WO2017083069A1 - Compositions nutritionnelles comprenant un hydrolysat de caséine, ainsi que du butyrate alimentaire et/ou un composé pour stimuler la formation de butyrate endogène - Google Patents

Compositions nutritionnelles comprenant un hydrolysat de caséine, ainsi que du butyrate alimentaire et/ou un composé pour stimuler la formation de butyrate endogène Download PDF

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Publication number
WO2017083069A1
WO2017083069A1 PCT/US2016/057646 US2016057646W WO2017083069A1 WO 2017083069 A1 WO2017083069 A1 WO 2017083069A1 US 2016057646 W US2016057646 W US 2016057646W WO 2017083069 A1 WO2017083069 A1 WO 2017083069A1
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Prior art keywords
nutritional composition
seq
protein
butyrate
kcal
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PCT/US2016/057646
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English (en)
Inventor
Teartse Tim LAMBERS
Eric A.F. VAN TOL
Juan M. Gonzalez
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Mjn U.S. Holdings Llc
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Priority claimed from US14/936,014 external-priority patent/US20170127693A1/en
Priority claimed from US14/959,107 external-priority patent/US10034937B2/en
Priority claimed from US15/011,797 external-priority patent/US20170215464A1/en
Priority to MX2018005663A priority Critical patent/MX2018005663A/es
Priority to AU2016351456A priority patent/AU2016351456B2/en
Priority to JP2018523445A priority patent/JP2018537084A/ja
Priority to BR112018008040A priority patent/BR112018008040A2/pt
Priority to EP16790819.3A priority patent/EP3373748A1/fr
Application filed by Mjn U.S. Holdings Llc filed Critical Mjn U.S. Holdings Llc
Priority to CN201680065416.9A priority patent/CN108347984A/zh
Priority to CA3004740A priority patent/CA3004740A1/fr
Priority to SG11201803123PA priority patent/SG11201803123PA/en
Publication of WO2017083069A1 publication Critical patent/WO2017083069A1/fr
Priority to PH12018500992A priority patent/PH12018500992A1/en
Priority to HK18115346.9A priority patent/HK1256282A1/zh
Priority to AU2020257046A priority patent/AU2020257046B2/en

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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 COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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 COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • 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
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/11—Lactobacillus

Definitions

  • NUTRITIONAL COMPOSITIONS COMPRISING A CASEIN HYDROLYSATE, AS WELL AS DIETARY BUTYRATE AND/OR A COMPOUND FOR STIMULATING FORMATION OF ENDOGENOUS BUTYRATE
  • the present disclosure relates generally to nutritional compositions comprising dietary butyrate and a component, which can stimulate the production of endogenous butyrate.
  • the nutritional compositions are suitable for administration to pediatric subjects. Additionally, the disclosure relates to nutritional compositions including a prebiotic comprising polydextrose and galacto-oligosaccharides, dietary butyrate, and a protein equivalent source. Further, disclosed are methods for reducing the incidence of allergy and/or improving tolerance to cow's milk allergy in target subjects.
  • the disclosed nutritional compositions may provide additive and or/synergistic beneficial health effects.
  • compositions including butyrate or butyrate derivatives often suffer from difficulties regarding the bioavailability of butyrate upon administration.
  • certain butyrate derivatives undergo degradation or oxidation, which ultimate affect the bioavailability of the butyrate derivative upon ingestion.
  • compositions including butyrate derivatives may not provide therapeutic efficacy upon ingestion given the degradation of the butyrate derivative.
  • compositions including butyrate may suffer from poor palatability.
  • the unpleasant taste and odor of compositions including butyrate can make the oral administration of certain nutritional compositions including butyrate difficult, especially in the pediatric population.
  • certain butyric acid derivatives at room may suffer from poor palatability.
  • the present disclosure is directed, in an embodiment, to a nutritional composition that includes dietary butyrate and a component which can stimulate the production of endogenous butyrate in the human gut.
  • the dietary butyrate may be encapsulated.
  • the endogenous butyrate may be provided by stimulating short chain fatty acid ("SCFA") production by the gut microbiota and the dietary butyrate may be provided by an enriched lipid fraction derived from milk.
  • SCFA short chain fatty acid
  • the present disclosure relates generally to nutritional compositions comprising dietary butyrate and a component for stimulating the production of endogenous butyrate. Additionally, the disclosure relates to methods for improving the shelf stability and/or organoleptic properties of nutritional compositions including butyrate.
  • Nutritional composition means a substance or formulation that satisfies at least a portion of a subject's nutrient requirements.
  • the terms “nutritional(s)”, “nutritional formula(s)”, “enteral nutritional(s)”, and “nutritional supplement(s)” are used as non-limiting examples of nutritional composition(s) throughout the present disclosure.
  • “nutritional composition(s)” may refer to liquids, powders, gels, pastes, solids, concentrates, suspensions, or ready-to-use forms of enteral formulas, oral formulas, formulas for infants, formulas for pediatric subjects, formulas for children, growing-up milks and/or formulas for adults.
  • a pediatric subject means a human less than 13 years of age. In some embodiments, a pediatric subject refers to a human subject that is between birth and 8 years old. In other embodiments, a pediatric subject refers to a human subject between 1 and 6 years of age. In still further embodiments, a pediatric subject refers to a human subject between 6 and 12 years of age.
  • the term “pediatric subject” may refer to infants (preterm or fullterm) and/or children, as described below.
  • infant means a human subject ranging in age from birth to not more than one year and includes infants from 0 to 12 months corrected age.
  • corrected age means an infant's chronological age minus the amount of time that the infant was born premature. Therefore, the corrected age is the age of the infant if it had been carried to full term.
  • infant includes low birth weight infants, very low birth weight infants, and preterm infants.
  • Preterm means an infant born before the end of the 37 th week of gestation.
  • Full term means an infant born after the end of the 37 th week of gestation.
  • Child means a subject ranging in age from 12 months to about 13 years. In some embodiments, a child is a subject between the ages of 1 and 12 years old. In other embodiments, the terms “children” or “child” refer to subjects that are between one and about six years old, or between about seven and about 12 years old. In other embodiments, the terms “children” or “child” refer to any range of ages between 12 months and about 13 years.
  • infant formula means a composition that satisfies at least a portion of the nutrient requirements of an infant. In the United States, the content of an infant formula is dictated by the federal regulations set forth at 21 C.F.R. Sections 100, 106, and 107.
  • the term "medical food” refers enteral compositions that are formulated or intended for the dietary management of a disease or disorder.
  • a medical food may be a food for oral ingestion or tube feeding (nasogastric tube), may be labeled for the dietary management of a specific medical disorder, disease or condition for which there are distinctive nutritional requirements, and may be intended to be used under medical supervision.
  • peptide as used herein describes linear molecular chains of amino acids, including single chain molecules or their fragments.
  • the peptides described herein include no more than 50 total amino acids.
