the start (Oh) and at 24h after initiation of the colonic incubations.
  • OTUs operational taxonomic units
  • PCA Principal component analysis
  • Numeric ranges are inclusive of the numbers defining the range and all percentages disclosed herein are on a w/w basis, unless stated otherwise.
  • the term “about” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical value or range, it modifies that value or range by extending the boundaries above and below the numerical value(s) set forth. In general, the terms “about” and “approximately” are used herein to modify a numerical value(s) above and below the stated value(s) by 10%.
  • the present invention provides a combination of lactose and human milk oligosaccharides (HMOs) 2’-FL, LNnT, 3’-FL, LNT, and at least one of 3’-SL or 6’-SL for use in the dietary management of gut health in a subject.
  • HMOs human milk oligosaccharides
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3'-FL, LNT, 3’-SL, and 6’- SL for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the combination may be administered to a subject in the form of a composition (e.g. as a composition comprising a lactose mixture and a HMO mixture).
  • a composition e.g. as a composition comprising a lactose mixture and a HMO mixture.
  • the combination may be administered by any suitable route and in any suitable form.
  • the combination is administered by oral and/or enteral administration.
  • the combination is administered by oral administration.
  • the combination may be administered separately, simultaneously or sequentially. In preferred embodiments, the combination is administered simultaneously.
  • Lactose is a disaccharide made up of glucose and galactose.
  • the glucose can be in either the a-pyranose form or the p-pyranose form.
  • Lactose is the main carbohydrate source in breastmilk.
  • the combination, preferably the nutritional composition, of the present invention may comprise a lactose-containing carbohydrate component, wherein the lactose represents from about 68% to about 97%, optionally from about 70% to about 90%, further optionally from about 72% to about 80%, of the carbohydrate calories.
  • the nutritional composition is an infant formula as described herein, and any lactose-containing carbohydrate known for use in infant formulas, or otherwise effective for such use, can be used as a lactose-containing carbohydrate component.
  • lactose is from about 49% to about 100% of the non-HMO carbohydrate in the combination, preferably the nutritional composition. In particular embodiments, lactose is about 100% of the non-HMO carbohydrate in the combination, preferably the nutritional composition.
  • Lactose is present in the nutritional composition in some particular amounts. In an embodiment of the invention, lactose is present in the nutritional composition in an amount up to about 53 g/L or up to about 110g/L of the composition as consumed. In a particular embodiment, lactose is present in an amount of about 37 g/L of the composition as consumed. In a particular embodiment, lactose is present in the nutritional composition in an amount of about 18-110 g/L of the composition as consumed, such as about 24-98 g/L, 49-98 g/L or 58-88 g/L or 65-80 g/L of the composition as consumed. In another particular embodiment, lactose is present in the nutritional composition in an amount of about 73 g/L of the composition as consumed.
  • lactose is present in the nutritional composition in an amount of up to about 34 g per 100 g of composition based on the dry weight of the composition or up to about 67 g per 100g of composition based on the dry weight of the composition. Lactose may be in an amount of about 22-34 g per 100g of the composition based on the dry weight of the composition or about 27 g per 100 g of the composition based on the dry weight of the composition. In an embodiment of the invention, lactose may be in the nutritional composition in an amount of about 44-67 g per 100g of the composition based on the dry weight of the composition. Lactose may be in an amount of about 27 g per 100 g of the composition based on the dry weight of the composition. Lactose may be in an amount of about 55 g per 100 g of the composition based on the dry weight of the composition.
  • Lactose for use in the present invention is not particularly limited with the exception that it must be suitable for including in a composition, preferably nutritional composition, for administration to a human of any age.
  • Lactose for use in the present invention may be synthesised by any suitable means known in the art, by, e.g. enzymatic, biotechnological, and/or chemical processes including chemical synthesis, fermentation and/or production by suitable bacteria or yeast, or derived or otherwise obtained from cow’s milk, which generally contains about 5% lactose.
  • the lactose can be added in purified or partially purified form, or added as a fractional ingredient of cow’s milk or processed cow’s milk products. Some of the lactose can also be provided as inherent excipients in other added ingredients, e.g., excipient lactose in many protein sources.
  • the lactose-containing carbohydrate may also contain non-lactose carbohydrates (e.g. a minority of non-lactose carbohydrates), non-limiting sources of which include hydrolyzed or intact, naturally and/or chemically modified, starches sourced from corn, tapioca, rice or potato, in waxy or non-waxy forms.
  • suitable carbohydrate sources include hydrolyzed corn starch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, glucose, fructose, high fructose corn syrup, and combinations thereof.
  • lactose Suitable doses of lactose are described in e.g. Scientific Opinion on the essential composition of infant and follow-on formulae. EFSA Journal 2014; 12(7):3760, 106 pp. doi:10.2903/j.efsa.2014.3760.
  • HMOs Human Milk Oligosaccharides
  • HMOs have become the subject of much interest in recent years due to their roles in numerous biological processes occurring in the human organism.
  • Mammalian milk contains at least 130 of these complex oligosaccharides (Urashima et al, Milk Oligosaccharides, Nova Biomedical Books, New York, 2011 , ISBN: 978-1-61122-831-1).
  • HMOs are found in human milk. Each 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. Almost all HMOs have a lactose moiety at their reducing end while sialic acid and/or fucose (when present) occupy terminal positions at the non-reducing ends. HMOs can be acidic (e.g. charged sialic acid containing oligosaccharides) or neutral (e.g. fucosylated oligosaccharides).
  • HMOs in the combination comprise, consist essentially of, or preferably consist of 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optionally LNT.
  • the combination may comprise 2’-FL, LNnT, 3’-FL, and 3’-SL and/or 6’-SL.
  • the combination may comprise 2’-FL, LNnT, 3’-FL, LNT, and 3’-SL and/or 6’-SL.
  • the combination may comprise 2'-FL, LNnT, 3’-FL and 3’-SL.
  • the combination may comprise 2’-FL, LNnT, 3’-FL and 6’-SL.
  • the combination may comprise 2’-FL, LNnT, 3’-FL, 3’-SL and 6’-SL.
  • the combination may comprise 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT.
  • the nutritional composition may comprise no other HMO aside from 2’-FL, LNnT, 3’-FL and at least one of 3’-SL or 6’-SL.
  • the HMOs in the composition may comprise, consist essentially of, or consist of 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL and LNT.
  • the nutritional composition may comprise no other HMO aside from 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL and LNT.
  • the HMOs may be obtained by any suitable method. Suitable methods for synthesising HMOs will be well known to those of skill in the art. For example, processes have been developed for producing HMOs by microbial fermentation, enzymatic processes, chemical syntheses, or combinations of these technologies (Zeuner et al., 2019. Molecules, 24(11), p.2033).
  • the 2’-FL may be produced by biotechnological means using specific fucosyltransferases and/or fucosidases either through the use of enzyme-based fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes may either express their natural enzymes and substrates or may be engineered to produce respective substrates and enzymes. Alternatively, 2’-FL may be produced by chemical synthesis from lactose and free fucose.
  • 2’-FL may be present in the nutritional composition in some particular amounts. In an embodiment of the invention, 2’-FL is present in the nutritional composition in an amount of up to about 1 .5 g/L of the composition as consumed. 2’-FL may be in the nutritional composition in an amount of 0.2-1 .5 g/L of the composition as consumed, such as 0.25-1.5 g/L or 0.5-1 .5 g/L or 0.8-1.2 g/L of the composition as consumed. In another particular embodiment, 2’-FL is present in the nutritional composition in an amount of about 1.2 g/L of the composition as consumed. In another particular embodiment, 2’-FL is present in the nutritional composition in an amount of about 1.0 g/L of the composition as consumed.
  • 2’-FL is present in the nutritional composition in an amount of up to about 1.2 g per 100g of composition based on the dry weight of the composition.
  • 2’-FL may be in the nutritional composition in an amount of 0.38-1.2 g per 100g of the composition based on the dry weight of the composition, such as 0.2-1 ,2g or 0.38-1 ,2g or 0.61-1 ,5g per 100 g of the composition based on the dry weight of the composition.
  • 2’-FL is present in the nutritional composition in an amount of about 0.9 g per 100 g of the composition based on the dry weight of the composition.
  • 2’-FL is present in the nutritional composition in an amount of about 0.8 g per 100 g of the composition based on the dry weight of the composition.
  • the 3’-FL may be synthesized by enzymatic, biotechnological, and/or chemical processes.
  • the 3’-FL may be manufactured through fermentation using a genetically modified microorganism.
  • the 3’-FL may be produced as described in WO 2013/139344.
  • 3’-FL may be present in the nutritional composition in some particular amounts. In an embodiment of the invention, 3’-FL is present in the nutritional composition in an amount of up to about 1.1 g/L of the composition as consumed, 3’-FL may be in the nutritional composition in an amount of 0.1 -1.1 g/L of the composition as consumed, such as 0.13-1.1 g/L or 0.25-0.75 g/L or 0.4-0.6 g/L of the composition as consumed. In another particular embodiment, 3’-FL is present in the nutritional composition in an amount of about 0.9 g/L of the composition as consumed. In another particular embodiment, 3’-FL is present in the nutritional composition in an amount of about 0.5 g/L of the composition as consumed.
  • 3’-FL is present in the nutritional composition in an amount of up to about 0.8 g per 100g of composition based on the dry weight of the composition.
  • 3’-FL may be in the nutritional composition in an amount of 0.08-0.8 g per 100g of the composition based on the dry weight of the composition, such as 0.1-0.8g/L or 0.2-0.6g or 0.3-0.5g per 100 g of the composition based on the dry weight of the composition.
  • 3’-FL is present in the nutritional composition in an amount of about 0.7g per 100 g of the composition based on the dry weight of the composition.
  • 3’-FL is present in the nutritional composition in an amount of about 0.4 g per 100 g of the composition based on the dry weight of the composition.
  • LNnT may be synthesised chemically by enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyltransferases as described, for example, in US Patent No. 5,288,637 and WO 1996/010086.
  • LNnT may be prepared by chemical conversion of Keto-hexoses (e.g. fructose) either free or bound to an oligosaccharide (e.g. lactulose) into N-acetylhexosamine or an N-acetylhexosamine-containing oligosaccharide as described in Wrodnigg, T.M. and Stutz, A.E. (1999) Angew. Chem. Int. Ed.
  • Keto-hexoses e.g. fructose
  • an oligosaccharide e.g. lactulose
  • N-acetyl-lactosamine produced in this way may then be transferred to lactose as the acceptor moiety.
  • the LNnT may be produced as described in WO 2011/100980 or WO 2013/044928.
  • LNnT may be present in the nutritional composition in some particular amounts.
  • LNnT is present in the nutritional composition in an amount of up to about 0.75 g/L of the composition as consumed, LNnT may be in the nutritional composition in an amount of 0.1-0.75 g/L of the composition as consumed, such as 0.13-0.75 g/L or 0.25-0.75 g/L or 0.4-0.6 g/L of the composition as consumed.
  • LNnT is present in the nutritional composition in an amount of about 0.7 g/L of the composition as consumed.
  • LNnT is present in the nutritional composition in an amount of about 0.5 g/L of the composition as consumed.
  • LNnT is present in the nutritional composition in an amount of up to about 0.6 g per 100g of composition based on the dry weight of the composition.
  • LNnT may be in an amount of 0.08-0.6 g per 100g of the composition based on the dry weight of the composition, such as 0.1-0.6g/L or 0.2-0.6g or 0.3-0.5g per 100 g of the composition based on the dry weight of the composition.
  • LNnT is present in the nutritional composition in an amount of about 0.6g per 100 g of the composition based on the dry weight of the composition.
  • LNnT is present in the nutritional composition in an amount of about 0.4 g per 100 g of the composition based on the dry weight of the composition.
  • the 3’-SL may be synthesized by enzymatic, biotechnological, and/or chemical processes.
  • the 3’-SL may be produced as described in WO 2014/153253.
  • 3’-SL may be present in the nutritional composition in some particular amounts.
  • 3’-SL is present in the nutritional composition in an amount of up to about 0.24 g/L of the composition as consumed, 3’-SL may be in the nutritional composition in an amount of 0.02-0.24 g/L of the composition as consumed, such as 0.025-0.24 g/L or 0.05- 0.15 g/L or 0.08-0.12 g/L of the composition as consumed.
  • 3’-SL is present in the nutritional composition in an amount of about 0.2 g/L of the composition as consumed.
  • 3’-SL is present in the nutritional composition in an amount of about 0.1 g/L of the composition as consumed.
  • 3’-SL is present in the nutritional composition in an amount of up to about 0.18 g per 100g of composition based on the dry weight of the composition.
