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WO2018143793A1 - Modulation alimentaire du fonctionnement du cerveau - Google Patents

Modulation alimentaire du fonctionnement du cerveau Download PDF

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Publication number
WO2018143793A1
WO2018143793A1 PCT/NL2017/050065 NL2017050065W WO2018143793A1 WO 2018143793 A1 WO2018143793 A1 WO 2018143793A1 NL 2017050065 W NL2017050065 W NL 2017050065W WO 2018143793 A1 WO2018143793 A1 WO 2018143793A1
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WO
WIPO (PCT)
Prior art keywords
glutamine
nutritional composition
infant
oligosaccharide
fructo
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.)
Ceased
Application number
PCT/NL2017/050065
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English (en)
Inventor
Ingrid Brunhilde RENES
Ruurd VAN ELBURG
Nana BARTKE
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.)
Nutricia NV
Original Assignee
Nutricia NV
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 Nutricia NV filed Critical Nutricia NV
Priority to PCT/NL2017/050065 priority Critical patent/WO2018143793A1/fr
Priority to CN201880022749.2A priority patent/CN110545678A/zh
Priority to PCT/NL2018/050072 priority patent/WO2018143806A1/fr
Publication of WO2018143793A1 publication Critical patent/WO2018143793A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to nutritional compositions comprising synbiotics and glutamine for accelerating the maturation of brain structure and accelerating the ability of learning and maturation of cognition.
  • the invention is in particular suitable for infants that are born prematurely.
  • breast-feeding is the preferred method of feeding infants. However, there are circumstances that make breast-feeding impossible or less desirable. In those cases infant formulae are a good alternative.
  • the composition of modern infant formulae is adapted in such a way that it meets many of the special nutritional requirements of the fast growing and developing infant. Still further improvements can be made.
  • the present invention relates to nutritional compositions for infants, in particular infant formulae, which comprises specific ingredients for modulating brain structure and functioning.
  • WO2014/070016 discloses that dietary supplementation with Bifidobacterium breve in combination with non-digestible oligosaccharides, preferably further in combination with glutamine, resulted in improved cognitive and behavioral performance and in particular that anxiety levels were lowered and spatial memory was improved.
  • the present inventors now surprisingly found in an animal model study that supplementation of the diet with a prebiotic and a probiotic and glutamine, in brain tissue, microstructural maturation was enhanced evidenced by beneficial influences on orientation dispersion index in brain cortical gray matter, white matter fiber bundles radial diffusivity and fractional anisotropy values.
  • test animals receiving a diet supplemented with a prebiotic and a probiotic and glutamine were quicker in learning the objective set out in a T- maze compared to the control group.
  • a prebiotic and a probiotic and glutamine is particularly suitable to enhance maturation of brain microstructure in mammalian offspring, in particular in an infant.
  • a prebiotic and a probiotic and glutamine is particularly suitable to accelerate maturation of cognition, accelerate learning ability and/or accelerate reaching memory objectives in mammalian offspring, in particular in an infant.
  • the present invention thus concerns a method for enhancing maturation of brain microstructure in an infant, comprising adminstering to the infant a nutritional composition comprising a prebiotic fiber and a probiotic bacterium and glutamine.
  • the invention can also be worded as the use of a prebiotic fiber and a probiotic bacterium and glutamine in the manufacture of a nutritional composition for enhancing maturation of brain microstructure in an infant.
  • the invention can also be worded as a nutritional composition comprising a prebiotic fiber and a probiotic bacterium and glutamine, for use in enhancing maturation of brain microstructure in an infant.
  • the invention concerns a method for accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives in an infant, comprising adminstering to the infant a nutritional composition comprising a prebiotic fiber and a probiotic bacterium and glutamine.
  • the invetion can also be worded as the use of a prebiotic fiber and a probiotic bacterium and glutamine in the manufacture of a nutritional composition for accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives in an infant.
  • the invention can also be worded as a nutritional composition comprising a prebiotic fiber and a probiotic bacterium and glutamine, for use in accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives in an infant.
  • the nutritional composition comprises a prebiotic fiber.
  • prebiotic fiber is known in the art and refers to dietary fibers or non- digestible saccharides which are nutritional components that are typically resistant to digestion and absorption in the small intestine, hence which are not or only partially digested by the action of acids or digestive enzymes such as present in for instance small intestine and stomach, with preferably a complete or partial fermentation in the large intestine, in particular by intestinal flora.
  • sucrose, lactose, maltose and maltodextrins are considered digestible.
  • galacto-oligosaccharides fructo-oligosaccharides and fructo- polysaccharides are considered non-digestible saccharide.
  • the term 'prebiotic fiber' refers to non-digestible saccharide.
  • saccharide preferably refers to a saccharide with a degree of polymerization (DP) of 2 to 250, preferably a DP of 2 to 100, more preferably of 2 to 60.