  • Peptides may further form oligomers or multimers consisting of at least two identical or different molecules.
  • peptidomimetics of such peptides where amino acid(s) and/or peptide bond(s) have been replaced by functional analogs are also encompassed by the term "peptide”.
  • Such functional analogues may include, but are not limited to, all known amino acids other than the 20 gene-encoded amino acids such as selenocysteine.
  • peptide may also refer to naturally modified peptides where the modification is effected, for example, by glycosylation, acetylation, phosphorylation and similar modification which are well known in the art.
  • the peptide component is distinguished from a protein source also disclosed herein.
  • peptides may, for example, be produced recombinantly, semi-synthetically, synthetically, or obtained from natural sources such as after hydrolysation of proteins, including but not limited to casein, all according to methods known in the art.
  • molar mass distribution when used in reference to a hydrolyzed protein or protein hydrolysate pertains to the molar mass of each peptide present in the protein hydrolysate.
  • a protein hydrolysate having a molar mass distribution of greater than 500 Daltons means that each peptide included in the protein hydrolysate has a molar mass of at least 500 Daltons.
  • the peptides disclosed in Table 1 and Table 2 are derived from a protein hydrolysate having a molar mass distribution of greater than 500 Daltons.
  • a protein hydrolysate may be subjected to certain filtering procedures or any other procedure known in the art for removing peptides, amino acids, and/or other proteinaceous material having a molar mass of less than 500 Daltons.
  • any method known in the art may be used to produce the protein hydrolysate having a molar mass distribution of greater than 500 Dalton.
  • protein equivalent or “protein equivalent source” includes any protein source, such as soy, egg, whey, or casein, as well as non-protein sources, such as peptides or amino acids. Further, the protein equivalent source can be any used in the art, e.g., nonfat milk, whey protein, casein, soy protein, hydrolyzed protein, peptides, amino acids, and the like.
  • Bovine milk protein sources useful in practicing the present disclosure include, but are not limited to, milk protein powders, milk protein concentrates, milk protein isolates, nonfat milk solids, nonfat milk, nonfat dry milk, whey protein, whey protein isolates, whey protein concentrates, sweet whey, acid whey, casein, acid casein, caseinate (e.g. sodium caseinate, sodium calcium caseinate, calcium caseinate), soy bean proteins, and any combinations thereof.
  • the protein equivalent source can, in some embodiments comprise hydrolyzed protein, including partially hydrolyzed protein and extensively hydrolyzed protein.
  • the protein equivalent source may, in some embodiments, include intact protein. More particularly, the protein source may include a) about 20% to about 80% of the peptide component described herein, and b) about 20% to about 80 % of an intact protein, a hydrolyzed protein, or a combination thereof.
  • protein equivalent source also encompasses free amino acids.
  • the amino acids may comprise, but are not limited to, 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.
  • the amino acids may be branched chain amino acids.
  • small amino acid peptides may be included as the protein component of the nutritional composition. Such small amino acid peptides may be naturally occurring or synthesized.
  • Fractionation procedure includes any process in which a certain quantity of a mixture is divided up into a number of smaller quantities known as fractions. The fractions may be different in composition from both the mixture and other fractions. Examples of fractionation procedures include but are not limited to, melt fractionation, solvent
  • essential amino acid refers to an amino acid that cannot be synthesized de novo by the organism being considered or that is produced in an insufficient amount, and therefore must be supplied by diet.
  • an essential amino acid is one that cannot be synthesized de novo by a human.
  • non-essential amino acid refers to an amino acid that can be synthesized by the organism or derived by the organism from essential amino acids.
  • a non-essential amino acid is one that can be synthesized in the human body or derived in the human body from essential amino acids.
  • Milk fat globule membrane includes components found in the milk fat globule membrane including but not limited to milk fat globule membrane proteins such as Mucin 1 , Butyrophilin, Adipophilin, CD36, CD14, Lactadherin (PAS6/7), Xanthine oxidase and Fatty Acid binding proteins etc.
  • growing-up milk refers to a broad category of nutritional compositions intended to be used as a part of a diverse diet in order to support the normal growth and development of a child between the ages of about 1 and about 6 years of age.
  • “Milk” means a component that has been drawn or extracted from the mammary gland of a mammal.
  • the nutritional composition comprises components of milk that are derived from domesticated ungulates, ruminants or other mammals or any combination thereof.
  • Nutritionally complete means a composition that may be used as the sole source of nutrition, which would supply essentially all of the required daily amounts of vitamins, minerals, and/or trace elements in combination with proteins, carbohydrates, and lipids. Indeed, “nutritionally complete” describes a nutritional composition that provides adequate amounts of carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals and energy required to support normal growth and development of a subject. [0028] A nutritional composition that is "nutritionally complete” for a full term infant will, by definition, provide qualitatively and quantitatively adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for growth of the full term infant.
  • a nutritional composition that is "nutritionally complete” for a child will, by definition, provide qualitatively and quantitatively adequate amounts of all carbohydrates, lipids, essential fatty acids, proteins, essential amino acids, conditionally essential amino acids, vitamins, minerals, and energy required for growth of a child.
  • Exogenous butyrate or “dietary butyrate” each refer to butyrate or butyrate derivatives which are intentionally included in the nutritional composition of the present disclosure itself, rather than generated in the gut.
  • Endogenous butyrate or “butyrate from endogenous sources” each refer to butyrate present in the gut as a result of ingestion of the disclosed composition that is not added as such, but is present as a result of other components or ingredients of the composition; the presence of such other components or ingredients of the composition stimulates butyrate production in the gut.
  • cow's milk allergy describes a food allergy, i.e. an immune adverse reaction to one or more of the proteins contained in cow's milk in a human subject.
  • the principal symptoms are gastrointestinal, dermatological, and respiratory symptoms. These can translate into skin rashes, hives, vomiting, diarrhea, constipation and distress.
  • the clinical spectrum extends to diverse disorders: anaphylactic reactions, atopic dermatitis, wheeze, infantile colic, gastro esophageal reflux disease (GERD), esophagitis, colitis gastroenteritis, headache/migraine and constipation.
  • the nutritional composition of the present disclosure may be substantially free of any optional or selected ingredients described herein, provided that the remaining nutritional composition still contains all of the required ingredients or features described herein.
  • the term "substantially free” means that the selected composition may contain less than a functional amount of the optional ingredient, typically less than 0.1 % by weight, and also, including zero percent by weight of such optional or selected ingredient.
  • compositions of the present disclosure can comprise, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, as well as any additional or optional ingredients, components or limitations described herein or otherwise useful in nutritional compositions.
  • the present disclosure is directed to nutritional compositions including butyrate and LGG.
  • butyrate for use herein include butyric acid, butyrate salts, and glycerol esters of butyric acid.
  • the nutritional compositions may further include a carbohydrate source, a protein source, and a fat or lipid source.