  • 3’-SL may be in the nutritional composition in an amount of 0.015-0.18 g per 100g of the composition based on the dry weight of the composition, such as 0.019-0.18 g/L or 0.038-0.11 g or 0.06-0.09 g per 100 g of the composition based on the dry weight of the composition.
  • 3’-SL is present in the nutritional composition in an amount of about 0.15 g per 100 g of the composition based on the dry weight of the composition.
  • 3’-SL is present in the nutritional composition in an amount of about 0.08 g per 100 g of the composition based on the dry weight of the composition.
  • the 6’-SL may be synthesized by chemical methods including stereoselective 6’-O-sialylation of either 4’,6’-sugar diols or 6’-sugar alcohols using glycosylhalide, thioglycoside or diethylphosphite donor activations.
  • the 6’-SL may be enzymatically produced using glycosyltransferases and sialidases.
  • the 6’-SL may be produced as described in WO 2011/100979.
  • 6’-SL may be present in the nutritional composition in some particular amounts. In an embodiment of the invention, 6’-SL is present in the nutritional composition in an amount of up to about 0.84 g/L of the composition as consumed, 6’-SL may be in the nutritional composition in an amount of 0.04-0.84 g/L of the composition as consumed, such as 0.05-0.84 g/L or 0.1- 0.3 g/L or 0.16-0.24g/L of the composition as consumed. In another particular embodiment, 6’- SL is present in the nutritional composition in an amount of about 0.7 g/L of the composition as consumed. In another particular embodiment, 6’-SL is present in the nutritional composition in an amount of about 0.2 g/L of the composition as consumed.
  • 6’-SL is present in the nutritional composition in an amount of up to about 0.64 g per 100g of composition based on the dry weight of the composition.
  • 6’-SL may be in the nutritional composition in an amount of 0.003-0.64 g per 100g of the composition based on the dry weight of the composition, such as 0.038-0.64 g/L or 0.076-0.23 g or 0.12-0.18 g per 100 g of the composition based on the dry weight of the composition.
  • 6’-SL is present in the nutritional composition in an amount of about 0.53 g per 100 g of the composition based on the dry weight of the composition.
  • 6’-SL is present in the nutritional composition in an amount of about 0.08 g per 100 g of the composition based on the dry weight of the composition.
  • the LNT may be synthesized by enzymatic, biotechnological and/or chemical processes.
  • the LNT may be produced as described in WO 2012/155916 or WO 2013/044928.
  • a mixture of LNT and LNnT can be made as described in WO 2013/091660.
  • LNT may be present in the nutritional composition in some particular amounts.
  • LNT is present in the nutritional composition in an amount of up to about 0.96 g/L of the composition as consumed, LNT may be in an amount of 0.06-0.96 g/L of the composition as consumed, such as 0.075-0.96 g/L or 0.15-0.45 g/L or 0.24-0.36 g/L of the composition as consumed.
  • LNT is present in the nutritional composition in an amount of about 0.8 g/L of the composition as consumed.
  • LNT is present in the nutritional composition in an amount of about 0.3 g/L of the composition as consumed.
  • LNT is present in the nutritional composition in an amount of up to about 0.73 g per 100g of composition based on the dry weight of the composition.
  • LNT may be in the nutritional composition in an amount of 0.046-0.73 g per 100g of the composition based on the dry weight of the composition, such as 0.057-0.73 g/L or 0.11-0.34 g or 0.18-0.27 g per 100 g of the composition based on the dry weight of the composition.
  • LNT is present in the nutritional composition in an amount of about 0.6 g per 100 g of the composition based on the dry weight of the composition.
  • LNT is present in the nutritional composition in an amount of about 0.2 g per 100 g of the composition based on the dry weight of the composition.
  • the combination comprises the HMOs 2’-FL, LNnT, 3’-FL, and 3’-SL.
  • the HMOs in the combination consist of, or consist essentially of, 2’-FL, LNnT, 3’-FL, and 3’-SL.
  • the combination comprises, consists essentially of the HMOs, or consists of the HMOs 2’-FL (about 0.8-1.2 g/L of the composition as consumed), 3’-FL (about 0.4-0.6 g/L of the composition as consumed), LNnT (about 0.4-0.6 g/L of the composition as consumed), 3’-SL (about 0.08-0.12 g/L of the composition as consumed), and optionally LNT (about 0.24-0.36g/L of the composition as consumed).
  • the combination comprises the HMOs 2’-FL, LNnT, 3’-FL, and 6’-SL.
  • the HMOs in the combination consist of, or consist essentially of, 2’-FL, LNnT, 3’-FL, and 6’-SL.
  • the combination comprises, consists essentially of the HMOs, or consists of the HMOs 2’-FL (about 0.8-1.2 g/L of the composition as consumed), 3’-FL (about 0.4-0.6 g/L of the composition as consumed), LNnT (about 0.4-0.6 g/L of the composition as consumed), 6’-SL (about 0.16-0.24 g/L of the composition as consumed), and optionally LNT (about 0.24-0.36g/L of the composition as consumed).
  • the nutritional composition comprise with reference to the total amount of HMOs in the combination, preferably nutritional composition: i. about 22 wt % to about 65 wt % of 2’-FL, preferably about 35 wt % to about 52 wt %, preferably about 43 wt %; ii. about 11 wt % to about 33 wt % of LNnT, preferably about 17 wt % to about 26 wt %, preferably about 22 wt %; iii.
  • the nutritional composition comprise with reference to the total amount of HMOs: i. about 22 wt % to about 65 wt % of 2’-FL, preferably about 35 wt % to about 52 wt %, preferably about 43 wt %; ii. about 11 wt % to about 33 wt % of LNnT, preferably about 17 wt % to about 26 wt %, preferably about 22 wt %; iii. about 11 wt % to about 33 wt % 3’-FL, preferably about 17 wt % to about 26 wt %, preferably about 22 wt %; and iv.
  • the invention provides a combination comprising the HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL and LNT.
  • the HMOs in the combination consist of, or consist essentially of, 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL and LNT.
  • the combination comprises, consists essentially of the HMOs, or consists of the HMOs 2’-FL (about 0.8-1 .2 g/L of the composition as consumed), 3’-FL (about 0.4-0.6 g/L of the composition as consumed), LNnT (about 0.4-0.6 g/L of the composition as consumed); 3’-SL (about 0.08-0.12 g/L of the composition as consumed), 6’-SL (about 0.16-0.24 g/L of the composition as consumed), and LNT (about 0.24-0.36g/L of the composition as consumed).
  • the nutritional composition comprise with reference to the total amount of HMOs: i. about 19 wt % to about 58 wt % of 2’-FL, preferably about 31 wt % to about 46 wt %, preferably about 38 wt % ; ii. about 10 wt % to about 29 wt % of LNnT, preferably about 15 wt % to about 23 wt %, preferably about 19 wt %; iii. about 10 wt % to about 29 wt % 3’-FL, preferably about 15 wt % to about 23 wt %, preferably about 19 wt %; and iv.
  • the nutritional composition comprises the 2’-FL and LNnT in a 2’-FL:LNnT weight ratio from 1 :10 to 12:1 , such as from 1 :7 to 10:1 or from 1 :5 to 5:1 or from 2:1 to 5:1 or from 1 :3 to 3:1 , or from 1 :2 to 2:1 , or from 1 :1 to 3:1 , or from 1 :5 to 1 :0.5; for example 2:1 or 10:1.
  • the nutritional composition comprises the 2’-FL and LNnT in a 2’-FL:LNnT weight ratio of about 2:1.
  • the subject may be administered any suitable amounts of HMOs, in any suitable form and via any suitable route of administration (e.g. in any form and via any route described herein).
  • Suitable doses of human oligosaccharides are described in e.g. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. EFSA Journal, 13(11), p.4299; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2019.
  • the HMO combination is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.1 g/day, at least about 0. 5 g/day, at least about 1 g/day, or at least about 2 g/day.
  • the HMO combination is administered to the subject in an amount of about 10 g/day or less, about 8 g/day or less, or about 5 g/day or less.
  • the HMO combination is administered to the subject in an amount of from about 0.05 g/day to about 10 g/day, from about 0.1 g/day to about 10 g/day, from about 0.5 g/day to about 10 g/day, from about 1 g/day to about 8 g/day or from about 2 g/day to about 5 g/day.
  • 2’-FL is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.1 g/day, at least about 0.2 g/day. At least about 0.5 g/day at least about 0.8 g/day, or at least about 1 g/day.
  • 2’-FL is administered to the subject in an amount of about 5 g/day or less, about 4 g/day or less, or about 3 g/day or less.
  • 2’-FL is administered to the subject in an amount of from about 0.5 g/day to about 5 g/day, from about 0.8 g/day to about 4 g/day or from about 1 g/day to about 3 g/day.
  • LNnT is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.2 g/day, at least about 0.3 g/day, or at least about 0.4 g/day.
  • LNnT is administered to the subject in an amount of about 2.5 g/day or less, about 2 g/day or less, or about 1 .5 g/day or less.
  • LNnT is administered to the subject in an amount of from about 0.2 g/day to about 2.5 g/day, from about 0.3 g/day to about 2 g/day or from about 0.4 g/day to about 1.5 g/day.
  • 3’-FL is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.1 g/day, at least about 0.15 g/day, or at least about 0.2 g/day.
  • 3’-FL is administered to the subject in an amount of about 1 g/day or less, about 0.8 g/day or less, or about 0.6 g/day or less.
  • 3’-FL is administered to the subject in an amount of from about 0.1 g/day to about 1 g/day, from about 0.15 g/day to about 0.8 g/day or from about 0.2 g/day to about 0.6 g/day.
  • 3’-SL is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.1 g/day, at least about 0.15 g/day, or at least about 0.2 g/day.
  • 3’-SL is administered to the subject in an amount of about 1 g/day or less, about 0.8 g/day or less, or about 0.6 g/day or less.
  • 3’-SL is administered to the subject in an amount of from about 0.1 g/day to about 1 g/day, from about 0.15 g/day to about 0.8 g/day or from about 0.2 g/day to about 0.6 g/day.
  • 6’-SL is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.1 g/day, at least about 0.15 g/day, or at least about 0.2 g/day.
  • 6’-SL is administered to the subject in an amount of about 1 g/day or less, about 0.8 g/day or less, or about 0.6 g/day or less.
  • 6’-SL is administered to the subject in an amount of from about 0.1 g/day to about 1 g/day, from about 0.15 g/day to about 0.8 g/day or from about 0.2 g/day to about 0.6 g/day.
  • LNT is administered to the subject in an amount of at least about 0.05 g/day, at least about 0.2 g/day, at least about 0.3 g/day, or at least about 0.4 g/day.
  • LNT is administered to the subject in an amount of about 2.5 g/day or less, about 2 g/day or less, or about 1.5 g/day or less.
  • LNT is administered to the subject in an amount of from about 0.2 g/day to about 2.5 g/day, from about 0.3 g/day to about 2 g/day or from about 0.4 g/day to about 1.5 g/day.
  • 2’-FL is administered to the subject in an amount of from about 0.05 g/day to about 5 g/day; LNnT is administered to the subject in an amount of from about 0.05 g/day to about 2.5 g/day; 3’-FL is administered to the subject in an amount of from about 0.05 g/day to about 1 g/day; 3’-SL is administered to the subject in an amount of from about 0.05 g/day to about 1 g/day; 6’-SL is administered to the subject in an amount of from about 0.05 g/day to about 1 g/day; and/or LNT is administered to the subject in an amount of from about 0.05 g/day to about 2.5 g/day.
  • composition comprising HMOs which “consist essentially of’ recited HMOs may comprise trace amounts of non-recited HMOs which do not materially affect the characteristics of the composition.
  • the expression “nutritional composition” means a composition which nourishes a subject.
  • the nutritional composition is usually to be taken orally and it usually includes a lipid or fat source and a protein source.
  • the nutritional composition is a synthetic nutritional composition.
  • synthetic nutritional composition means a mixture obtained by chemical and/or biological means (i.e. the synthetic nutritional composition is not breast milk).
  • 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
  • the nutritional composition in powder form and is reconstituted in water.
  • the nutritional composition is for an infant or young child.
  • the infant may be, for example, 0-12 months.
  • the young-child may be, for example, 1-3 years of age.
  • the nutritional composition is an infant formula or a youngchild formula.
  • infant formula may refer to a foodstuff intended for particular nutritional use by infants during the first year of life and satisfying by itself the nutritional requirements of this category of person, as defined in European Commission Regulation (Ell) 2016/127 of 25 September 2015.
  • infant formula encompasses both “starter infant formula” and “follow-up formula” or “follow-on formula”.
  • a “follow-up formula” or “follow-on formula” is given from the 6 th month onwards.
  • the infant formula of the present invention may be a hypoallergenic infant formula.
  • the infant formula of the present invention may be an extensively hydrolysed infant formula (eHF) or an amino acid-based infant formula (AAF).
  • eHF extensively hydrolysed infant formula
  • AAF amino acid-based infant formula
  • pHF partially hydrolysed infant formula
  • eHF epidermal growth factor
  • CMP milk protein
  • amino acid-based formula may refer to a formula comprising only free amino acids as a protein source.
  • the AAF may contain no detectable peptides.
  • the AAF may be a hypoallergenic infant formula which provides complete nutrition for infants with food protein allergy and/or food protein intolerance.
  • the AAF may be a hypoallergenic infant formula which provides complete nutrition for infants who cannot digest intact CMP or who are intolerant or allergic to CMP, and who may have extremely severe or life-threatening symptoms and/or sensitisation against multiple foods.
  • a “hypoallergenic” composition is a composition which is unlikely to cause allergic reactions and wherein the source of protein is provided by extensively hydrolysed protein or by free amino acids.