  • a saccharide with a DP in a certain range may include a mixture of saccharides with different average DP's, for example, if a saccharide with a DP of 2 to 100 is included in the present composition, this may include compositions which contain oligosaccharides with an average DP between 2 and 5, and polysaccharides with an average DP between 20 and 60.
  • Oligosaccharide' refers to a prebiotic fiber with an average DP below 10 and the term 'polysaccharide' refers to a prebiotic fiber with an average DP of 10 and higher.
  • the nutritional composition preferably comprises a prebiotic, or non-digestible saccharide, selected from the group consisting fructo- oligosaccharide, galacto-oligosaccharide, fructo-polysaccharide, gluco-oligosaccharide, arabino-oligosaccharide, mannan-oligosaccharide, xylo-oligosaccharide, fuco- oligosaccharide, arabinogalacto-oligosaccharide, glucomanno-oligosaccharide, galactomanno- oligosaccharide, arabino-polysaccharide, mannan-polysaccharide, xylo-polysaccharide, fuco- polysaccharide, arabinogalacto-polysaccharide, glucomanno-polysaccharide, galactomanno- polysaccharide, sialic acid comprising oligosaccharide, sialic acid
  • the nutritional composition preferably comprises a prebiotic fiber selected from the group consisting of a fructo-oligosaccharide, a galacto- oligosaccharide, a fructo-polysaccharide, a combination of a fructo-oligosaccharide and a galacto-oligosaccharide tide, a combination of a fructo-oligosaccharide and a fructo- polysaccharide, a combination of a galacto-oligosaccharide and a fructo-polysaccharide and a combination of a fructo-oligosaccharide, a galacto-oligosaccharide and a fructo- polysaccharide.
  • a prebiotic fiber selected from the group consisting of a fructo-oligosaccharide, a galacto- oligosaccharide, a fructo-polysaccharide, a combination of a fructo-oligosaccharide and a galact
  • the nutritional composition that is administered according to the present method or according to the present use comprises galacto-oligosaccharide, more preferably transgalacto- oligosaccharide.
  • the nutritional composition comprises galacto-oligosaccharide with an average DP between 2 and 10.
  • the nutritional composition that is administered according to the present method or according to the present use comprises fructo-polysaccharide.
  • the nutritional composition comprises fructo-polysaccharide with an average DP between 10 and 60, preferably with an average DP between 20 and 60.
  • the nutritional composition comprises a mixture of galacto- oligosaccharide and fructo-polysaccharide.
  • the nutritional composition comprises galacto-oligosaccharide with an average DP between 2 and 10 and fructo-polysaccharide with an average DP between 10 and 60, preferably with an average DP between 20 and 60.
  • the nutritional composition comprises galacto-oligosaccharides and fructo- polysaccharides in a weight ratio of 20 to 0.5, more preferably 20 to 1, most preferably from 12 to 2.
  • the nutritional composition that is administered according to the present method or according to the present use comprises fructo-oligosaccharide.
  • the nutritional composition comprises fructo-oligosaccharide with an average DP between 2 and 10.
  • the nutritional composition comprises a mixture of fructo- oligosaccharide and fructo-polysaccharide.
  • the nutritional composition comprises fructo-oligosaccharide with an average DP between 2 and 10 and fructo-polysaccharide with an average DP between 10 and 60, preferably with an average DP between 20 and 60.
  • the nutritional composition comprises fructo-oligosaccharides and fructo- polysaccharides in a weight ratio of 20 to 0.05, more preferably 10 to 0.1.
  • the nutritional composition that is administered according to the present method or according to the present use comprises a mixture of galacto-oligosaccharide and fructo-oligosaccharide.
  • the nutritional composition comprises galacto- oligosaccharide with an average DP between 2 and 10 and fructo-oligosaccharide with an average DP between 2 and 10.
  • the nutritional composition comprises galacto- oligosaccharides and fructo-oligosaccharides in a weight ratio of 20 to 0.05, more preferably 10 to 0.1.
  • the nutritional composition that is administered according to the present method or according to the present use comprises a mixture of galacto-oligosaccharide and fructo-oligosaccharide and fructo-polysaccharide.
  • the nutritional composition comprises galacto-oligosaccharide with an average DP between 2 and 10 and fructo- oligosaccharide with an average DP between 2 and 10 and fructo-polysaccharide with an average DP between 10 and 60, preferably with an average DP between 20 and 60.
  • the nutritional composition comprises galacto-oligosaccharides and fructo-oligosaccharides and fructo-polysaccharides in a weight ratio of to 20 to 1 : 10 to 0.05 : 10 to 0.05.