  • the nutritional compositions may include a component capable of stimulating endogenous butyrate production; in other embodiments, the nutritional compositions may include both dietary and endogenous butyrate.
  • the benefit to providing both exogenous and endogenous butyrate is accelerated tolerance acquisition towards cow's milk. Additionally, the benefit to providing both exogenous and endogenous butyrate together with Lactobacillus rhamnoses GG (“LGG”) is accelerated tolerance acquisition toward cow's milk.
  • Conventional dietary management of cow's milk allergy includes the use of formulations containing protein hydrolysates and amino acids rather than intact proteins, and certain probiotics such as Lactobacillus rhamnoses GG (“LGG”), which contribute to accelerated tolerance acquisition towards cow's milk.
  • the inclusion of a component to stimulate endogenous butyrate production by the gut microbiota may further accelerate tolerance acquisition and/or may be applied as a functional replacement of LGG in a nutritional composition.
  • certain probiotics, such as LGG in combination with butyrate, either endogenous or exogenous butyrate can contribute to accelerated tolerance acquisition towards cow's milk.
  • the component for stimulating endogenous buyrate is a prebiotic comprising both polydextrose (“PDX”) and galacto-oligosaccharides (“GOS").
  • PDX polydextrose
  • GOS galacto-oligosaccharides
  • a prebiotic component including PDX and GOS can enhance endogenous butyrate production by microbiota.
  • Butyrate has epigenetic (histone deacetylase inhibition activity) that results in regulatory responses such as generation of regulatory T-cells. In the context of cow s milk allergy, these regulatory responses may result in accelerated tolerance acquisition to cow's milk protein.
  • the nutritional composition may also contain one or more other prebiotics which can exert additional health benefits, which may include, but are not limited to, selective stimulation of the growth and/or activity of one or a limited number of beneficial gut bacteria, stimulation of the growth and/or activity of ingested probiotic microorganisms, selective reduction in gut pathogens, and favorable influence on gut short chain fatty acid profile.
  • Such prebiotics may be naturally-occurring, synthetic, or developed through the genetic manipulation of organisms and/or plants, whether such new source is now known or developed later.
  • Prebiotics useful in the present disclosure may include oligosaccharides, polysaccharides, and other prebiotics that contain fructose, xylose, soya, galactose, glucose and mannose.
  • prebiotics useful in the present disclosure include PDX and GOS, and can, in some embodiments, also include, polydextrose powder, lactulose, lactosucrose, raffinose, gluco-oligosaccharide, inulin, fructo-oligosaccharide (FOS), isomalto- oligosaccharide, soybean oligosaccharides, lactosucrose, xylo-oligosaccharide (XOS), chito- oligosaccharide, manno-oligosaccharide, aribino-oligosaccharide, siallyl-oligosacoharide, fuco- oligosaccharide, and gentio-oligosaccharides.
  • polydextrose powder polydextrose powder
  • lactulose lactosucrose
  • raffinose gluco-oligosaccharide
  • inulin fructo-oligosaccharide
  • the total amount of prebiotics present in the nutritional composition may be from about 1.0 g/L to about 10.0 g/L of the composition. More preferably, the total amount of prebiotics present in the nutritional composition may be from about 2.0 g/L and about 8.0 g/L of the composition. In some embodiments, the total amount of prebiotics present in the nutritional composition may be from about 0.01 g/100 Kcal to about 1.5 g/100 Kcal. In certain embodiments, the total amount of prebiotics present in the nutritional composition may be from about 0.15 g/100 Kcal to about 1.5 g/100 Kcal. In some embodiments, the prebiotic component comprises at least 20% w/w PDX and GOS.
  • the amount of PDX in the nutritional composition may, in an embodiment, be within the range of from about 0.0 5 g/100 Kcal to about 1.5 g/100 Kcal. In another embodiment, the amount of polydextrose is within the range of from about 0.2 g/100 Kcal to about 0.6 g/100 Kcal. In some embodiments, PDX may be included in the nutritional composition in an amount sufficient to provide between about 1.0 g/L and 10.0 g/L In another embodiment, the nutritional composition contains an amount of PDX that is between about 2.0 g/L and 8.0 g/L. And in still other embodiments, the amount of PDX in the nutritional composition may be from about 0.05 g/100 Kcal to about 1.5 g/100 Kcal.
  • the prebiotic component also comprises GOS.
  • the amount of GOS in the nutritional composition may, in an embodiment, be from about 0.015 g/100 Kcal to about 1.0 g/100 Kcal. In another embodiment, the amount of GOS in the nutritional composition may be from about 0.2 g/100 Kcal to about 0.5 g/100 Kcal.
  • GOS and PDX are supplemented into the nutritional composition in a total amount of at least about 0.015 g/100 Kcal or about 0.015 g/100 Kcal to about 1.5 g/100 Kcal.
  • the nutritional composition may comprise GOS and PDX in a total amount of from about 0.1 to about 1.0 g/100 Kcal.
  • the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 5 g/100 Kcal to about 500 g/100 kcal. In some embodiments, the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 15 g/100 Kcal to about 450 g/100 kcal. In some embodiments, the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 20 g/100 Kcal to about 400 g/100 kcal. In some embodiments, the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 25 g/100 Kcal to about 350 g/100 kcal. In some embodiments, the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 30 g/100 Kcal to about 280 g/100 kcal.
  • the nutritional composition includes from about 0.01 g to about 10 g of dietary butyrate per 100 g of total fat in the nutritional composition. In some embodiments, the nutritional composition includes from about 0.1 g to about 8 g of dietary butyrate per 100 g of total fat in the nutritional composition. In some embodiments, the nutritional composition includes from about 0.4 g to about 7 g of dietary butyrate per 100 g of total fat in the nutritional composition. In some embodiments, the nutritional composition includes from about 0.7 g to about 6.5 g of dietary butyrate per 100 g of total fat in the nutritional composition. In some embodiments, the nutritional composition includes from about 1.2 g to about 5.1 g of dietary butyrate per 100 g of total fat in the nutritional composition.
  • the dietary butyrate is provided by one or more of the following: butyric acid; butyrate salts, including sodium butyrate, potassium butyrate, calcium butyrate, and/or magnesium butyrate; glycerol esters of butyric acid; and/or corresponding mixtures and corresponding salts of pharmaceutically acceptable bases or acids, pure diastereoisomeric forms and enantiomeric forms or mixtures thereof.
  • the dietary butyrate can be supplied by any suitable source known in the art.
  • Non- limiting sources of dietary butyrate includes animal source fats and derived products, such as but not limited to milk, milk fat, butter, buttermilk, butter serum, cream; microbial fermentation derived products, such as but not limited to yogurt and fermented buttermilk; and plant source derived seed oil products, such as pineapple and/or pineapple oil, apricot and/or apricot oil, barley, oats, brown rice, bran, green beans, legumes, leafy greens, apples, kiwi, oranges.
  • the dietary butyrate is synthetically produced.