  • a hypoallergenic infant formula may be tolerated by more than 90% of infants with CMP allergy. This is in line with the guidance provided by the American Academy of Pediatrics (Committee on Nutrition, 2000. Pediatrics, 106(2), pp.346-349).
  • Infants can be fed solely with the infant formula or the infant formula can be used as a complement of human milk.
  • young-child formula may refer to a foodstuff intended to partially satisfy the nutritional requirements of young children ages 1 to 3 years.
  • the expression “young-child formula” encompasses “toddler’s milk”, “growing up milk”, or “formula for young children”.
  • the ESPGHAN Committee on Nutrition has recently reviewed the young-child formula (Hojsak, l.,et al., 2018. Journal of pediatric gastroenterology and nutrition, 66(1), pp.177-185).
  • a young-child formula may meet the compositional requirements proposed in Hojsak, I., et al., 2018. Journal of pediatric gastroenterology and nutrition, 66(1), pp.177-185 and/or Suthutvoravut, II., et al., 2015. Annals of Nutrition and Metabolism, 67(2), pp.119-132.
  • the young-child formula of the present invention may be a hypoallergenic young-child formula.
  • the young-child formula of the present invention may be an extensively hydrolysed young-child formula or an amino acid-based young-child formula.
  • the young-child formula may be a partially hydrolysed young-child formula (pHF).
  • the infant formula or a young-child formula of the invention may be in the form of a powder or liquid.
  • the liquid may be, for example, a concentrated liquid formula or a ready-to-feed formula.
  • the formula may be in the form of a reconstituted infant or young-child formula (i.e. a liquid formula that has been reconstituted from a powdered form).
  • the concentrated liquid infant or young child formula is preferably capable of being diluted into a liquid composition suitable for feeding an infant or child, for example by the addition of water.
  • the infant or young-child formula is in a powdered form.
  • the powder is capable of being reconstituted into a liquid composition suitable for feeding an infant or child, for example by the addition of water.
  • the nutritional composition may have an energy density of about 60-72 kcal per 100 mL, when formulated as instructed.
  • the nutritional composition may have an energy density of about 60-70 kcal per 100 mL, when formulated as instructed.
  • 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 fortifier such as a human milk fortifier, or a supplement.
  • the composition of the invention is an infant formula, a young-child formula or a supplement.
  • the nutritional composition of the invention is an infant formula.
  • the term “fortifier” refers to a composition which comprises one or more nutrients having a nutritional benefit for infants.
  • milk fortifier it is meant any composition used to fortify or supplement either human breast milk, infant formula, growing-up milk or human breast milk fortified with other nutrients.
  • the human milk fortifier of the present invention can be administered after dissolution in human breast milk, infant formula, growing-up milk or human breast milk fortified with other nutrients, or otherwise it can be administered as a stand-alone composition.
  • the human milk fortifier of the present invention can be also identified as being a “supplement”.
  • the milk fortifier of the present invention is a supplement.
  • the nutritional composition 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 of the present invention is a dietary supplement.
  • the nutritional composition is a supplement, it can be provided in the form of unit doses.
  • 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, 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, matrix compounds, coatings, emulsifiers, surface-active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, compounds, dispersing agents, wetting agents, processing aids (solvents
  • 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 under the recommendations of Government bodies such as the LISRDA.
  • the nutritional composition is selected from the group consisting of a beverage product, an amino acid-based beverage, a yogurt product, fermented milk, a fruit juice, a dried powder in sachet format or a cereal bar. These nutritional compositions are well suited for administering plant phenols to, for example, older children and adult humans.
  • the nutritional composition is a food for specific medical purposes such as a health care nutritional composition for oral feeding, and/or a nutritional product for enteral or parental feeding. In the latter case, it will only include ingredients that are suitable for parenteral feeding. Ingredients that are suitable for parental feeding are known to the person skilled in the art.
  • the nutritional composition of the present invention can be in solid (e.g. powder), liquid or gelatinous form.
  • the term “protein” includes peptides and free amino acids.
  • the protein content of the nutritional composition may be calculated by any method known to those of skill in the art.
  • the protein content may be determined by a nitrogen-to-protein conversion method.
  • the protein content is calculated as nitrogen content x 6.25, as defined in European Commission Regulation (Ell) 2016/127 of 25 September 2015.
  • the nitrogen content may be determined by any method known to those of skill in the art. For example, nitrogen content may be measured by the Kjeldahl method.
  • the protein content of the nutritional composition of the invention is preferably in the range 1.6-3.2 g protein per 100 kcal. In some embodiments, the protein content of the nutritional composition is in the range 1.8-3.0 g protein per 100 kcal.
  • Infant formulas such as an eHF or an AAF, with a lower protein content may support appropriate growth and development of allergic infants, as well as being safe and well- tolerated.
  • the nutritional composition of the invention may comprise up to about 2.5 g protein per 100 kcal.
  • the nutritional composition may comprise about 2.3 g or less protein per 100 kcal, 2.0 g or less protein per 100 kcal, about 1.9 g protein per 100 kcal.
  • the nutritional composition of the invention comprises about 1.8 g or more protein per 100 kcal.
  • the nutritional composition may comprise about 1.86 g or more protein per 100 kcal, 1.9 g or more protein per 100 kcal, 2.0 g or more protein per 100 kcal, or 2.1 g or more protein per 100 kcal.
  • the nutritional composition comprises about 1.86 g or more protein per 100 kcal, in line with present Ell regulations for infant formula (EFSA NDA Panel (2014) EFSA journal 12(7): 3760).
  • the nutritional composition of the invention may comprise 1.8-2.8 g protein per 100 kcal, 1.86-2.4g protein per 100 kcal, 1.9-2.4 g protein per 100 kcal, 2.0-2.4 g protein per 100 kcal, 2.0-2.3 g protein per 100 kcal, 2.1-2.3 g protein per 100 kcal, or 2.15-2.25 g protein per 100 kcal.
  • the nutritional composition of the invention may comprise 2.24-3.36 g protein per 100 kcal or 2.5-3.1g protein per 100 kcal.
  • the source of protein may be any source suitable for use in a nutritional composition.
  • the protein source may comprise free amino acids as the only protein source or comprise an animal and/or vegetable derived protein as the only protein source.
  • the protein source is comprised or consists of a mix of animal derived protein and vegetable derived protein.
  • the protein source is comprised or consists of a mix of a cow’s milk protein, preferably extensively hydrolysed whey protein, and one or more hydrolysed vegetable proteins, preferably pea protein.
  • the protein is cow’s milk protein.
  • the protein is the cow’s milk protein casein, whey, or a combination thereof.
  • the nutritional composition does not comprise cow’s milk protein.
  • the protein source is a hydrolysed vegetable protein such as a rice-based formula or a soy-based formula or a pea-based formula or a combination of at least two of rice, soy and pea.
  • the nutritional composition does not comprise dairy protein. Accordingly, in some embodiments, 100% by weight of the total protein is non-dairy protein.
  • the combination preferably nutritional composition, comprises an extensively hydrolysed dairy protein such as a protein derived from goat milk, donkey milk, camel milk, or cow milk.
  • the combination, preferably nutritional composition comprises an extensively hydrolysed cow’s milk protein such as extensively hydrolysed casein or extensively hydrolysed whey.
  • An extensively hydrolysed/hydrolysed whey-based formula may be more palatable than an extensively hydrolysed/hydrolysed casein-based formula and/or the subject may only be sensitised to casein protein.
  • more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or about 100% of the protein is whey protein.
  • the protein source is whey protein.
  • the whey protein may be a whey from cheese making, particularly a sweet whey such as that resulting from the coagulation of casein by rennet, an acidic whey from the coagulation of casein by an acid, or the acidifying ferments, or even a mixed whey resulting from coagulation by an acid and by rennet.
  • This starting material may be whey that has been demineralised by ion exchange and/or by electrodialysis and is known as demineralised whey protein (DWP).
  • DWP demineralised whey protein
  • the source of the whey protein may be sweet whey from which the caseino- glycomacropeptide (CGMP) has been totally or partially removed. This is called modified sweet whey (MSW). Removal of the CGMP from sweet whey results in a protein material with threonine and tryptophan contents that are closer to those of human milk. A process for removing CGMP from sweet whey is described in EP880902.
  • the whey protein may be a mix of DWP and MSW.
  • the amount of casein in the nutritional composition is undetectable, for example less than 0.2 mg/kg.
  • the amount of casein may be determined by any method known to those of skill in the art. Degree of hydrolysis
  • Hydrolysed proteins may be characterised as “partially hydrolysed” or “extensively hydrolysed” depending on the degree to which the hydrolysis reaction is carried out.
  • WAG World Allergy Organization
  • CMPA Cow’s milk protein allergy
  • partially hydrolysed proteins are one in which 60-70% of the protein/peptide population has a molecular weight of less than 1000 Daltons, whereas extensively hydrolysed proteins are one in which at least 95% of the protein/peptide population has a molecular weight of less than 1000 Dalton.
  • extensively hydrolysed proteins are alternatively defined in the industry as one in which at least 95% of the protein/peptide population has a molecular weight of less than 1200 Dalton. See Nutten et al. Allergy (2020) 75:1446-1518.
  • Partially hydrolysed proteins are usually considered as hypoallergenic (HA) whereas extensively hydrolysed proteins are usually considered as non-allergenic.
  • the hydrolysed proteins of the invention may have an extent of hydrolysis that is characterised by NPN/TN %.
  • NPN/TN% means the Non Protein Nitrogen divided by the Total Nitrogen X 100.
  • NPN/TN% may be measured as detailed in Adler-Nissen J-, 1979, J. Agric. Food Chem., 27 (6), 1256-1262.
  • extensively hydrolysed proteins are characterised as having a NPN/TN% of greater than 95%, whereas partially hydrolysed proteins are characterized as having a NPN/TN% in the range 75%-85%.
  • Partially hydrolysed proteins may also be characterised in that 60-70% of their protein/peptide population has a molecular weight of less than 1000 Daltons.
  • the protein may have an NPN/TN% greater than 90%, greater than 95% or greater than 98%.
  • the hydrolysed proteins of the invention has a NPN/TN % in the range of greater than 95%.
  • the protein may have an NPN/TN% greater than 90%, greater than 95% or greater than 98%.
  • the extent of hydrolysis may also be determined by the degree of hydrolysis.
  • the “degree of hydrolysis” (DH) is defined as the proportion of cleaved peptide bonds in a protein hydrolysate and may be determined by any method known to those of skill in the art. Suitably the degree of hydrolysis is determined by pH-stat, trinitrobenzenesulfonic acid (TNBS), o- phthaldialdehyde (OPA), trichloroacetic acid soluble nitrogen (SN-TCA), or formol titration methods. (Rutherfurd, S.M. (2010) Journal of AOAC International 93(5): 1515-1522).
  • the degree of hydrolysis (DH) of the protein can, for example, be more than 90, more than 95 or more than 98.
  • the extent of hydrolysis may also be determined by the peptide molecular mass distribution.
  • the peptide molecular mass distribution may be determined by high performance size exclusion chromatography, optionally with UV detection (HPSEC/UV) (Johns, P.W. et al. (2011) Food chemistry 125(3): 1041-1050).
  • HPSEC/UV UV detection
  • the peptide molecular mass distribution may be a HPSEC peak area-based estimate determined at 205 nm, 214 nm or 220 nm.
  • the “percentage of peptides by weight” that have a certain molecular mass may be estimated by the “fraction of peak area as a percentage of total peak area”, that have the molecular mass, determined at 205 nm, 214 nm or 220 nm.
  • the extent of hydrolysis may be determined by the methods described in WO 2016/156077.
  • the peptide molecular mass distribution may be determined by any method known to those of skill in the art, for example by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) (Chauveau, A. et al.
  • peptides should be greater than about 1500 Da in size (approximately 15 amino acids) and to crosslink IgE molecules and to induce an immune response, they must be greater than about 3000 Da in size (approximately 30 amino acids) (Nutten (2016) EMJ Allergy Immunol 3(1): 50-59).
  • At least about 95%, at least about 98%, at least about 99% or about 100% of the peptides by weight in the eHF have a molecular mass of less than about 3000 Da. There may, for example, be no detectable peptides about 3000 Da or greater in size in the eHF.
  • At least about 95%, at least about 98%, at least about 99% or about 100% of the peptides by weight in the eHF have a molecular mass of less than about 1500 Da.
  • at least 99% of the peptides by weight have a molecular mass of less than about 1500 Da.