  • the nutritional composition according to the present method or use comprises 0.5 to 20 wt.% prebiotic fiber per g dry weigth of the nutritional composition, more preferably 0.5 to 10 wt.%, even more preferably 1.5 to 7.5 wt.%. In one embodiment, the nutritional composition according to the present method or use comprises 80 mg to 2 g prebiotic fiber per 100 ml, more preferably 150 mg to 1.50 g, even more preferably 300 mg to 1 g per 100 ml.
  • the nutritional composition comprises a probiotic.
  • probiotic is known in the art and refers to micro-organisms, preferably bacteria, which have a beneficial effect on a host when ingested by or administered to that host.
  • the probiotic is preferably a lactic acid producing bacteria.
  • the nutritional composition preferably comprises a probiotic of the genus Lactobacillus or Bifidobacterium or of both.
  • the Lactobacillus is one or more selected from L. rhamnosus, L. casei,
  • L. paracasei L. helveticus, L. delbrueckii, L. reuteri, L. brevis, L. crispatus, L. sakei, L. jensenii, L. sanfransiscensis, L. fructivorans, L. kefiri, L. curvatus, L. paraplantarum, L. kefirgranum, L. parakefir, L. fermentum, L. plantarum, L. acidophilus, L. johnsonii, L. gasseri, L. xylosus, L. salivarius etc.
  • Preferred species are L. rhamnosus, L. casei, L. paracasei, L. reuteri, L.
  • the crispatus .L fermentum L. plantarum L. acidophilus, L. johnsonii L. gasseri and L. salivarius, more preferably one or more selected from L. plantarum, L. casei and L. rhamnosus., more preferably the prociotic comprises a strain belonging to the species J. casei.
  • the Bifidobacterium is one or more selected from B. longum, B. breve, B. animalis, B. infantis, B. bifidum, B. adolescentis, B. pseudolongum, B. catenulatum,
  • the nutritional composition preferably comprises a Bifidobacterium.
  • the nutritional composition comprises a Bifidobacterium breve.
  • Bifidobacterium breve is a Gram-positive, anaerobic, branched rod-shaped bacterium.
  • the B. breve preferably has at least 95 % identity of the 16 S rRNA sequence when compared to the type strain of B. breve ATCC 15700, more preferably at least 97% identity (Stackebrandt & Goebel, 1994, Int. J. Syst. Bacteriol. 44:846-849).
  • Preferred B. breve strains are those isolated from the faeces of healthy human milk-fed infants.
  • the present composition contains at least one B. breve selected from the group consisting of B. breve Bb- 03 (Rhodia/Danisco), B. breve M-16V (Morinaga), B. breve R0070 (Institute Rosell, Lallemand), B. breve BR03 (Probiotical), B. breve BR92) (Cell Biotech), DSM 20091, LMG 11613, YIT4065, FERM BP-6223 and CNCM 1-2219. Most preferably, the B.
  • B. breve M-16V is selected from the group consisting of B. breve M-16V and B. breve CNCM 1-2219, most preferably M- 16V.
  • B. breve 1-2219 was published in WO 2004/093899 and was deposited at the Collection National e de Cultures de Microorganisms, Institute Pasteur, Paris, France on 31 May 1999 by Compagnie Gervais Danone.
  • B. breve M-16V was deposited as BCCM/LMG23729 and is commercially available from Morinaga Milk Industry Co., Ltd.
  • the nutritional composition that is administered according to the present method or according to the present use preferably comprises 10 2 to 10 13 colony forming units (cfu) of a probiotic, preferably B. breve, per gram dry weight of the nutritional composition, preferably 10 4 to 10 12 , more preferably 10 5 to 10 10 , most preferably from 10 5 to lxlO 8 cfu of a probiotic, preferably B. breve B. breve, per gram dry weight of the nutritional composition.
  • the amount of the probiotic preferably B.
  • the nutritional composition comprises 10 3 to 10 13 cfu of a probiotic, preferably B. breve, per 100 ml, more preferably 10 6 to 10 11 cfu per 100 ml, most preferably 10 7 to 10 9 cfu per 100 ml.
  • the nutritional composition according to the present method or use preferably comprises viable probiotic, preferably B. breve.
  • the nutritional composition according to the present method or use preferably comprises non-viable probiotic, preferably B. breve equivalent to the amounts of cfu as described above.
  • the equivalent of cfu can be determined by performing the 5 'nuclease assay with appropriate probes and primers, preferably the B. breve probes and primers as disclosed in WO 2005/039319 in the nutritional composition comprising non-viable B. breve and compare this with a calibration curve obtained from a comparable nutritional composition to which known amounts in cfu of viable probiotic, preferably B. breve have been added.
  • Viable bifidobacteria can be commercially obtained as described above.
  • Probiotic cells preferably B. breve cells can be made non- viable by methods known in the art, including heat treatment steps (including sterilization, pasteurization, UHT treatment), radiation (UV), treatment with oxygen, treatment with bactericidals such as ethanol, sonication, ultra-high pressure application, high pressure homogenization and use of a cell disruptor.