  • the chemical structure of the dietary butyrate may be modified as necessary.
  • the dietary butyrate produced synthetically can be purified by any means known in the art to produce a purified dietary butyrate additive that can be incorporated into the nutritional compositions disclosed herein.
  • the dietary butyrate may be provided by dairy lipids and/or triglyceride bound forms of butyrate.
  • the dietary butyrate may be provided in an encapsulated form.
  • the encapsulation of the dietary butyrate may provide for longer shelf-stability and may provide for improved organoleptic properties of the nutritional composition.
  • the dietary butyrate may be encapsulated or coated by the use of, or combination of, fat derived materials, such as mono- and di- glycerides; sugar and acid esters of glycerides; phospholipids; plant, animal and microbial derived proteins and hydrocolloids, such as starches, maltodextrins, gelatin, pectins, glucans, caseins, soy proteins, and/or whey proteins.
  • the dietary butyric acid may also be provided in a coated form.
  • a coated form For example, coating certain glycerol esters of butyric acids and/or amide derivatives of butyric acids with fat derived materials, such as mono- and di-glycerides; sugar and acid esters of glycerides;
  • phospholipids may improve the shelf-stability of the dietary butyrate and may further improve the overall organoleptic properties of the nutritional composition.
  • the dietary butyrate comprises glycerol esters of butyric acid.
  • Glycerol esters of butyric acid may offer minimal complexity when formulated and processed in the nutritional composition. Additionally, glycerol esters of butyric acid may improve the shelf life of the nutritional composition including dietary butyrate an may further have a low impact on the sensory attributes of the finished product.
  • the dietary butyrate may comprise butyrate salts, for example, sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, and
  • dietary butyrate comprises a suitable butyrate salt that has been coated with one or more fats or lipids.
  • the nutritional composition may be a dry-powdered composition into which the dietary butyrate is incorporated.
  • the dietary butyrate may comprise any of the butyrate compounds disclosed herein that are formulated to be in complex form with chitosan or one or cyclodextrins.
  • cyclodextrins are cyclic oligosaccharides composed of six (a- cyclodextrin), seven ( ⁇ -cyclodextrin), or eight (gamma-cyclodextrin) units of a-1 ,4- glucopyranose.
  • Cyclodextrins are further characterized by a hydrophilic exterior surface and a hydrophobic core.
  • the aliphatic butyrate chain would form a complex with the cyclodextrin core, thus increasing its molecular weight and, thus, reducing the volatility of the butyrate compound. Accordingly, the bioavailability of dietary butyrate may be improved when the dietary butyrate includes butyrate
  • cyclodextrins are bulky hydrophobic molecules that are resistant to stomach acid as well as gastrointestinal enzymes, thus administration of the butyrate-cyclodextrin complex as described herein would promote absorption of the dietary butyrate in the small intestines.
  • the dietary butyrate is provided from an enriched lipid fraction derived from milk.
  • bovine milk fat has a butyric acid content that may be 20 times higher than the butyric acid content in human milk fat.
  • SCFAs short chain fatty acids
  • C4 butyric acid
  • bovine milk fat and/or enriched fractions of bovine milk fat may be included in a nutritional composition to provide dietary butyrate.
  • the enriched lipid fraction derived from milk may be produced by any number of fractionation techniques. These techniques include but are not limited to melting point fractionation, organic solvent fractionation, super critical fluid fractionation, and any variants and combinations thereof.
  • mixtures that may be subjected to the fractionation procedures to produce the enriched lipid fraction include, but are not limited to, bovine whole milk, bovine cream, caprine milk, ovine milk, yak milk, and/or mixtures thereof.
  • bovine whole milk bovine cream
  • caprine milk ovine milk
  • yak milk and/or mixtures thereof.
  • the milk mixture used to create the enriched lipid fraction is bovine milk.
  • the enriched lipid fraction may comprise an one of the following ingredients: saturated fatty acids; trans-fatty acids; branched-chain fatty acids ("BCFAs"), including odd-branched chain fatty acids (“OBCFAs”); conjugated linoleic acid (“CLA”); monounsaturated fatty acids; polyunsaturated fatty acids; cholesterol;
  • BCFAs branched-chain fatty acids
  • OBCFAs odd-branched chain fatty acids
  • CLA conjugated linoleic acid
  • monounsaturated fatty acids polyunsaturated fatty acids
  • cholesterol cholesterol
  • milk fat globule membrane including milk fat globule membrane protein.
  • the enriched lipid fraction includes, per 100 Kcal, one or more of the following: from about 0.1 g to 8.0 g of saturated fatty acids;
  • the following example illustrates a milk fat fraction having an enriched concentration of butyric acid (C4) that may be produced by a fractionation procedure.
  • AMF anhydrous milk fat
  • SCC02 super-critical carbon dioxide fraction (super olein).
  • eltFrac melt crystallization fraction separated at 10°C.
  • the PDX- and GOS-containing prebiotic and dietary butyrate is incorporated into a nutritional composition that is an infant formula.
  • infant formulas are not formulated with dietary butyrate.
  • One reason that infant formulas include little to no dietary butyrate is due to the unpleasant organoleptic properties exhibited by the nutritional composition when butyrate compounds are incorporated into the nutritional composition. For example, many butyrate compounds exhibit an odor that makes consuming the nutritional composition in which they are incorporated an unpleasant experience.
  • the pediatric and infant population will not readily consume nutritional products having an unpleasant odor, taste, and/or mouthfeel. Accordingly, there exists a need for a nutritional composition formulated for administration to a pediatric subject or an infant that provides butyrate in the gut yet does not have diminished organoleptic properties.
  • a nutritional composition formulated for administration to a pediatric subject or an infant that provides butyrate in the gut yet does not have diminished organoleptic properties.
  • the incorporation of a prebiotic to stimulate butyrate production by gut microbiota and certain dietary butyrate compounds disclosed herein, i.e. glycerol esters of butyric acid and amide derivatives of amino acids, into pediatric and infant nutritional compositions will provide butyrate while still providing a pleasant sensory experience.
  • the nutritional composition includes a protein equivalent source, wherein the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21 , SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31 , SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63.
  • the peptide component may comprise additional peptides disclosed in Table 1.
  • the composition may include at least 10 additional peptides disclosed in Table 1.
  • 20% to 80% of the protein equivalent source comprises the peptide component, and 20% to 80% of the protein equivalent source comprises an intact protein, a partially hydrolyzed protein, and combinations thereof.
  • the term additional means selecting different peptides than those enumerated.
  • 1 % to 99% of the protein equivalent source includes a peptide component comprising at least 3 peptides selected from the group consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21 , SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31 , SEQ ID NO 32, SEQ ID NO 51 , SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63, and at least 5 additional peptides selected from Table 1; and wherein 1% to 99% of the protein equivalent source comprises an intact protein, a partially hydrolyzed protein, or combinations thereof.