  • At least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the peptides by weight in the eHF have a molecular mass of less than about 1200 Da. More preferably, at least 95% or 98% of the peptides by weight in the eHF have a molecular mass of less than about 1200 Da.
  • at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the peptides by weight in the eHF have a molecular mass of less than about 1000 Da.
  • at least about 95% of the peptides by weight in the eHF have a molecular mass of less than about 1000 Da.
  • the eHF has no detectable peptides about 3000 Da or greater in size; and at least about 95% of the peptides by weight have a molecular mass of less than about 1200 Da.
  • PEPT 1 is a dedicated facilitator transport route for small peptide absorption (e.g. di- and tri-peptides).
  • intestinal PEPT1 is important for nutritional intake, and later for diet transition following weaning.
  • At least about 30%, at least about 40%, or at least about 50% of the peptides by weight in the eHF may, for example, be di- and tri-peptides.
  • at least about 45%, at least about 50%, 45-55%, or 50-54% of the peptides by weight in the eHF are di- and tri-peptides.
  • More preferably, about 51-53%, or most preferably, about 52% of the peptides by weight in the eHF are di- and tri-peptides.
  • at least about 30%, at least about 40%, at least about 50%, or at least 80%, of the peptides by weight in the eHF have a molecular mass of less than 600 Da.
  • At least about 45%, at least about 50%, at least 60-80%, or at least 80% of the peptides by weight in the eHF have a less than 600 Da. More preferably, at least about 80of the peptides by weight in the eHF have a molecular mass of between 240 and 600 Da.
  • the principal recognised cow’s milk allergens are alpha-lactalbumin (aLA), beta-lactoglobulin (bLG), and bovine serum albumin (BSA).
  • aLA alpha-lactalbumin
  • bLG beta-lactoglobulin
  • BSA bovine serum albumin
  • the eHF may have non-detectable aLA content, for example about 0.010 mg/kg aLA or less; the eHF may have non-detectable bLG content, for example about 0.010 mg/kg bLG or less; and/or the eHF may have non-detectable BSA content, for example about 0.010 mg/kg BSA or less.
  • the eHF comprises no detectable amounts of aLA, bLG, and BSA.
  • the content of aLA, bLG, and BSA may be determined by any method known to those of skill in the art, for example ELISA.
  • Proteins for use in the nutritional composition, preferably the infant formula of the invention may be hydrolysed by any suitable method known in the art.
  • proteins may be enzymatically hydrolysed, for example using a protease.
  • protein may be hydrolysed using alcalase (e.g. at an enzyme:substrate ratio of about 1-15% by weight and for a duration of about 1-10 hours).
  • alcalase e.g. at an enzyme:substrate ratio of about 1-15% by weight and for a duration of about 1-10 hours.
  • the temperature may range from about 40°C to 60°C, for example about 55°C.
  • the reaction time may be, for example, from 1 to 10 hours, and pH values before starting hydrolysis may, for example, fall within the range 6 to 9, preferably 6.5 to 8.5, more preferably 7.0 to 8.0.
  • Porcine enzymes in particular porcine pancreatic enzymes may be used in the hydrolysis process.
  • WO1993004593A1 discloses a hydrolysis process using trypsin and chymotrypsin, which includes a two-step hydrolysis reaction with a heat denaturation step in between to ensure that the final hydrolysate is substantially free of intact allergenic proteins.
  • the trypsin and chymotrypsin used in these methods are preparations produced by the extraction of porcine pancreas.
  • WO2016156077A1 discloses a process for preparing a milk protein hydrolysate comprising hydrolysing a milk-based proteinaceous material with a microbial alkaline serine protease in combination with bromelain, a protease from Aspergillus, and a protease from Bacillus.
  • the nutritional composition of the invention may comprise free amino acids.
  • free amino acids are the only source of protein.
  • the levels of free amino acids may be chosen to provide an amino acid profile that is sufficient for infant nutrition, in particular an amino acid profile that satisfies nutritional regulations (e.g. European Commission Directive 2006/141/EC).
  • Free amino acids may, for example, be incorporated in the eHF of the invention to supplement the amino acids comprised in the peptides.
  • Example free amino acids for use in the nutritional composition of the invention include histidine, isoleucine, leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, threonine, tryptophan, valine, alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, proline, serine, carnitine, taurine and mixtures thereof.
  • Free amino acids provide a protein equivalent source (i.e. contribute to the nitrogen content). As described above, having a high proportion of di- and tri-peptides may improve nitrogen (protein) absorption, even in patients with gut impairment. Accordingly, having a low proportion of free amino acids may also improve nitrogen (protein) absorption, even in patients with gut impairment.
  • the free amino acids in the eHF may be present in a concentration of 50% or less, 40% or less, 30% or less, or 25% or less by weight based on the total weight of amino acids.
  • the eHF comprises 25% or less by weight of free amino acids based on the total weight of amino acids. More preferably, the free amino acids in the eHF are present in a concentration of 20-25%, 21-23%, or about 22% by weight based on the total weight of amino acids.
  • the free amino acids content may be determined by any method known of skill in the art.
  • the free amino acids content may be obtained by separation of the free amino acids present in an aqueous sample extract by ion exchange chromatography and photometric detection after post-column derivatisation with ninhydrin reagent.
  • Total amino acid content may be obtained by hydrolysis of the test portion in 6 mol/L HCI under nitrogen and separation of individual amino acids by ion-exchange chromatography, as described above.
  • the carbohydrate may be any carbohydrate that is suitable for use in a nutritional composition.
  • the carbohydrate content of the nutritional composition of the invention is preferably in the range 9-14 g carbohydrate per 100 kcal.
  • carbohydrates for use in the nutritional composition include saccharose, maltodextrin and starch.
  • the nutritional composition may comprise mixtures of carbohydrates.
  • the carbohydrate content comprises maltodextrin. In some embodiments, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60% or at least about 70% by weight of the total carbohydrate content is maltodextrin. In one embodiment, at least about 50% of the total non-HMO carbohydrate content is maltodextrin.
  • the carbohydrate comprises lactose and maltodextrin. In some embodiments, at least about 50% of the total non-HMO carbohydrate content is lactose and at least about 50% of the total non-HMO carbohydrate content is maltodextrin.
  • about 100 % of the total non-HMO carbohydrate content is lactose.
  • the fat content of the nutritional composition of the invention is preferably in the range 4.0-6.0 g fat per 100 kcal.
  • Example fats for use in the nutritional composition of the invention include sunflower oil, low erucic acid rapeseed oil, safflower oil, canola oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palm oleic, high oleic sunflower oil and high oleic safflower oil, and microbial fermentation oil containing long chain, polyunsaturated fatty acids.
  • the fat may also be in the form of fractions derived from these oils, such as palm olein, medium chain triglycerides (MCT) and esters of fatty acids such as arachidonic acid, linoleic acid, palmitic acid, stearic acid, docosahexaeonic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, caproic acid, and the like.
  • oils such as palm olein, medium chain triglycerides (MCT) and esters of fatty acids such as arachidonic acid, linoleic acid, palmitic acid, stearic acid, docosahexaeonic acid, linolenic acid, oleic acid, lauric acid, capric acid, caprylic acid, caproic acid, and the like.
  • MCT medium chain triglycerides
  • fats include structured lipids (i.e. lipids that are modified chemically or enzymatically in order to change their structure).
  • the structured lipids are sn2 structured lipids, for example comprising triglycerides having an elevated level of palmitic acid at the sn2 position of the triglyceride.
  • Structured lipids may be added or may be omitted.
  • Oils containing high quantities of preformed arachidonic acid (ARA) and/or docosahexaenoic acid (DHA), such as fish oils or microbial oils, may be added.
  • ARA arachidonic acid
  • DHA docosahexaenoic acid
  • Long chain polyunsaturated fatty acids such as dihomo-y-linolenic acid, arachidonic acid (ARA), eicosapentaenoic acid and docosahexaenoic acid (DHA), may also be added.
  • ARA arachidonic acid
  • DHA docosahexaenoic acid
  • Oils containing high quantities of SOFA such as acetate, propionate or butyrate or any other lipidic product derived from microbial fermentation may also be added.
  • MCTs Medium chain triglycerides
  • MOT MOT-based on-the-uptake
  • MCT Methylcholine
  • Nutrients 10(3): 289 A high concentration of MOT may impair early weight gain. MOT is not stored and does not support fat storage. For instance, Borschel et al. have reported that infants fed formula without MOT gained significantly more weight between 1-56 days than infants fed formulas containing 50% of the fat from MCT (Borschel, M. et al. (2016) Nutrients 10(3): 289).
  • the fat may, for example, be medium-chain triglycerides (MCTs) in the nutritional composition of the present invention.
  • MCTs medium-chain triglycerides
  • about 25% or less by weight, 20% or less by weight, 15% or less by weight, 10% or less by weight, 5% or less by weight, 4% or less by weight, 3% or less by weight, 2% or less by weight, 1% or less by weight, 0.5% or less by weight, or 0.1% or less by weight of the fat is medium chain triglycerides (MCTs).
  • MCTs medium chain triglycerides
  • 0-30% by weight, 0-25% by weight, 0-20% by weight, 0-15% by weight, 0-10% by weight, 0-5% by weight, 0-4% by weight, 0-3% by weight, 0-2% by weight, 0-1% by weight, 0-0.5% by weight, or 0-0.1 % by weight of the fat is medium chain triglycerides (MCTs).
  • MCTs medium chain triglycerides
  • the nutritional composition comprises no added MCTs.
  • about 0% by weight of the fat is MCTs and/or the composition comprises no detectable MCTs.
  • the nutritional composition comprises no MCTs.
  • the combination or nutritional composition of the invention may further comprise butyrate, in particular dietary butyrate.
  • Butyrate may be present in the nutritional composition in an amount from about 1 mg/L to about 30 mg/L of the composition as consumed. Butyrate may be present in the nutritional composition in an amount of from about 1.6 mg/L to about 2.4 mg/L of the composition as consumed, or from about 8 mg/L to about 12 mg/L of the composition as consumed, or from about 16 mg/L to about 24 mg/L of the composition as consumed.
  • butyrate is present in the nutritional composition in some particular amounts.
  • butyrate is present in the nutritional composition in an amount about 30 mg/L of the composition as consumed.
  • Butyrate may be in the nutritional composition in an amount of about 10-30 mg/L of the composition as consumed, such as about 13-27 mg/L or 16-24 mg/L or 18-22 mg/L of the composition as consumed.
  • butyrate is present in the nutritional composition in an amount of about 20 mg/L of the composition as consumed.
  • butyrate is present in the nutritional composition in an amount of up to about 23 mg per 100g of composition based on the dry weight of the composition. In an embodiment of the invention, butyrate may be in the nutritional composition in an amount of 12-18 mg per 100g of the composition based on the dry weight of the composition. Butyrate may be in an amount of about 15 mg per 100 g of the composition based on the dry weight of the composition.
  • the dietary butyrate may, for example, be in the forms disclosed in WO2019/228851 or W02020/127642.
  • the corresponding amount of the butyrate source in the nutritional composition is sufficient to provide butyrate in the nutritional composition in an amount up to about 30 mg/L of the composition as consumed.
  • the butyrate source may be present in the nutritional composition in an amount sufficient to provide butyrate in the nutritional composition in an amount from about 1 mg/L to about 30 mg/L of the composition as consumed.
  • the butyrate source may be present in the nutritional composition in an amount sufficient to provide butyrate in the nutritional composition in an amount from about 1 .6 mg/L to about 2.4 mg/L of the composition as consumed, or from about 8 mg/L to about 12 mg/L of the composition as consumed, or from about 16 mg/L to about 24 mg/L of the composition as consumed.
  • the amount of the butyrate source in the nutritional composition is sufficient to provide butyrate in the nutritional composition in an amount of about 10-30 mg/L of the composition as consumed, such as about 13-27 mg/L or 16-24 mg/L or 18-22 mg/L of the composition as consumed. In another particular embodiment, the amount of the butyrate source in the nutritional composition is sufficient to provide butyrate in the nutritional composition in an amount of about 20 mg/L of the composition as consumed.
  • the combination or nutritional composition may comprise a compound having the formula: or combinations thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently, a long chain fatty acid having between 16 and 20 carbons.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is oleic acid, palmitic acid, stearic acid or linoleic acid.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is palmitic acid.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 and/or R 6 as defined herein is an unsaturated fatty acid, preferably monounsaturated.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each a long chain fatty acid having 18 carbons, wherein the long chain fatty acid having 18 carbons is monounsaturated.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each oleic acid.
  • a combination comprising lactose and HMOs as described herein may comprise a source of butyrate in the form of one of more compounds having the formula or combinations thereof.