  • the probiotic, preferably B. breve is heat-killed.
  • the presence of nonviable probiotic, preferably B. breve advantageously provides many product technological benefits, including increased shelf-life, a reduced incidence of bacterial contamination, decreased post-acidification of the product, improved dosage control and improved convenience of reconstitution.
  • the nutritional composition comprises a probiotic.
  • Glutamine in the present invention refers to L-glutamine.
  • Glutamine is one of the most abundant amino acids in plasma and human milk and is considered conditionally essential in preterm infants.
  • Glutamine is utilized as a source of energy and for nucleotide synthesis in all rapidly dividing cells, such as the intestinal lining and certain immune cells.
  • glutamine is a substrate for neurotransmitters and an important source of energy for the nervous system.
  • Glutamine is preferably present in an easily absorbable form. In particular in infants with an immature intestinal tract, glutamine present in intact protein is less easily absorbed. Therefore the nutritional composition in the method or use according to the present invention preferably comprises glutamine in the form of free amino acid, glutamine containing dipeptide and/or glutamine containing tripeptide, most preferably glutamine containing dipeptide and/or free glutamine. Free glutamine and glutamine containing dipeptide and glutamine containing tripeptide are commercially available, for example at Ajinomoto, USA.
  • the nutritional composition in the method or use of the present invention preferably comprises glutamine levels higher then normally present in human milk protein or standard infant formula based on cow's milk derived protein.
  • the nutritional composition in the method or use of the present invention comprises at least 12 wt.%, more preferably at least 15 wt.%, even more preferably at least 30 wt.% glutamine based on total protein.
  • the nutritional composition comprises less than 80 wt.%, more preferably less than 50 wt.% glutamine based on total protein.
  • the nutritional composition comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine based on dry weight of the nutritional composition.
  • the nutritional composition comprises less than 20 wt.%), more preferably less than 10 wt.% glutamine based on dry weight of the nutritional composition.
  • the nutritional composition in the method or use of the present invention comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine based on 100 kcal of the nutritional composition.
  • the nutritional composition comprises less than 5 g, even more preferably less than 2 g glutamine based on 100 kcal of the nutritional composition.
  • the nutritional composition comprises at least 0.4 g, more preferably at least 0.6 g, even more preferably at least 1.25 g glutamine per 100 ml.
  • the nutritional composition comprises less than 6 g, even more preferably less than 2.5 g glutamine per 100 ml.
  • the nutritional composition comprises at least 12 wt.%, more preferably at least 15 wt.%), even more preferably at least 30 wt.% glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide based on total protein.
  • the nutritional composition comprises less than 80 wt.%, more preferably less than 50 wt.%) glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide based on total protein.
  • the nutritional composition comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.%) glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide, based on dry weight of the nutritional composition.
  • the nutritional composition comprises less than 20 wt.%, more preferably less than 10 wt.% glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide, based on dry weight of the nutritional composition.
  • the nutritional composition comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide, based on 100 kcal.
  • the nutritional composition comprises less than 5 g, even more preferably less than 2 g glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide, based on 100 kcal.
  • the nutritional composition comprises at least 0.4 g, more preferably at least 0.6 g, even more preferably at least 1.25 g glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide per 100 ml.
  • the nutritional composition comprises less than 6 g, even more preferably less than 2.5 g glutamine in the form of free amino acid and glutamine containing dipeptide and glutamine containing tripeptide per 100 ml.
  • the nutritional composition in the method or use according to the invention is a nutritional supplement.
  • the nutritional supplement is also referred to as a glutamine-based supplement.
  • the nutritional supplement, or the glutamine- based supplement is in the form of a powder, preferably in a unit dose.
  • the glutamine-based supplement in a unit dose preferably in the form of a powder, comprises at least 5 wt.%, or at least 8 wt.% glutamine in the form of free glutamine, glutamine dipeptide and/or glutamine tripeptide based on dry weight of the glutamine-based supplement.
  • the glutamine-based supplement comprises at least 30 wt.%, more preferably at least 50 wt.%), most preferably more than 75 wt.%> glutamine based on total protein.
  • the glutamine-based supplement comprises at least 1.5 wt.%, more preferably at least 2 wt.%, more preferably at least 4 wt.% glutamine, even more preferably at least 15 wt.%, even more preferably at least 40 wt.%, most preferably at least 75 wt.% glutamine based on dry weight of the glutamine-based supplement.
  • the glutamine-based supplement comprises at least 0.3 g, more preferably at least 0.5 g, more preferably at least 1 g glutamine, even more preferably at least 5, more preferably at least 10, most preferably at least 20 g glutamine based on 100 kcal.