  • 2% to 80% of the protein equivalent source includes a peptide component comprising at least 3 peptides selected from the group
  • SEQ ID NO 4 consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51 , SEQ ID NO 57, SEQ ID NO
  • hydrolyzed protein or combinations thereof. In some embodiments 20% to 80% of the
  • protein equivalent source includes a peptide component comprising at least 3 peptides selected from the group consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63, and at least 5 additional peptides selected from Table 1 ; and wherein 20% to 80% of the protein equivalent source comprises an intact protein, a partially hydrolyzed protein, or combinations thereof.
  • Table 1 identifies the amino acid sequences of the peptides that may be
  • Table 2 below further identifies a subset of amino acid sequences from Table 1 that may be included in the peptide component disclosed herein.
  • the peptide component may be present in the nutritional composition in an amount from about 0.2 g/100 Kcal to about 5.6 g/100 Kcal. In other embodiments the peptide component may be present in the nutritional composition in an amount from about 1 g/100 Kcal to about 4 g/100 Kcal. In still other embodiments, the peptide component may be present in the nutritional composition in an amount from about 2 g/100 Kcal to about 3 g/100 Kcal.
  • the peptide component disclosed herein may be formulated with other ingredients in the nutritional composition to provide appropriate nutrient levels for the target subject.
  • the peptide component is included in a nutritionally complete formula that is suitable to support normal growth.
  • the peptide component may be provided as an element of a protein equivalent source.
  • the peptides identified in Tables 1 and 2 may be provided by a protein equivalent source obtained from cow's milk proteins, including but not limited to bovine casein and bovine whey.
  • the protein equivalent source comprises hydrolyzed bovine casein or hydrolyzed bovine whey.
  • the peptides identified in Table 1 and Table 2 may be provided by a casein hydrolysate. Such peptides may be obtained by hydrolysis or may be synthesized in vitro by methods know to the skilled person.
  • a non-limiting example of a method of hydrolysis is disclosed herein. In some embodiments, this method may be used to obtain the protein hydrolysate and peptides of the present disclosure.
  • the proteins are hydrolyzed using a proteolytic enzyme, Protease N.
  • Protease N "Amano" is commercially available from Amano Enzyme U.S.A. Co., Ltd., Elgin, III.
  • Protease N is a proteolytic enzyme preparation that is derived from the bacterial species Bacillus subtilis.
  • protease powder is specified as "not less than 150,000 units/g", meaning that one unit of Protease N is the amount of enzyme which produces an amino acid equivalent to 100 micrograms of tyrosine for 60 minutes at a pH of 7.0.
  • Protease N can be used at levels of about 0.5% to about 1.0% by weight of the total protein being hydrolyzed.
  • the protein hydrolysis by Protease N is typically conducted at a temperature of about 50° C. to about 60° C.
  • the hydrolysis occurs for a period of time so as to obtain a degree of hydrolysis between about 4% and 10%.
  • hydrolysis occurs for a period of time so as to obtain a degree of hydrolysis between about 6% and 9%.
  • hydrolysis occurs for a period of time so as to obtain a degree of hydrolysis of about 7.5%. This level of hydrolysis may take between about one half hour to about 3 hours.
  • a constant pH should be maintained during hydrolysis.
  • the pH is adjusted to and maintained between about 6.5 and 8. In a particular embodiment, the pH is maintained at about 7.0.
  • a caustic solution of sodium hydroxide and/or potassium hydroxide can be used to adjust the pH during hydrolysis. If sodium hydroxide is used to adjust the pH, the amount of sodium hydroxide added to the solution should be controlled to the level that it comprises less than about 0.3% of the total solid in the finished protein hydrolysate. A 10% potassium hydroxide solution can also be used to adjust the pH of the solution to the desired value, either before the enzyme is added or during the hydrolysis process in order to maintain the optimal pH.
  • the amount of caustic solution added to the solution during the protein hydrolysis can be controlled by a pH-stat or by adding the caustic solution continuously and proportionally.
  • the hydrolysate can be manufactured by standard batch processes or by continuous processes.
  • the hydrolysate is subjected to enzyme deactivation to end the hydrolysis process.
  • the enzyme deactivation step may consist include at heat treatment at a temperature of about 82° C. for about 10 minutes. Alternatively, the enzyme can be deactivated by heating the solution to a temperature of about 92° C, for about 5 seconds. After enzyme deactivation is complete, the hydrolysate can be stored in a liquid state at a temperature lower than 10° C.
  • the protein equivalent source comprises a hydrolyzed protein, which includes partially hydrolyzed protein and extensively hydrolyzed protein, such as casein.
  • the protein equivalent source comprises a hydrolyzed protein including peptides having a molar mass distribution of greater than 500 Daltons.
  • the hydrolyzed protein comprises peptides having a molar mass distribution in the range of from about 500 Daltons to about 1 ,500 Daltons.
  • the hydrolyzed protein may comprise peptides having a molar mass distribution range of from about 500 Daltons to about 2,000 Daltons.
  • the protein equivalent source may comprise the peptide component, intact protein, hydrolyzed protein, including partially hydrolyzed protein and/or extensively hydrolyzed protein, and combinations thereof.
  • 20% to 80% of the protein equivalent source comprises the peptide component disclosed herein.
  • 30% to 60% of the protein equivalent source comprises the peptide component disclosed herein.
  • 40% to 50% of the protein equivalent source comprises the peptide component.
  • 20% to 80% of the protein equivalent source comprises intact protein, partially hydrolyzed protein, extensively hydrolyzed protein, or combinations thereof. In some embodiments, 40% to 70% of the protein equivalent source comprises intact proteins, partially hydrolyzed proteins, extensively hydrolyzed protein, or a
  • 50% to 60% of the protein equivalent source may comprise intact proteins, partially hydrolyzed protein, extensively hydrolyzed protein, or a combination thereof.
  • the protein equivalent source comprises partially hydrolyzed protein having a degree of hydrolysis of less than 40%. In still other embodiments, the protein equivalent source may comprise partially hydrolyzed protein having a degree of hydrolysis of less than 25%, or less than 15%.
  • the nutritional composition comprises between about 1 g and about 7 g of a protein equivalent source per 100 Kcal. In other embodiments, the nutritional composition comprises between about 3.5 g and about 4.5 g of protein equivalent source per 100 Kcal.
  • the administration of a nutritional composition as disclosed herein may reduce allergic response and may improve tolerance to cow's milk allergy in certain subjects.
  • the combination of prebiotic, dietary butyrate, and the protein equivalent source provide synergistic health benefits.
  • the nutritional composition may be protein-free in some embodiments and comprise free amino acids as an element of the protein equivalent source.
  • the amino acids may be branched chain amino acids.
  • small amino acid peptides may be included as the protein component of the nutritional composition. Such small amino acid peptides may be naturally occurring or synthesized.
  • the amount of free amino acids in the nutritional composition may vary from about 1 g/100 Kcal to about 5 g/100 Kcal.