  • the nutritional composition as described herein comprises about 100 mg/L as consumed of at least one of compounds (5), (6), (7), and (8).
  • the nutritional composition as described herein comprises about 100 mg of at least one of compounds (5), (6), (7), and (8) and is the equivalent of about 20 mg/L dietary butyrate in the composition as consumed.
  • An alternative source of dietary butyrate may be a triglyceride composed of a mixture of a C4 fatty acid, such as butyric acid (C4:0), and a C8 fatty acid, such as caprylic acid (C8:0).
  • the triglycerides comprising caprylic acid and butyric acid may be prepared by inter-esterification of a mix of triglycerides comprising either butyric acid (C4:0) or caprylic acid (C8:0).
  • BBB Tributyrin
  • CCC Tricaprylin is e.g. Neobee 895 (available e.g. by Stepan Specialty).
  • the nutritional composition may also contain all vitamins and minerals understood to be essential in the daily diet in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals.
  • Example vitamins, minerals and other nutrients for use in the nutritional composition of the invention, particularly the infant formula 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 their salt form.
  • the nutritional composition may comprise one or more carotenoids.
  • the nutritional composition may also comprise at least one probiotic.
  • probiotic refers to microbial cell preparations or components of microbial cells with beneficial effects on the health or well-being of the host. In particular, probiotics may improve gut barrier function.
  • yeasts such as Saccharomyces, Debaromyces, Candida, Pichia and Torulopsis
  • bacteria such as the genera Bifidobacterium, Bacteroides, Clostridium, Fusobacterium, Melissococcus, Propionibacterium, Streptococcus, and Lactobacillus.
  • the combination as described herein, preferably the nutritional composition comprises one or more bacterium of the genera Bifidobacterium and/or Lactobacillus.
  • Preferred probiotics are those which as a whole are safe, are L(+) lactic acid producing cultures and have acceptable shelf-life for products that are required to remain stable and effective for up to 24 months.
  • Bifidobacterium Enterococcus, Lactococcus, Staphylococcus, Peptostrepococcus, Bacillus, Pediococcus, Micrococcus, Leuconostoc, Weissella, Aerococcus, Oenococcus and Lactobacillus.
  • probiotic microorganisms are: Saccharomyces cereviseae, Bacillus coagulans, Bacillus licheniformis, Bacillus subtilis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, Bifidobacterium longum subsp. longum, Enterococcus faecium, Enterococcus faecalis, Lactobacillus acidophilus, Lactobacillus alimentarius, Lactobacillus casei subsp.
  • the nutritional composition of the invention may also contain other substances which may have a beneficial effect such as prebiotics, lactoferrin, fibres, nucleotides, nucleosides and the like.
  • the nutritional composition of the invention may be prepared in any suitable manner.
  • the nutritional composition described herein may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the further emulsifiers may be included at this point. The vitamins and minerals may be added at this point but vitamins are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved in 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. Commercially available liquefiers may be used to form the liquid mixture. The liquid mixture may then be homogenised.
  • the liquid mixture may then be thermally treated to reduce bacterial loads. This may be carried out, for example, by means of steam injection, or using an autoclave or heat exchanger, for example a plate heat exchanger.
  • the liquid mixture may then be cooled and/or homogenised.
  • the pH and solid content of the homogenised mixture may be adjusted at this point.
  • the homogenised mixture may then be transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. If a liquid nutritional composition is preferred, the homogenised mixture may be sterilised, then aseptically filled into a suitable container or maybe first filled into a container and then retorted.
  • the subject may be any suitable subject.
  • the subject may be a mammal.
  • the subject is a human.
  • the subject is an animal, preferably wherein the animal is a pet.
  • a pet may be an animal selected from dogs, cats, birds, fish, rodents such as mice, rats, and guinea pigs, rabbits, etc.
  • the pet is a small dog breed.
  • the subject is a juvenile, an adolescent, a child.
  • the term “juvenile” may refer to an individual that has not yet reached adulthood.
  • the term “adolescent” may refer to an individual during the period from the onset of puberty to adulthood.
  • the term “child” may refer an individual between the stages of birth and puberty.
  • the subject is about 3 years of age or older. In some embodiments, the subject is about 4 years of age or older or about 5 years of age or older. In some embodiments, the subject is about 10 years of age or younger. In some embodiments, the subject is about 9 years of age or younger, about 8 years of age or younger, about 7 years of age or younger, about 6 years of age or younger, or about 5 years of age or younger.
  • the subject is about 3 years to about 10 years of age, about 3 years to about 9 years of age, about 3 years to about 8 years of age, about 3 years to about 7 years of age, about 3 years to about 6 years of age, or about 3 years to about 5 years of age.
  • the subject may be an infant, young child or child; preferably the subject is an infant or young child. In some embodiments, the subject is an infant or young child having or is suspected of having Cow’s Milk Protein Allergy (CMPA).
  • CMPA Milk Protein Allergy
  • the infant may be a subject who is less than 12 months old.
  • the young child may be a subject who is from 12 months to 36 months old (1 to 3 years).
  • the child may be a subject who is from 3 years to 7 years old.
  • the subject may be an infant or young child who has not been breastfed or wherein breastfeeding has been halted.
  • the subject may be suffering from dysbiosis of the gut microbiota.
  • the subject may have or be suspected of having Cow’s Milk Protein Allergy (CMPA).
  • CMPA Milk Protein Allergy
  • CMPA may be defined as a reproducible immune-mediated allergic response to one or more proteins in cow's milk and is one of the most common presentations of food allergy seen in early childhood. It can be classified according to the underlying immune mechanism: Immunoglobulin (Ig)E-mediated food allergy produces immediate symptoms, which may affect multiple organ systems, typically up to 2 hours after cow's milk ingestion. Non-lgE-mediated food allergy reactions usually manifest between 2 and 72 hours after cow's milk ingestion. Mixed IgE and non-lgE allergic reactions are typically delayed.
  • IgE-mediated food allergy produces immediate symptoms, which may affect multiple organ systems, typically up to 2 hours after cow's milk ingestion.
  • Non-lgE-mediated food allergy reactions usually manifest between 2 and 72 hours after cow's milk ingestion.
  • Mixed IgE and non-lgE allergic reactions are typically delayed.
  • Diagnosis of IgE-mediated allergy is typically based on presentation of symptoms, such as urticaria, angio-oedema, itching, cough, hoarseness, wheeze, or breathlessness after cow's milk ingestion. Diagnosis of non-lgE- mediated allergy should be suspected if there are one or more symptoms such as gastro- oesophageal reflux disease, abdominal discomfort, constipation, diarrhoea, or atopic eczema, particularly if symptoms are treatment-resistant.
  • a subject with a CMPA may exhibit outgrowth of the CMPA associated with the induction of oral tolerance after administration of a composition as defined herein, or a nutritional composition as defined here.
  • Oral tolerance may be associated with a partial or complete oral desensitisation in a subject with an allergy, particularly a cow’s milk protein allergy.
  • induction of oral tolerance is understood to mean that oral tolerance against an allergen such as a cow’s milk protein is induced as compared to oral tolerance before starting administration of a combination or nutritional composition as defined herein.
  • Some embodiments of the combination as defined herein, or nutritional composition as defined herein is for use in induction of oral tolerance in a subject with an allergy, particularly a cow’s milk protein allergy.
  • In some embodiments of the combination as defined herein, or nutritional composition as defined herein is for use in partial or complete oral desensitisation in a subject with an allergy, particularly a cow’s milk protein allergy.
  • the term “manage,” “managing,” and “management” as used herein, including in the context of “dietary management”, may refer to the prevention or reduction in severity or frequency of one or more symptoms of a disease or condition, including ameliorating one or more existing symptoms of a disease or condition, preventing one or more existing symptoms of disease or condition, preventing one or more underlying causes of a disease or condition, ameliorating one or more underlying cause of a disease or condition, reducing the prevalence of one or more symptoms of a disease or condition, and/or reducing the occurrence of one or more symptoms of a disease or condition. It will be understood to include stabilizing a disease or condition and preventing progression of a disease or condition.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optionally LNT for use in the treatment of dysbiosis of the gut microbiota in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the treatment of dysbiosis of the gut microbiota in a subject.
  • the present invention provides the use of a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, at least one of 3’-SL or 6’-SL, and optionally LNT in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the present invention provides a method for the dietary management of dysbiosis of the gut microbiota in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the present invention also provides a method for the treatment of dysbiosis of the gut microbiota in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • Dysbiosis of the gut microbiota is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution.
  • the most typical features of dysbiosis are a decrease in the diversity of the microbiota, a loss of beneficial microbiota, or an overgrowth of harmful microbiota.
  • Dysbiosis may be assessed and identified using a range of tests and criteria, for example as described in Wei et al. (2021 ; Applied and Environmental Microbiology; 87(11)).
  • Approaches to determine dysbiosis may comprise e.g. 16S rRNA gene profiling or sequencing to apply one or more of the following: large-scale bacterial marker profiling, relevant taxon-based methods, neighbourhood classification, and combined alpha and beta diversity measures.
  • dysbiosis may be characterized by lower levels of Bifidobacteriaceae and enrichment of Proteobacteria and other gram negative gut bacteria. Measurements of Bifidobacteriaceae at about 10% of the microbiota in CMPA infants as compared to levels of about 80% in healthy infants.
  • dysbiosis in the context of the present invention may refer to an abundance of HMO utilizing Bifidobacteriaceae in the gut microbiota of less than about 10%, less that about 5%, less than about 2% or less than about 1%.
  • dysbiosis in the context of the present invention may refer to the overgrowth of a pathogen or an overgrowth of Proteobacteria.
  • dysbiosis may refer to the overgrowth of one or more of Staphylococcaceae, Clostridiaceae, and Enterococcaceae.
  • dysbiosis in the context of the present invention may refer to relatively low numbers of Bifidobacteriaceae and relatively high numbers of Enterobacteriaceae and/or Clostridiaceae in view of the total number of bacteria in a sample.
  • Overgrowth of a pathogen or a Proteobacteria can be determined by any means known in the art.
  • the relative concentration of bacteria are determined by 16S rRNA gene sequencing (as is known in the art and described in the examples) and/or shotgun metagenomic sequences (as it is known in the art), preferably the relative concentration of bacteria are determined by 16S rRNA gene sequencing. Both methods are commercially available, see, e.g., WorldWideWeb microbiomeinsights.com.
  • dysbiosis in the context of the present invention may be associated with proteolytic fermentation by the gut microbiota.
  • Proteolytic fermentation may be associated with the formation of metabolites such as phenol and indole that exert detrimental health effects.
  • Dysbiosis of the gut microbiota may be associated with the pathogenesis of both intestinal and extra-intestinal disorders.
  • Intestinal disorders include, for example, inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease
  • extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity.
  • the intestinal disorder may be one or more of inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and coeliac disease.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • coeliac disease coeliac disease
  • extra-intestinal disorder is one or more of allergy, asthma, atopic dermatitis, metabolic syndrome, cardiovascular disease, obesity, and type 2 diabetes.
  • Branched chain fatty acids (BCFA)
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the treatment of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the present invention provides a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT for use in the treatment of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the present invention provides a method for the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the present invention provides a method for the treatment of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the reduction of BCFA in a subject.
  • the present invention provides a method for the reduction of BCFA in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of malnutrition in a subject.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the treatment of malnutrition in a subject.