  • the glutamine-based supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final nutritional composition
  • glutamine enriched nutritional composition comprises at least 12 wt.%, more preferably at least 15 wt.%), more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine based on total protein.
  • the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine based on dry weight of the nutritional composition.
  • the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine based on 100 kcal.
  • the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 12 wt.%, more preferably at least 15 wt.%), more preferably at least 20 wt.%, even more preferably at least 30 wt.% glutamine in the form of free amino acid and/or dipeptide based on total protein.
  • the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 1.5 wt.%, more preferably at least 2 wt.%, even more preferably at least 4 wt.% glutamine in the form of amino acid and/or dipeptide based on dry weight of the nutritional composition.
  • the nutritional supplement is added to human milk, standard preterm formula, or human milk fortified with standard human milk fortifier in such an amount that the final glutamine enriched nutritional composition comprises at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 1 g glutamine in the form of free amino acid and/or dipeptide based on 100 kcal.
  • the daily dose of glutamine provided to the infant is between 0.01 and 0.5 g/kg body weight, preferably between 0.05 and 0.4 g/kg body weight, even more preferably between 0.1 and 0.35 g/kg body weight.
  • the nutritional composition in the method or use according to the present invention advantageously concerns a composition wherein the lipid provides 5 to 50% of the total calories, the protein provides 5 to 50% of the total calories, and the carbohydrate provides 15 to 90%) of the total calories.
  • the lipid provides 35 to 50%) of the total calories
  • the protein provides 7.5 to 12.5% of the total calories
  • the carbohydrate provides 40 to 55% of the total calories.
  • the nutritional composition preferably comprises at least one lipid selected from the group consisting of animal lipid (excluding human lipids) and vegetable lipids.
  • the present composition comprises a combination of vegetable lipids and at least one oil selected from the group consisting of fish oil, animal oil, algae oil, fungal oil, and bacterial oil.
  • the nutritional composition comprising a prebiotic fiber and a probiotic excludes human milk.
  • the nutritional composition preferably comprises protein.
  • the protein in the nutritional composition is preferably selected from the group consisting of non-human animal proteins (preferably milk proteins, preferably proteins from cow's milk), vegetable proteins (preferably soy protein and/or rice protein), free amino acids and mixtures thereof.
  • the nutritional composition preferably contains casein, whey, hydrolyzed casein and/or hydrolyzed whey protein.
  • the protein comprises intact proteins, more preferably intact bovine whey proteins and/or intact bovine casein proteins.
  • the protein is preferably selected from the group consisting of hydrolyzed milk protein, more preferably selected from the group consisting of hydrolyzed whey protein and hydrolyzed casein.
  • the nutritional composition preferably comprises digestible carbohydrates.
  • the nutritional composition preferably comprises a digestible carbohydrate, wherein at least 35 wt.%, more preferably at least 50 wt.%, more preferably at least 75 wt.%, even more preferably at least 90 wt.%), most preferably at least 95 wt.%> is lactose.
  • the nutritional composition preferably comprises at least 25 grams lactose per 100 gram dry weight of the nutritional composition, preferably at least 40 grams lactose per 100 gram.
  • the nutritional composition When in liquid from, the nutritional composition preferably has a caloric density between 0.1 and 2.5 kcal/ml, even more preferably a caloric density of between 0.5 and 1.5 kcal/ml, most preferably between 0.6 and 0.8 kcal/ml.
  • the amount of nutritional composition administered per day is preferably between 50 and 2000 ml, more preferably between 200 and 1500, most preferably between 400 and 1000 ml.
  • the nutritional composition in the method or use according to the present invention is an infant formula.
  • the nutritional composition in the method or use according to the present invention is a preterm infant formula, or briefly preterm formula.
  • the preterm formula comprises all macro- and micronutrients needed for preterm infants so as to achieve a growth similar to fetal growth coupled with satisfactory functional development.
  • the preterm formula comprises from 5 to 25 wt.%> protein, preferably 9 to 20 wt.%), more preferably 13 to 18 wt.%> protein based on the dry weight of the preterm formula.
  • the preterm formula comprises from 1.8 to 3.0 g protein, preferably, preferably 2.0 to 3.0 g, preferably 2.5 g to 2.6 g protein, per 100 ml.
  • the preterm formula in ready to drink form has in a preferred embodiment about 70 to 90 kcal, preferably 75 to 85 kcal per 100 ml.
  • the preterm formula preferably has an osmolarity below 450 mOsmol/1, more preferably below 400, even more preferably below 350. Particularly in preterm infants, a too high osmolarity is a disadvantage.
  • the nutritional composition in the method or use according to the invention is in dry form, preferably in the form of a powder. This powder is suitable for reconstitution with water or another aqueous phase. When the nutritional composition is in powder form it advantageously has a better shelf life.