  • the protein equivalent source comprises amino acids and is substantially free of whole, intact protein. Further in certain embodiments, the protein equivalent source comprises amino acids and is substantially free of peptides. In certain embodiments, the protein equivalent source includes from about 10% to about 90% w/w of essential amino acids based on the total amino acids included in the protein equivalent source. In certain embodiments, the protein equivalent source includes from about 25% to about 75% w/w of essential amino acids based on the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 40% to about 60% of essential amino acids based on the total amino acids included in the protein equivalent source.
  • the protein equivalent source includes non-essential amino acids. In certain embodiments, the protein equivalent source includes from about 10% to about 90% w/w of non-essential amino acids based on the total amino acids included in the protein equivalent source. In certain embodiments, the protein equivalent source includes from about 25% to about 75% w/w of non-essential amino acids based on the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 40% to about 60% w/w of non-essential amino acids based on the total amino acids included in the protein equivalent source.
  • the protein equivalent source includes leucine. In some embodiments, the protein equivalent source includes from about 2% to about 15% w/w leucine per the total amount of amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 4% to about 10% w/w leucine per the total amount of amino acids included in the protein equivalent source.
  • the protein equivalent source includes lysine. In some embodiments, the protein equivalent source includes from about 2% to about 10% w/w lysine per the total amino acids included in the protein equivalent source. In some
  • the protein equivalent source includes from about 4% to about 8% w/w lysine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes valine. In some embodiments, the protein equivalent source includes from about 2% to about 15% w/w valine per the total amino acids included in the protein equivalent source. In some
  • the protein equivalent source includes from about 4% to about 10% w/w valine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes isoleucine. In some embodiments, the protein equivalent source includes from about 1% to about 8% w/w isoleucine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 7% w/w isoleucine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes threonine. In some embodiments, the protein equivalent source includes from about 1% to about 8% w/w threonine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 7% w/w threonine per the total amino acids in the protein equivalent source. [0092] In some embodiments, the protein equivalent source includes tyrosine. In some embodiments, the protein equivalent source includes from about 1% to about 8% w/w tyrosine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 7% w/w tyrosine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes phenylalanine. In some embodiments, the protein equivalent source includes from about 1% to about 8% w/w phenylalanine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 7% w/w phenylalanine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes histidine. In some embodiments, the protein equivalent source includes from about 0.5% to about 4% w/w histidine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 1.5% to about 3.5% w/w histidine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes cystine. In some embodiments, the protein equivalent source includes from about 0.5% to about 4% w/w cystine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 1.5% to about 3.5% w/w cystine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes tryptophan. In some embodiments, the protein equivalent source includes from about 0.5% to about 4% w/w tryptophan per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 1.5% to about 3.5% w/w tryptophan per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes methionine. In some embodiments, the protein equivalent source includes from about 0.5% to about 4% w/w methionine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 1.5% to about 3.5% w/w methionine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes aspartic acid. In some embodiments, the protein equivalent source includes from about 7% to about 20% w/w aspartic acid per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 10% to about 17% w/w aspartic acid per the total amino acids in the protein equivalent source. [0099] In some embodiments, the protein equivalent source includes proline. In some embodiments, the protein equivalent source includes from about 5% to about 12% w/w proline per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 7% to about 10% w/w proline per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes alanine. In some embodiments, the protein equivalent source includes from about 3% to about 10% w/w alanine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 5% to about 8% w/w alanine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes glutamate. In some embodiments, the protein equivalent source includes from about 1.5% to about 8% w/w glutamate per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 6% w/w glutamate per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes serine. In some embodiments, the protein equivalent source includes from about 1.5% to about 8% w/w serine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3% to about 5% w/w serine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes arginine. In some embodiments, the protein equivalent source includes from about 2% to about 8% w/w arginine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 3.5% to about 6% w/w arginine per the total amino acids in the protein equivalent source.
  • the protein equivalent source includes glycine. In some embodiments, the protein equivalent source includes from about 0.5% to about 6% w/w glycine per the total amino acids included in the protein equivalent source. In some embodiments, the protein equivalent source includes from about 1.5% to about 3.5% w/w glycine per the total amino acids in the protein equivalent source.
  • the nutritional composition comprises between about 1 g and about 7 g of a protein equivalent source per 100 Kcal. In other embodiments, the nutritional composition comprises between about 3.5 g and about 4.5 g of protein equivalent source per 100 Kcal.
  • the nutritional composition comprises between about 0.5 g/100 Kcal and about 2.5 g/100 Kcal of essential amino acids. In certain embodiments, the nutritional composition comprises between about 1.3 g/100 Kcal to about 1.6 Kcal of essential amino acids.
  • the nutritional composition comprises between about 0.5 g/100 Kcal and about 2.5 g/100 Kcal of essential amino acids. In certain embodiments, the nutritional composition comprises between about 1.3 g/100 Kcal to about 1.6 Kcal of nonessential amino acids.
  • the nutritional composition comprises from about 0.2 g/100 Kcal to about 0.5 g/100 Kcal of leucine. In some embodiments, the nutritional composition comprises from about 0.1 g/100 Kcal to about 0.4 g/100 Kcal of lysine. In some
  • the nutritional composition comprises from about 0.1 g/100 Kcal to about 0.4 g/100 Kcal of valine. In some embodiments, the nutritional composition comprises from about 0.08 g/100 Kcal to about 0.23 g/100 Kcal of isoleucine. In some embodiments, the nutritional composition comprises from about 0.08 g/100 Kcal to about 0.20 g/100 Kcal of threonine. In some embodiments, the nutritional composition comprises from about 0.10 g/100 Kcal to about 0.15 g/100 Kcal of tyrosine. In some embodiments, the nutritional composition comprises from about 0.05 g/100 Kcal to about 0.15 g/100 Kcal of
  • the nutritional composition comprises from about 0.01 g/100 Kcal to about 0.09 g/100 Kcal of histidine. In some embodiments, the nutritional composition comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of cystine. In some embodiments, the nutritional composition comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of tryptophan. In some embodiments, the nutritional composition comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of methionine.
  • the nutritional composition comprises from about 0.2 g/100 Kcal to about 0.7 g/100 Kcal of aspartic acid. In some embodiments, the nutritional composition comprises from about 0.1 g/100 Kcal to about 0.4 g/100 Kcal of proline. In some embodiments, the nutritional composition comprises from about 0.1 g/100 Kcal to about 0.3 g/100 Kcal of alanine. In some embodiments, the nutritional composition comprises from about 0.08 g/100 Kcal to about 0.25 g/100 Kcal of glutamate. In some embodiments, the nutritional composition comprises from about 0.08 g/100 Kcal to about 0.2 g/100 Kcal of serine.
  • the nutritional composition comprises from about 0.08 g/100 Kcal to about 0.15 g/100 Kcal of arginine. In some embodiments, the nutritional composition comprises from about 0.02 g/100 Kcal to about 0.08 g/100 Kcal of glycine.