  • the present invention provides a method for the dietary management of malnutrition in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the present invention provides a method for the treatment of malnutrition in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the BCFA may comprise isobutyrate, isovalerate, isocaproate and/or 2-methylbutyrate.
  • the BCFA may comprise isobutyrate, isovalerate, and/or isocaproate.
  • the combination reduces levels of BCFA compared to an infant who has not been administered the combination as defined herein.
  • the combination reduces levels of BCFA compared to an infant who has been administered a nutritional composition comprising lactose but not one or more HMOs of the present combination.
  • BCFA produced by the microbiota include isovaleric, isobutyric, isocaproate and 2-methylbutyric acids, which are produced by the fermentation of the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, respectively.
  • BCFA are indicative of proteolytic fermentation by the gut microbiota and are associated with the formation of metabolites such as phenol and indole.
  • isovaleric acid can inhibit Na+, K+-ATP-ase, a key enzyme responsible to maintain the basal potential membrane necessary for a normal neurotransmission, providing insights into the participation of BCFA in the gut-brain axis communication.
  • the disease or disorder associated with metabolism of BCFA may be one or more of malnutrition, Rett syndrome, colorectal cancer, anorexia nervosa, and depression.
  • Rett syndrome is an infrequent X-linked neurodevelopmental disorder that affects female, in which changes in microbiota composition may account for several of the symptoms associated with this pathology.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of at least one pathogen in a subject. In one aspect, the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of at least one pathogen in a subject, wherein the pathogen is an enteric pathogen that is one or more of a bacterial, viral or protozoal pathogen.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of at least one pathogen in a subject, wherein the pathogen is an enteric pathogen that is a viral pathogen, wherein the viral pathogen is a norovirus and/or a rotavirus.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of a pathogenic bacteria in a subject.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of a pathogenic bacteria in a subject, wherein the pathogenic bacteria is one or more C. difficile, C. perfringens, Campylobacter or Escherichia coli.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of C. difficile and/or C. perfringens.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of C. difficile and/or C. perfringens, wherein the dietary management decreases the abundance of C. difficile and/or C. perfringens.
  • the present invention provides a method for the dietary management of at least one pathogen in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • the pathogen may be associated with dysbiosis in the subject.
  • the present invention may be directed to the dietary management of C. difficile and/or C. perfringens.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of at least one pathogen in a subject, wherein the subject is an infant, young child or child who has not been breastfed or wherein breast-feeding has been halted.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of C. difficile and/or C. perfringens, wherein the subject is an infant, young child or child who has not been breastfed or wherein breast-feeding has been halted.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use in the dietary management of C.
  • C. difficile and/or C. perfringens wherein the dietary management reduces the abundance of C. difficile and/or C. perfringens, and wherein the subject is an infant, young child or child who has not been breastfed or wherein breast-feeding has been halted.
  • a reduction in the abundance of C. difficile and/or C. perfringens may be determined by analysis of the total gut microbiota.
  • a reduction in the abundance of C. difficile and/or C. perfringens may be determined by resolution or reduction of one or more symptoms associated with an overgrowth of C. difficile and/or C. perfringens. In one embodiment, resolution or reduction of at least one of diarrhoea and fever.
  • the present invention provides a method for the dietary management of at least one pathogen in a subject, the method comprising administering a combination as defined herein, preferably in the form of a nutritional composition, to the subject, wherein the subject is an infant, young child or child who has not been breastfed or wherein breast-feeding has been halted.
  • proteolytic fermentation gives rise to the production of compounds such as ammonia, phenols, amines, hydrogen sulfide, and p-cresol, which may be harmful to host health. Because of this, high rates of colonic proteolytic fermentation accompanied by low levels of saccharolytic fermentation are considered detrimental for host health.
  • Molecules associated with proteolytic fermentation can cause cell damage (e.g. toxic for colonocytes) on the intestinal environment (Aguirre et al., 2016; Res. Microbiol. 167, 114-125) and can contribute to inflammatory conditions (Yao et al.’, 2016; Aliment Pharmacol Ther, 2016. 43(2): p. 181-96, and Popkov et af, 2022; Int J Mol Sci, 23(1)) and have detrimental health effects (Nowak et al. 2006; Anaerobe 12, 80-84).
  • cell damage e.g. toxic for colonocytes
  • the uremic toxins 4-cresol and 2- or 3-hydroxyphenylacetic acid formed via bacterial tyrosine and phenylalanine fermentation can have negative mucosal and systemic effects (Evenepoel et al. 2009; Kidney Int Suppl, 2009(114): p. S12-9.; and Zheng et al. 2021 ; Front Neurosci, 2021. 15: p. 738220). A reduction in fecal toxic metabolites may therefore contribute to maintaining systemic immune balance.
  • the present invention provides a combination as defined herein, preferably in the form of a nutritional composition, for use reduction of proteolytic fermentation by the gut microbiota in a subject.
  • the present invention provides a method for the reduction of proteolytic fermentation by the gut microbiota in a subject, the method comprising a combination as defined herein, preferably in the form of a nutritional composition, to the subject.
  • Example 1 Combinations of HMO blends and lactose reduce branched chain fatty acid production in gut microbiota in an ex vivo colonic fermentation model
  • FIG. 1 bottom panel shows that at 48 hours, combinations of HMO and lactose induce lower levels of BCFA than lactose alone or HMO alone.
  • lactose was based on an estimated intake of 70 g lactose per day and assuming an in vivo absorption along the small intestine of 96%.
  • CM PA twelve infants with suspected CM PA fulfilling the following criteria were included in the study: 1-7 months of age; fed an extensively hydrolyzed or amino acid-based formula (as per medical recommendation) or breastfed; gestational age at birth >36 weeks; no antibiotics for 30 days prior to study participation; no previous necrotizing enterocolitis or gut surgery; and no consumption of probiotics or prebiotics for 14 days prior to study participation (L reuteri (DSM 17938), L. rhamnosus LGG (ATCC 53103) and Bifidobacterium animalis subsp.
  • lactis BB- 12 were allowed as commonly used in this population and not known to be consumed by 2’-FL, 3’-FL, 3’-SL, 6’SL and LNnT (See, e.g., Thongaram et al. Journal of Dairy Science (2017) 100:7825-7833).
  • One infant was partially breastfed (infant 2), and one exclusively breastfed (infant 12).
  • Fecal samples were collected by parents/caregivers after having provided informed consent for participation in the study. In total, 10 male and 2 female donor samples were assessed. The age of the test subjects ranged from 2-7 months and was on average 4.3 months (4.2 months for male; 4.8 months for female infants).
  • the study was approved by the Ethics Committee of the University Hospital Ghent (reference number BC-09977).
  • Microbiota taxonomic analysis quantitative 16S rRNA gene profiling
  • DNA was extracted via the SPINeasy DNA Kit for Soil (MP Biomedicals, Eschwege, Germany), according to manufacturer’s instructions. Subsequently, library preparation and sequencing were performed on an Illumina MiSeq platform with v3 chemistry. 16S rRNA gene V3-V4 hypervariable regions were amplified using primers 341 F (50 -COT ACG GGN GGC WGC AG- 30) and 785Rmod (50 -GAC TAG HVG GGT ATC TAA KCC-30). Pre-processing and OTU (operational taxonomic unit) picking from amplicons was performed with Mothur v1.35.1 (Schloss et al.
  • BCFA Branched chain fatty acids
  • a combination comprising lactose and human milk oligosaccharides (HMOs) 2'- fucosyllactose (2’-FL), lactoW-neotetraose (LNnT), 3-fucosyllactose (3’-FL), and at least one of 3’-sialyllactose (3’-SL) or 6’-sialyllactose (6’-SL) for use in the dietary management of dysbiosis of the gut microbiota in a subject.
  • the combination for use according to para 1 comprising the HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and lacto-N-tetraose (LNT).
  • branched chain fatty acids such as isobutyrate, isovalerate, and/or isocaproate.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • coeliac disease coeliac disease
  • a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, and at least one of 3’-SL or 6’-SL for use in the dietary management of a disease or disorder associated with metabolism and/or accumulation of BCFA in a subject.
  • the combination for use according to para 10, comprising the HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, 6’-SL, and LNT.
  • a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, and at least one of 3’-SL or 6’-SL for use in the dietary management of
  • pathogen in a subject, wherein the pathogen is one or more of bacterial, viral or protozoal pathogen;
  • pathogen in a subject, wherein the pathogen is one or more viral pathogens, preferably rotavirus or norovirus;
  • pathogen in a subject, wherein the pathogen is one or more bacterial pathogens, preferably C. difficile, C. perfringens, Campylobacter or Escherichia coli.
  • BCFA comprises isobutyrate, isovalerate, and/or isocaproate.
  • a combination comprising lactose and HMOs 2’-FL, LNnT, 3’-FL, and at least one of 3’-SL or 6’-SL for use in the reduction of BCFA in a subject.
  • the nutritional composition for use according to any one of paras 30 to 33 comprising the HMOs 2’-FL (about 0.8-1.2 g/L of the composition as consumed), 3’-FL (about 0.4-0.6 g/L of the composition as consumed), LNnT (about 0.4-0.6 g/L of the composition as consumed); 3’-SL (about 0.08-0.12 g/L of the composition as consumed), 6’-SL (about 0.16-0.24 g/L of the composition as consumed), and LNT (about 0.24-0.36 g/L of the composition as consumed).
  • the nutritional composition for use according to any one of paras 30 to 34 comprising the HMOs 2’-FL (about 1 g/L of the composition as consumed), 3’-FL (about 0.5 g/L of the composition as consumed), LNnT (about 0.5 g/L of the composition as consumed); 3’-SL (about 0.1 g/L of the composition as consumed), 6’-SL (about 0.2 g/L of the composition as consumed), and LNT (about 0.3 g/L of the composition as consumed).
  • eHF extensively hydrolysed formula
  • eHF extensively hydrolysed formula
  • AAF amino acid-based formula
  • pHF partially hydrolysed infant formula
  • the nutritional composition for use according to para 40, wherein the protein source in the partially hydrolysed formula (pHF) is a partially hydrolysed whey.
  • combination or nutritional composition for use according to any one of the preceding paras, wherein the combination or nutritional composition further comprising butyrate in an amount from about 1 mg/L to about 30 mg/L of the composition as consumed.
  • combination or nutritional composition for use according to any one of the preceding paras, wherein the combination or nutritional composition further comprises butyrate in an amount of from about 1.6 mg/L to about 2.4 mg/L of the composition as consumed, or from about 8 mg/L to about 12 mg/L of the composition as consumed, or from about 16 mg/L to about 24 mg/L of the composition as consumed.
  • combination or nutritional composition for use according to any one of paras 1 to 50, wherein the combination or nutritional composition further comprises a compound having the formula: or combinations thereof as a source of dietary butyrate; wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently, a long chain fatty acid having between 16 and 20 carbons.
  • combination or nutritional composition for use according to para 55 wherein the combination or nutritional composition comprises the equivalent of from about 1 mg/L to about 30 mg/L dietary butyrate in the composition as consumed.
  • combination or nutritional composition for use according to any one of paras 55 to 57, wherein the combination or nutritional composition comprises the equivalent of from about 16 mg/L to about 24 mg/L dietary butyrate in the composition as consumed or about 20 mg/L dietary butyrate in the composition as consumed.
  • combination or nutritional composition for use according to any one of paras 1 to 50, wherein the combination or nutritional composition further comprises a triglyceride composed of a mixture of butyric acid (C4:0) and caprylic acid (C8:0) as a source of dietary butyrate.
  • a triglyceride composed of a mixture of butyric acid (C4:0) and caprylic acid (C8:0) as a source of dietary butyrate.
  • HMOs in the combination comprise or consist of, with reference to the total amount of HMOs in the combination: i. the HMOs 2’-FL, LNnT, 3’-FL, 3’-SL, and 6’SL comprising or consisting of: a. about 22 wt % to about 65 wt % of 2’-FL, preferably about 35 wt % to about 52 wt %, preferably about 43 wt %; b.
  • the combination for use according to any one of paras 1 to 29 and 50 to 70 comprising the HMOs 2’-FL (about 1 g/L of the combination as consumed), 3’-FL (about 0.5 g/L of the combination as consumed), LNnT (about 0.5 g/L of the combination as consumed); 3’-SL (about 0.1 g/L of the composition as consumed), 6’-SL (about 0.2 g/L of the combination as consumed), and LNT (about 0.3 g/L of the combination as consumed).
  • combination or nutritional composition for use according to any one of the preceding paras, wherein the combination or nutritional composition further comprises one or more bacterium of the genera Bifidobacterium and/or Lactobacillus.
  • CMPA milk protein allergy