  • the nutritional composition in the method or use according to the present invention comprises long chain poly unsaturated fatty acids (LC-PUFA), more preferably n-3 and n-6 LC-PUFA, even more preferable arachidonic acid (ARA) and docosahexaenoic acid (DHA).
  • LC-PUFA is an important part of the fatty acyl chain composition of the brain membranes and therefore advantageously enhances brain microstructure maturation and supports accelerating maturation of cognition, supports accelerating learning ability and/or supports accelerating reaching memory objectives.
  • LC-PUFA in particular ARA and DHA, will have a further improved, or even synergistic, beneficial effect together with the prebiotic fiber, the probiotic and the glutamine.
  • n-3 LC-PUFA in particular docosahexaenoic acid (DHA)
  • DHA docosahexaenoic acid
  • the nutritional composition comprises n-3 LC-PUFA, even more preferably DHA. Since a low concentration of DHA is already effective, the content of n-3 LC- PUFA in the nutritional composition, preferably does not exceed 15 wt.% of the total fatty acid content, preferably does not exceed 10 wt.%, even more preferably does not exceed 5 wt.%.
  • the nutritional composition comprises at least 0.2 wt.%, preferably at least 0.5 wt.%, more preferably at least 0.75 wt.% n-3 LC-PUFA of the total fatty acid content.
  • the DHA content preferably does not exceed 5 wt.%, more preferably does not exceed 1 wt.%, but is preferably at least 0.1 wt.% of the total fatty acid.
  • n-3 LC-PUFA single cell oil preferably algal oil, fungal oil and/or microbial oil is used, since these oil sources have a low EPA/DHA ratio, which results in a beneficial effect on the brain.
  • the nutritional composition comprises fish oil, more preferably tuna oil.
  • n-6 LC-PUFA in particular arachidonic acid (ARA) is an important part of the fatty acyl chain composition of the brain membranes and advantageously enhances brain microstructure maturation.
  • the nutritional composition preferably comprises relatively low amounts of ARA.
  • the n-6 LC-PUFA content preferably does not exceed 5 wt.%, more preferably does not exceed 0.8 wt.%, more preferably does not exceed 0.75 wt.%, even more preferably does not exceed 0.5 wt.% based on total fatty acids.
  • the amount of n-6 LC-PUFA is preferably at least 0.02 wt.%, more preferably at least 0.05 wt.%, even more preferably at least 0.1 wt.%) based on total fatty acids, more preferably at least 0.25 wt.%>.
  • the weight ratio n-6 LC-PUFA / n-3 LC-PUFA, in particular the weight ratio of ARA/DHA in the nutritional composition is preferably from 3 to 0.5, more preferably from 2 to 1. Preferably the weight ratio is above 1. These ratio's ensure an optimal brain functioning.
  • LC-PUFA are preferably provided as free fatty acids, in triglyceride form, in diglyceride form, in monoglyceride form, in phospholipid form, or as a mixture of one of more of the above.
  • the nutritional composition contains LC-PUFA in triglyceride and/or phospholipid form, even more preferably phospholipid form since LC-PUFA in phospholipid form are better incorporated into membranes. Therefore a dietary source of LC-PUFA in the form of phospholipids will have a further improved effect on the brain than when administered in form of triglycerides.
  • a preferred source of LC-PUFA therefore is egg phospholipid. Commercial sources of egg oil, rich in phospholipids, and having arachidonic and docosahexaenoic fatty acyl chains in the phospholipid molecules are known.
  • the nutritional composition in the present method or use is preferably intended for infants and/or toddlers. Infants have an age of 0-12 months, toddlers have an age of 12-36 months. More preferably the nutritional composition is for infants, more preferably mammalian infants, more preferably human infants, most preferably human preterm infants.
  • the nutritional composition in the present method or use is preferably enterally administered, more preferably orally.
  • the present composition is preferably a nutritional formula, preferably an infant formula.
  • the nutritional composition can advantageously be applied as a complete nutrition for infants.
  • the nutritional composition preferably comprises lipid, protein, and carbohydrate and is preferably administered in liquid form.
  • the present invention includes the use of dry nutritional compositions, e.g. powders, which are accompanied with instructions as to admix said dry compositions, in particular nutritional formula, with a suitable liquid, e.g. water.
  • the nutritional composition in the present method or use is preferably intended for a preterm infant.
  • a preterm infant can also be named a premature infant.
  • a subgroup of premature infants are very preterm infants.
  • the nutritional composition in the present method or use is preferably intended for an infant that is born small for gestational age (SGA).
  • SGA infant is an infant whose birth weight lies below the 10th percentile for that gestational age.
  • An SGA infant has usually been the subject of intrauterine growth restriction (IUGR).
  • Premature and/or SGA infants include low birth weight infants (LBW infants), very low birth weight infants (VLBW infants), and extremely low birth weight infants (ELBW infants).