  • the nutritional composition(s) of the present disclosure including the protein equivalent source may be administered in one or more doses daily.
  • Any orally acceptable dosage form is contemplated by the present disclosure. Examples of such dosage forms include, but are not limited to pills, tablets, capsules, soft-gels, liquids, liquid concentrates, powders, elixirs, solutions, suspensions, emulsions, lozenges, beads, cachets, and combinations thereof.
  • the protein equivalent source may provide from about 5% to about 20% of the total calories for the nutritional composition. In some embodiments, the protein equivalent source may provide from about 8% to about 12 % of the total calories for the nutritional composition.
  • the nutritional compositions including dietary butyrate, prebiotic, and the protein equivalent source disclosed herein may reduce the incidence of allergic reactions in human subjects when administered.
  • the nutritional compositions may include dietary butyrate, prebiotic, and a protein equivalent source, where the protein equivalent source is substantially free of whole and/or intact protein.
  • the protein equivalent source provides amino acids in addition to dietary butyrate, which, in combination, may further prevent allergic reaction and decrease inflammation when administered.
  • the nutritional composition(s) of the present disclosure may also comprise a carbohydrate source.
  • Carbohydrate sources can be any used in the art, e.g., lactose, glucose, fructose, corn syrup solids, maltodextrins, sucrose, starch, rice syrup solids, and the like.
  • the amount of carbohydrate in the nutritional composition typically can vary from between about 5 g and about 25 g/100 Kcal. In some embodiments, the amount of carbohydrate is between about 6 g and about 22 g/ 100 Kcal. In other embodiments, the amount of carbohydrate is between about 12 g and about 14 g/100 Kcal. In some embodiments, corn syrup solids are preferred.
  • hydrolyzed, partially hydrolyzed, and/or extensively hydrolyzed carbohydrates may be desirable for inclusion in the nutritional composition due to their easy digestibility. Specifically, hydrolyzed carbohydrates are less likely to contain allergenic epitopes.
  • Non-limiting examples of carbohydrate materials suitable for use herein include hydrolyzed or intact, naturally or chemically modified, starches sourced from corn, tapioca, rice or potato, in waxy or non-waxy forms.
  • suitable carbohydrates include various hydrolyzed starches characterized as hydrolyzed cornstarch, maltodextrin, maltose, corn syrup, dextrose, corn syrup solids, glucose, and various other glucose polymers and combinations thereof.
  • Non-limiting examples of other suitable carbohydrates include those often referred to as sucrose, lactose, fructose, high fructose corn syrup, indigestible oligosaccharides such as fructooligosaccharides and combinations thereof.
  • the nutritional composition(s) of the disclosure may also comprise a protein source.
  • the protein source can be any used in the art, e.g., nonfat milk, whey protein, casein, soy protein, hydrolyzed protein, amino acids, and the like.
  • Bovine milk protein sources useful in practicing the present disclosure include, but are not limited to, milk protein powders, milk protein concentrates, milk protein isolates, nonfat milk solids, nonfat milk, nonfat dry milk, whey protein, whey protein isolates, whey protein concentrates, sweet whey, acid whey, casein, acid casein, caseinate [e.g. sodium caseinate, sodium calcium casemate, calcium caseinate) and any combinations thereof.
  • the proteins of the nutritional composition are provided as intact proteins. In other embodiments, the proteins are provided as a combination of both intact proteins and partially hydrolyzed proteins, with a degree of hydrolysis of between about 4% and 10%. In certain other embodiments, the proteins are more completely hydrolyzed. In still other embodiments, the protein source comprises amino acids. In yet another embodiment, the protein source may be supplemented with glutamine-containing peptides.
  • the whey asein ratio of the protein source is similar to that found in human breast milk.
  • the protein source comprises from about 40% to about 80% whey protein and from about 20% to about 60% casein.
  • the nutritional composition comprises between about 1 g and about 7 g of a protein source per 100 Kcal. In other embodiments, the nutritional composition comprises between about 3.5 g and about 4.5 g of protein per 100 Kcal.
  • the nutritional composition described herein comprises a fat source.
  • the enriched lipid fraction described herein may be the sole fat source or may be used in combination with any other suitable fat or lipid source for the nutritional composition as known in the art.
  • appropriate fat sources include, but are not limited to, animal sources, e.g., milk fat, butter, butter fat, egg yolk lipid; marine sources, such as fish oils, marine oils, single cell oils; vegetable and plant oils, such as corn oil, canola oil, sunflower oil, soybean oil, palm olein oil, coconut oil, high oleic sunflower oil, evening primrose oil, rapeseed oil, olive oil, flaxseed (linseed) oil, cottonseed oil, high oleic safflower oil, palm stearin, palm kernel oil, wheat germ oil; medium chain triglyceride oils and emulsions and esters of fatty acids; and any combinations thereof.
  • the nutritional composition comprises between about 1 g/100 Kcal to about 10 g/100 Kcal of a fat or lipid source. In some embodiments, the nutritional composition comprises between about 2 g/100 Kcal to about 7 g/100 Kcal of a fat source. In other embodiments the fat source may be present in an amount from about 2.5 g/100 Kcal to about 6 g/100 Kcal. In still other embodiments, the fat source may be present in the nutritional composition in an amount from about 3 g/100 Kcal to about 4 g/100 Kcal.
  • the fat or lipid source comprises from about 10% to about 35% palm oil per the total amount of fat or lipid. In some embodiments, the fat or lipid source comprises from about 15% to about 30% palm oil per the total amount of fat or lipid. Yet in other embodiments, the fat or lipid source may comprise from about 18% to about 25 % palm oil per the total amount of fat or lipid.
  • the fat or lipid source may be formulated to include from about 2% to about 16% soybean oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 4% to about 12% soybean oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 6% to about 10% soybean oil based on the total amount of fat or lipid.
  • the fat or lipid source may be formulated to include from about 2% to about 16% coconut oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 4% to about 12% coconut oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 6% to about 10% coconut oil based on the total amount of fat or lipid.
  • the fat or lipid source may be formulated to include from about 2% to about 16% sunflower oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 4% to about 12% sunflower oil based on the total amount of fat or lipid. In some embodiments, the fat or lipid source may be formulated to include from about 6% to about 10% sunflower oil based on the total amount of fat or lipid.
  • the oils i.e. sunflower oil, soybean oil, sunflower oil, palm oil, etc. are meant to cover fortified versions of such oils known in the art.
  • the use of sunflower oil may include high oleic sunflower oil.
  • the use of such oils may be fortified with certain fatty acids, as known in the art, and may be used in the fat or lipid source disclosed herein.
  • the fat or lipid source includes an oil blend including sunflower oil, medium chain triglyceride oil, and soybean oil.
  • the fat or lipid source includes a ratio of sunflower oil to medium chain triglyceride oil of about 1 :1 to about 2:1.