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pediatric Medicine (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

La présente invention concerne une combinaison comprenant du lactose et des oligosaccharides de lait humain (HMO) tels que du 2'-fucosyllactose (2'-FL), du lacto-/V-néotétraose (LNnT), du 3-fucosyllactose (3'-FL), au moins l'un du 3'-sialyllactose (3'-SL) ou du 6'-sialyllactose (6'-SL), et éventuellement du lacto-N-tétraose (LNT) pour une utilisation dans la gestion alimentaire de la dysbiose du microbiote intestinal chez un sujet ou pour une utilisation dans la gestion alimentaire d'une maladie ou d'un trouble associé au métabolisme et/ou à l'accumulation de BCFA chez un sujet.
PCT/EP2024/068245 2023-07-06 2024-06-28 Combinaison pour la gestion alimentaire de la santé intestinale Pending WO2025008277A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23183871 2023-07-06
EP23183871.5 2023-07-06

Publications (1)

Publication Number Publication Date
WO2025008277A1 true WO2025008277A1 (fr) 2025-01-09

Family

ID=87158434

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/068245 Pending WO2025008277A1 (fr) 2023-07-06 2024-06-28 Combinaison pour la gestion alimentaire de la santé intestinale

Country Status (1)

Country Link
WO (1) WO2025008277A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025068416A1 (fr) 2023-09-26 2025-04-03 N.V. Nutricia 3-fucosyllactose et butyrate pour allergie alimentaire
WO2025190540A1 (fr) * 2024-03-13 2025-09-18 Société des Produits Nestlé S.A. Stimulation de bactéries productrices de butyrate dans le microbiome intestinal

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993004593A1 (fr) 1991-08-30 1993-03-18 Teagasc, The Agriculture And Food Development Authority Hydrolysat de proteines lactoseriques hypoallergeniques
US5288637A (en) 1990-04-16 1994-02-22 The Trustees Of The University Of Pennsylvania Apparatus for the synthesis of saccharide compositions
WO1996010086A1 (fr) 1994-09-26 1996-04-04 The Rockefeller University Glycosyltransferases utilisees dans la biosynthese d'oligosaccharides, et genes codant ces glycosyltransferases
EP0880902A1 (fr) 1997-05-27 1998-12-02 Nestlé Produkte AG Procédé de traitement d'une matiére première lactosérique
WO2011100980A1 (fr) 2010-02-19 2011-08-25 Glycom A/S Procédé pour la préparation du tétrasaccharide lacto-n-néotétraose (lnnt) contenant de la n-acétyllactosamine
WO2011100979A1 (fr) 2010-02-19 2011-08-25 Glycom A/S Production de 6'-o-sialyllactose et intermédiaires
WO2012155916A1 (fr) 2011-05-13 2012-11-22 Glycom A/S Fabrication de lacto-n-tétraose
WO2013044928A1 (fr) 2011-09-30 2013-04-04 Glycom A/S Synthèse de structures à noyau hmo
WO2013091660A1 (fr) 2011-12-23 2013-06-27 Glycom A/S Procédé pour obtenir des précurseurs de lacto-n-tétraose et de lacto-n-neotétraose cristallin et des mélanges de ceux-ci
WO2013139344A1 (fr) 2012-03-20 2013-09-26 Glycom A/S Synthèse de trisaccharide de type 3-o-fucosyllactose et de ses intermédiaires
WO2014153253A1 (fr) 2013-03-14 2014-09-25 Glycosyn LLC Micro-organismes et procédés de production d'oligosaccharides sialylés et à base de n-acétylglucosamine
WO2016156077A1 (fr) 2015-03-30 2016-10-06 Nestec S.A. Hydrolysats de protéine à base de lait et compositions fabriquées avec ces derniers
CN108541221A (zh) * 2015-12-15 2018-09-14 格礼卡姆股份公司 Hmo的混合物
EP3494807A1 (fr) * 2017-12-11 2019-06-12 Jennewein Biotechnologie GmbH Sialyllactose séché par pulvérisation
WO2019228851A1 (fr) 2018-06-01 2019-12-05 Societe Des Produits Nestle S.A. Butyrate alimentaire
US20200138836A1 (en) * 2017-05-24 2020-05-07 Societe Des Produits Nestle S.A. Hmos blends for use in infants or young children for health purposes
US20200163981A1 (en) * 2017-05-09 2020-05-28 Societe Des Produits Nestle S.A. Synergistic production of butyrate associated with the complexity of hmos blend for use in infants or young children for health purposes
WO2020127642A1 (fr) 2018-12-21 2020-06-25 Société des Produits Nestlé S.A. Butyrate alimentaire pour le traitement ou la prévention d'un trouble allergique
WO2022078861A1 (fr) * 2020-10-16 2022-04-21 Société des Produits Nestlé S.A. Formule pour nourrissons ou jeunes enfants