  • LBW infants are defined as infants with a weight less than 2500 g.
  • VLBW infants as infants with a weight which is less than 1500 g
  • ELBW infants as infants with a weight less than 1000 g.
  • Preterm infants have an immature intestinal tract, hence it is preferred that the nutritional composition according to the invention is administered to the preterm infant starting at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth.
  • the nutritional composition in the present method or use is preferably intended for infants born via caesarean section.
  • a caesarean section is a surgical procedure where an infant is delivered through an incision made in the mother's abdominal wall, and then through the wall of the uterus. It is of relevance to improve and/or accelerate developing the appropriate Bifidobacteria population and Bifidobacterium species diversity in the gastrointestinal tract of C-section delivered infants at the onset of life outside the womb, and that will contribute to create a favourable gut ecosystem milieu through their metabolic capability.
  • the nutritional composition according to the invention is administered to the infant delivered via C-section starting at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth.
  • the present inventions concerns enhancing maturation of brain microstructure, preferably enhancing maturation of brain microstructure in an infant, more preferably in a preterm infant.
  • the present inventions concerns enhancing maturation of gray matter and/or enhancing maturation of white matter, preferably enhancing maturation of gray matter and/or enhancing maturation of white matter in an infant, preferably in a preterm infant.
  • the present inventions concerns accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives, preferably accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives in an infant, more preferably in a preterm infant.
  • the beneficial effects of enhancing maturation of brain microstructure preferably the enhancing maturation of gray matter and/or enhancing maturation of white matter occurs in the first 24 months of life, preferably in the first 12 months of life, more preferably in the first 6 months of life, more preferably in the first 3 months of life, most preferably in the first month of life.
  • the beneficial effects of accelerating maturation of cognition, accelerating learning ability and/or accelerating reaching memory objectives occurs in the first 24 months of life, preferably in the first 12 months of life, more preferably in the first 6 months of flife, more preferably in the first 3 months of life, most preferably in the first month of life.
  • the nutritional composition is adminstered in the first 24 months of life.
  • the nutritional composition is preferably adminstered in the first 12 months of life, more preferably in the first 6 months of life, more preferably in the first 3 months of life, most preferably in the first month of life.
  • the composition is administered to preterm infants starting at least in the first two weeks after birth, preferably within the first week after birth, more preferably at least within 5 days after birth, even more preferably at least within 3 days after birth, most preferably at least within 2 days after birth.
  • the enteral basal milk diet in both groups consisted of raw bovine milk that was fed from day 1, gradually increasing over the study period (32-224 mL/kg/d).
  • the piglets were randomly assigned to two groups: the intervention group and control group (PPG vs CON).
  • PPG vs CON intervention group and control group
  • scGOS and lcFOS were added in a ratio of 9: 1 to the milk diet in the PPG group.
  • Glutamine concentration was kept constant at 0.3 g/kg/d throughout the experiment in the PPG group.
  • B. breve M16-V was provided at 3.0 x 10 9 CFU per animal per day (reconstituted in 1 mL raw milk) as a single daily dose in the PPG group.
  • the control group (CON) was given the same volume of 1 mL using maltodextrin (0.03 g/ml) as placebo.
  • the CON diet was prepared by adding glucose at 4.14 g/L and lactose at 4.0 g/L.
  • a trial began when a guillotine door to the start box was opened by use of a string system operated from the adjacent room. The trial ended when the pig passed a choice line marked on the floor of the east or west arm of the maze. All sessions were video recorded and subsequently analyzed with Ethovision XT10 providing information on distance travelled and latency to choice.
  • Performance in the T-maze indicated as the mean proportion of correct choices, increased over time in both groups (P ⁇ 0.001).
  • the ability of PPG piglets to locate the food reward improved over time with piglets surpassing the performance criterion of 80% correct by day 5 of acquisition in an accelerated manner compared to CON animals.
  • CON animals required 1 day more ( Figure 1 A).
  • Figure 1 A As the average proportion of correct choices across a treatment group is influenced by pigs performing either very high or very low, a complementary way of displaying the data is the proportion of pigs reaching the learning criterion of 80% correct choices over time. From this analysis, the increase in the proportion of pigs reaching the learning criterion was higher in the PPG vs. CON pigs (P ⁇ 0.01, Figure IB).
  • Example 2 Ex vivo magnetic resonance imaging (M I) analyses of brain microstructure Fixed cerebral hemispheres were subjected to diffusion tensor MR imaging. MR experiments were performed on an actively- shielded 9.4T/31 cm magnet (Agilent) equipped with 12 cm gradient coils (400 mT/m, 120 ⁇ ) with a 3.5 mm diameter birdcage coil.
  • a total of 96 diffusion weighted images were acquired, 15 of them as bO reference images.