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288637A (en) 1990-04-16 1994-02-22 The Trustees Of The University Of Pennsylvania Apparatus for the synthesis of saccharide compositions
WO1993004593A1 (fr) 1991-08-30 1993-03-18 Teagasc, The Agriculture And Food Development Authority Hydrolysat de proteines lactoseriques hypoallergeniques
WO1996010086A1 (fr) 1994-09-26 1996-04-04 The Rockefeller University Glycosyltransferases utilisees dans la biosynthese d'oligosaccharides, et genes codant ces glycosyltransferases
EP0880902A1 (fr) 1997-05-27 1998-12-02 Nestlé Produkte AG Procédé de traitement d'une matiére première lactosérique
WO2011100980A1 (fr) 2010-02-19 2011-08-25 Glycom A/S Procédé pour la préparation du tétrasaccharide lacto-n-néotétraose (lnnt) contenant de la n-acétyllactosamine
WO2011100979A1 (fr) 2010-02-19 2011-08-25 Glycom A/S Production de 6'-o-sialyllactose et intermédiaires
WO2012155916A1 (fr) 2011-05-13 2012-11-22 Glycom A/S Fabrication de lacto-n-tétraose
WO2013044928A1 (fr) 2011-09-30 2013-04-04 Glycom A/S Synthèse de structures à noyau hmo
WO2013091660A1 (fr) 2011-12-23 2013-06-27 Glycom A/S Procédé pour obtenir des précurseurs de lacto-n-tétraose et de lacto-n-neotétraose cristallin et des mélanges de ceux-ci
WO2013139344A1 (fr) 2012-03-20 2013-09-26 Glycom A/S Synthèse de trisaccharide de type 3-o-fucosyllactose et de ses intermédiaires
WO2014153253A1 (fr) 2013-03-14 2014-09-25 Glycosyn LLC Micro-organismes et procédés de production d'oligosaccharides sialylés et à base de n-acétylglucosamine
WO2016156077A1 (fr) 2015-03-30 2016-10-06 Nestec S.A. Hydrolysats de protéine à base de lait et compositions fabriquées avec ces derniers
CN108541221A (zh) * 2015-12-15 2018-09-14 格礼卡姆股份公司 Hmo的混合物
US11432578B2 (en) * 2015-12-15 2022-09-06 Glycom A/S Mixture of HMOs
US20200163981A1 (en) * 2017-05-09 2020-05-28 Societe Des Produits Nestle S.A. Synergistic production of butyrate associated with the complexity of hmos blend for use in infants or young children for health purposes
US20200138836A1 (en) * 2017-05-24 2020-05-07 Societe Des Produits Nestle S.A. Hmos blends for use in infants or young children for health purposes
EP3494807A1 (fr) * 2017-12-11 2019-06-12 Jennewein Biotechnologie GmbH Sialyllactose séché par pulvérisation
WO2019228851A1 (fr) 2018-06-01 2019-12-05 Societe Des Produits Nestle S.A. Butyrate alimentaire
WO2020127642A1 (fr) 2018-12-21 2020-06-25 Société des Produits Nestlé S.A. Butyrate alimentaire pour le traitement ou la prévention d'un trouble allergique
US20220079908A1 (en) * 2018-12-21 2022-03-17 Societe Des Produits Nestle S.A. Dietary butyrate for treating or preventing an allergic disorder
WO2022078861A1 (fr) * 2020-10-16 2022-04-21 Société des Produits Nestlé S.A. Formule pour nourrissons ou jeunes enfants

Non-Patent Citations (45)

* Cited by examiner, † Cited by third party
Title
"American Academy of Pediatrics (Committee on Nutrition", PEDIATRICS, vol. 106, no. 2, 2000, pages 346 - 349
"EFSA NDA Panel", EFSA JOURNAL, vol. 12, no. 7, 2014, pages 3760
"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA", EFSA JOURNAL, vol. 13, no. 11, 2015, pages 4299
"EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA", EFSA JOURNAL, vol. 17, no. 12, 2019, pages e05907
"EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA", EFSA JOURNAL, vol. 18, no. 5, 2020, pages e06097
"EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA", EFSA JOURNAL, vol. 20, no. 5, 2022, pages e07331
ADLER-NISSEN J, J. AGRIC. FOOD CHEM., vol. 27, no. 6, 1979, pages 1256 - 1262
AGUIRRE ET AL., RES. MICROBIOL., vol. 167, 2016, pages 114 - 125
ALTSCHUL ET AL., J MOL BIOL, vol. 215, 1990, pages 403 - 410
BARENGOLTS ET AL., MICROORGANISMS, vol. 7, no. 9, 2019, pages 320
BENJAMINI-HOCHBERG, JOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES B (METHODOLOGICAL, vol. 57, 1995, pages 289 - 300
BORGHI ET AL., INT J MOL SCI., vol. 18, no. 2, 2017, pages 344
BORSCHEL, M. ET AL., NUTRIENTS, vol. 10, no. 3, 2018, pages 289
CHAUVEAU, A. ET AL., PEDIATRIC ALLERGY AND IMMUNOLOGY, vol. 27, no. 5, 2016, pages 541 - 543
CLINICAL & EXPERIMENTAL ALLERGY, vol. 44, 2014, pages 642 - 672
DA SILVA ET AL., SCI REP, vol. 2018, no. 8, 2018, pages 1466
EFSA JOURNAL, vol. 12, no. 7, 2014, pages 3760,106
EVENEPOEL ET AL., KIDNEY INT SUPPL, no. 114, 2009, pages 12 - 9
GRANADO-SERRANO ET AL., SCI REP., vol. 9, no. 1, 2019, pages 1772
HOJSAK, I. ET AL., JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION, vol. 66, no. 1, 2018, pages 177 - 185
JOHNS, P.W. ET AL., FOOD CHEMISTRY, vol. 125, no. 3, 2011, pages 1041 - 1050
LI ET AL., FRONT MICROBIOL., vol. 10, 2019, pages 2635
MACK ET AL., SCI REP., vol. 6, 2016, pages 26752
MAUBOIS, J.L.LORIENT, D., DAIRY SCIENCE & TECHNOLOGY, vol. 96, no. 1, 2016, pages 15 - 25
MEI WANG ET AL: "Fecal Microbiota Composition of Breast-Fed Infants Is Correlated With Human Milk Oligosaccharides Consumed :", JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION, vol. 60, no. 6, 1 June 2015 (2015-06-01), US, pages 825 - 833, XP055415934, ISSN: 0277-2116, DOI: 10.1097/MPG.0000000000000752 *
NICCOLAI ET AL., WORLD J GASTROENTEROL., vol. 25, no. 36, 2019, pages 5543 - 58
NOWAK ET AL., ANAEROBE, vol. 12, 2006, pages 80 - 84
NUTTEN ET AL., ALLERGY, vol. 75, 2020, pages 1446 - 1518
NUTTEN, EMJ ALLERGY IMMUNOL, vol. 3, no. 1, 2018, pages 50 - 59
POPKOV ET AL., INT J MOL SCI, vol. 23, no. 1, 2022
ROHART ET AL., PLOS COMPUTATIONAL BIOLOGY, vol. 13, 2017, pages e1005752
RUTHERFURD, S.M., JOURNAL OF AOAC INTERNATIONAL, vol. 93, no. 5, 2010, pages 1515 - 1522
SCHLOSS ET AL., APPL ENVIRON MICROBIOL, vol. 75, 2009, pages 7537 - 7541
SHANG JIACUI ET AL: "Correlations between oligosaccharides in breast milk and the composition of the gut microbiome in breastfed infants", JOURNAL OF DAIRY SCIENCE, AMERICAN DAIRY SCIENCE ASSOCIATION, US, vol. 105, no. 6, 7 April 2022 (2022-04-07), pages 4818 - 4828, XP087053849, ISSN: 0022-0302, [retrieved on 20220407], DOI: 10.3168/JDS.2021-20928 *
SURONO ET AL., PLOS ONE., vol. 16, no. 1, 2021, pages e0245399
SUTHUTVORAVUT, II. ET AL., ANNALS OF NUTRITION AND METABOLISM, vol. 67, no. 2, 2015, pages 119 - 132
SZCZESNIAK ET AL., NUTR NEUROSCI., vol. 19, no. 7, 2016, pages 279 - 83
THONGARAM ET AL., JOURNAL OF DAIRY SCIENCE, vol. 100, 2017, pages 7825 - 7833
VAN DEN ABBEELE ET AL., FRONT MICROBIOL, vol. 14, 2023, pages 1131662
WANG ET AL., EXP THER MED., vol. 13, no. 6, 2017, pages 2848 - 54
WEI ET AL., APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 87, no. 11, 2021
WRODNIGG, T.M.STUTZ, A.E., ANGEW. CHEM. INT. ED., vol. 38, 1999, pages 827 - 828
YAO ET AL., ALIMENT PHARMACOL THER, vol. 43, no. 2, 2016, pages 181 - 96
ZEUNER ET AL., MOLECULES, vol. 24, no. 11, 2019, pages 2033
ZHENG ET AL., FRONT NEUROSCI, vol. 2021, no. 15, 2021, pages 738220

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025068416A1 (fr) 2023-09-26 2025-04-03 N.V. Nutricia 3-fucosyllactose et butyrate pour allergie alimentaire
WO2025190540A1 (fr) * 2024-03-13 2025-09-18 Société des Produits Nestlé S.A. Stimulation de bactéries productrices de butyrate dans le microbiome intestinal

Similar Documents

Publication Publication Date Title
US11998577B2 (en) Methods for increasing growth of beneficial bacteria in the gastrointestinal tract
NL2004200C2 (en) Use of sialyl oligosaccharides in weight management.
CN101652080A (zh) 使用益生菌改善肠道微生物群
WO2025008277A1 (fr) Combinaison pour la gestion alimentaire de la santé intestinale
US20240009216A1 (en) Nutritional composition
US20250302083A1 (en) Extensively hydrolysed infant formula
JP2023545928A (ja) ヒト乳オリゴ糖を含む栄養組成物
US20230320401A1 (en) Infant or young child formula
JP7681008B2 (ja) 乳児用フォーミュラ
EP4084628B1 (fr) Formule infantile
WO2024227720A1 (fr) Composition nutritionnelle
CN120917147A (zh) 供使用的组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24737098

Country of ref document: EP

Kind code of ref document: A1