  • the remaining 81 were separated in 3 shells with the following distribution (# of directions/b-value in s/mm2): 21/1750, 30/3400 and 30/5100. All 81 directions were non-collinear and were uniformly distributed in each shell.
  • the total acquisition time was 15h per brain. Acquired data were fitted using the NODDI toolbox (55).
  • the diffusion tensor was spatially normalized to the study-specific DT template using DTI-TK (56).
  • the regions of interest were drawn on the DT study- specific template and were then transformed back to the subject space in order to compute ROI- averaged estimates of DTI and NODDI maps.
  • Four different brain regions were identified on the DT-template: cortex (Cx), corpus callosum (CC), internal capsule (IC) and Cortico-cortical tract (CCT).
  • Brain white matter microstructure assessed on NODDI derived parameters of the right cerebral hemisphere, showed -8% reduced radial diffusivity (P ⁇ 0.05) and 12% increased fractional anisotropy values (P ⁇ 0.05) in the cortico-cortical tract (Figure 2B), and tendencies to reduced radial (-7%) and mean (-5%) diffusivities in the internal capsule (Figure 2C; both P 0.09), in PPG pigs compared to the values in CON pigs. This is consistent with an increased maturation of association and projection white matter fiber bundles in the PPG group, respectively.
  • Example 3 Preterm formula with prebiotic fiber, B. breve and glutamine
  • Preterm formula in powder form comprising per 100 g about 474 kcal, 15.6 g protein, 49.8 g digestible carbohydrates (mainly lactose and maltodextrin), 22.9 g fat and 4.7 g non-digestible oligosaccharides.
  • the protein comprises about 92.5 wt.% casein and whey protein from cow's milk based on total protein in a weight ratio of 1 : 1.5.
  • About 7.5 wt.% of the protein is free L- glutamine.
  • the non-digestible oligosaccharides are galacto-oligosaccharides (Source Vivinal GOS, Borculo Domo) and fructo-polysaccharides (Source RaftilinHP, Orafti ) in a weight ratio of 9: 1. Due to the EU directives the non digestible disaccharides in the GOS do not qualify as dietary fiber. Hence the fiber content is labeled to be 3.3 g per 100 g powder. 10 7 cfu of Bifidobacterium breve M-16V (Morinaga) is present per g powder.
  • Fat is for the main part of vegetable origin but also tuna fish oil (source of DHA), algae oil (source of ARA) arachidonic acid (ARASCO, Martek) and egg lipid (source of DHA and ARA) are present as a source of LC-PUFA, resulting in 0.52 wt% ARA based on total fatty acyl chains and 0.40 wt% DHA based on total fatty acyl chains.
  • the composition comprises minerals, trace elements, vitamins, and other micronutrients as known in the art and according to guidelines for preterm infants.
  • the instructions are to dilute 16.9 g powder (3 scoops) with water until a final volume of 100 ml.
  • Example 4 Post discharge formula for use in premature or small for gestational infants after discharged from the hospital
  • Post-discharge formula are marketed for use in premature or small for gestational infants after discharged from the hospital or after when reaching the corrected a term age, until a corrected age of 6 months.
  • the formula comprises per 100 g about 491 kcal, 13.4 g protein, 49.1 g digestible carbohydrates (mainly lactose and maltodextrin), 26 g fat and 5.2 g non-digestible oligosaccharides.
  • the protein comprises about 92.5 wt.% casein and whey protein from cow's milk based on total protein in a weight ratio of 1 : 1.5. About 7.5 wt.% of the protein is free L-glutamine.
  • the non-digestible oligosaccharides are galacto- oligosaccharides (Source Vivinal GOS, Borculo Domo) and fructo-polysaccharides (Source RaftilinHP, Orafti ) in a weight ratio of 9: 1. Due to the EU directives the non digestible disaccharides in the GOS do not qualify as dietary fiber. Hence the fiber content is labeled to be 3.7 g per 100 g powder. 5.10 7 cfu of Bifidobacterium breve M-16V (Morinaga) is present per g powder.
  • Fat is for the main part of vegetable origin but also fish oil, algae oil and egg lipid are present as a source of LC-PUFA are present, resulting in 0.44 wt.% ARA based on total fatty acyl chains and 0.33 wt.% DHA based on total fatty acyl chains.
  • the composition comprises minerals, trace elements, vitamins, L-carnitine, choline, my-inositol and taurine and nucleotides as known in the art and according to guidelines for preterm infants.
  • the instructions are to dilute 15.3 g powder (3 scoops) with water until a final volume of 100 ml.

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Abstract

La présente invention concerne des compositions nutritionnelles pour nourrissons ou jeunes enfants comprenant une fibre prébiotique et une bactérie probiotique et de la glutamine destinées à être utilisées pour accélérer la maturation de la microstructure du cerveau et pour accélérer la maturation de la cognition.
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