  • the fat or lipid source includes a ratio of sunflower oil to soybean oil of from about 1 :1 to about 2:1.
  • the fat or lipid source may include a ratio of medium chain triglyceride oil to soybean oil of from about 1 :1 to about 2:1.
  • the fat or lipid source may comprise from about 15% to about 50% w/w sunflower oil based on the total fat or lipid content. In certain embodiments, the fat or lipid source includes from about 25% to about 40% w/w sunflower oil based on the total fat or lipid content. In some embodiments, the fat or lipid source comprises from about 30% to about 35% w/w sunflower oil based on the total fat or lipid content.
  • the fat or lipid source may comprise from about 15% to about 50% w/w medium chain triglyceride oil based on the total fat or lipid content. In certain embodiments, the fat or lipid source includes from about 25% to about 40% w/w medium chain triglyceride oil based on the total fat or lipid content. In some embodiments, the fat or lipid source comprises from about 30% to about 35% w/w medium chain triglyceride oil based on the total fat or lipid content.
  • the fat or lipid source may comprise from about 15% to about 50% w/w soybean oil based on the total fat or lipid content. In certain embodiments, the fat or lipid source includes from about 25% to about 40% w/w soybean oil based on the total fat or lipid content. In some embodiments, the fat or lipid source comprises from about 30% to about 35% w/w soybean oil based on the total fat or lipid content.
  • the nutritional composition comprises from about 1 g/100 Kcal to about 3 g/100 Kcal of sunflower oil. In some embodiments, the nutritional composition comprises from about 1.3 g/100 Kcal to about 2.5 g/100 Kcal of sunflower oil. In still other embodiments, the nutritional composition comprises from about 1.7 g/100 Kcal to about 2.1 g/100 Kcal of sunflower oil.
  • the sunflower oil as described herein may, in some
  • embodiments include high oleic sunflower oil.
  • the nutritional composition if formulated to include from about 1 g/100 Kcal to about 2.5 g/100 Kcal of medium chain triglyceride oil. In other embodiments, the nutritional composition includes from about 1.3 g/100 Kcal to about 2.1 g/100 Kcal of medium chain triglyceride oil. Still in further embodiments, the nutritional composition includes from about 1.6 g/100 Kcal to about 1.9 g/100 Kcal of medium chain triglyceride oil.
  • the nutritional composition may be formulated to include from about 1 g/100 Kcal to about 2.3 g/100 Kcal of soybean oil. In certain embodiments, the nutritional composition may be formulated to include from about 1.2 g/100 Kcal to about 2 g/100 Kcal of soybean oil. Still in certain embodiments, the nutritional composition may be formulated to include from about 1.5 g/100 Kcal to about 1.8 g/100 Kcal of soybean oil.
  • the term “sunflower oil”, “medium chain triglyceride oil”, and “soybean oil” are meant to cover fortified versions of such oils known in the art.
  • the use of sunflower oil may include high oleic sunflower oil.
  • the use of such oils may be fortified with certain fatty acids, as known in the art, and may be used in the fat or lipid source disclosed herein.
  • the fat or lipid source provides from about 35% to about 55% of the total calories of the nutritional composition. In other embodiments, the fat or lipid source provides from about 40% to about 47% of the total calories of the nutritional composition.
  • the nutritional composition may be formulated, in some embodiments, such that from about 10% to about 23 % of the total calories of the nutritional composition are provided by sunflower oil. In other embodiments, from about 13% to about 20% of the total calories in the nutritional composition may be provided by sunflower oil. Still, in other embodiments, from about 15 % to about 18% of the total calories of the nutritional composition may be provided by sunflower oil.
  • the nutritional composition may be formulated such that from about 10% to about 20% of the total calories are provided by MCT oil.
  • from about 12% to about 18% of the total calories in the nutritional composition may be provided by MCT oil. Still , in certain embodiments, from about 14% to about 17% of the calories of the nutritional composition may be provided by MCT oil.
  • the nutritional composition may be formulated such that from about 10% to 20% of the total calories of the nutritional composition are provided by soybean oil. In certain embodiments, from about 12% to about 18% of the total calories of the nutritional composition may be provided by soybean oil. In certain embodiments, from about 13% to about 16% of the total calories may be provided by soybean oil.
  • the nutritional composition may also include a source of LCPUFAs.
  • the amount of LCPUFA in the nutritional composition is advantageously at least about 5 mg/100 Kcal, and may vary from about 5 mg/100 Kcal to about 100 mg/100 Kcal, more preferably from about 10 mg/100 Kcal to about 50 mg/100 Kcal.
  • Non-limiting examples of LCPUFAs include, but are not limited to, DHA, ARA, linoleic (18:2 n-6), ⁇ -linolenic (18:3 n-6), dihomo- ⁇ -linolenic (20:3 n-6) acids in the n-6 pathway, a- linolenic (18:3 n-3), stearidonic (18:4 n-3), eicosatetraenoic (20:4 n-3), eicosapentaenoic (20:5 n-3), and docosapentaenoic (22:6 n-3).
  • the LCPUFA included in the nutritional composition may comprise DHA.
  • the amount of DHA in the nutritional composition is advantageously at least about 17 mg/100 Kcal, and may vary from about 5 mg/100 Kcal to about 75 mg/100 Kcal, more preferably from about 10 mg/100 Kcal to about 50 mg/100 Kcal.
  • the nutritional composition is supplemented with both DHA and ARA.
  • the weight ratio of ARA:DHA may be between about 1:3 and about 9:1. In a particular embodiment, the ratio of ARA:DHA is from about 1 :2 to about 4:1.
  • the DHA and ARA can be in natural form, provided that the remainder of the LCPUFA source does not result in any substantial deleterious effect on the infant.
  • the DHA and ARA can be used in refined form.
  • the disclosed nutritional composition described herein can, in some embodiments, also comprise a source of ⁇ -glucan.
  • Glucans are polysaccharides, specifically polymers of glucose, which are naturally occurring and may be found in cell walls of bacteria, yeast, fungi, and plants.
  • Beta glucans ( ⁇ -glucans) are themselves a diverse subset of glucose polymers, which are made up of chains of glucose monomers linked together via beta-type glycosidic bonds to form complex carbohydrates.
  • p-1 ,3-glucans are carbohydrate polymers purified from, for example, yeast, mushroom, bacteria, algae, or cereals.
  • Stone BA Clarke AE. Chemistry and Biology of (1-3)- Beta-Glucans. London:Portland Press Ltd; 1993.
  • the chemical structure of P-1,3-glucan depends on the source of the p-1,3-glucan.
  • various physiochemical parameters such as solubility, primary structure, molecular weight, and branching, play a role in biological activities of ⁇ -1 ,3-glucans.
  • Yadomae T. Structure and biological activities of fungal beta-1,3- glucans. Yakugaku Zasshi. 2000;120:413-431.
  • p-1 ,3-glucans are naturally occurring polysaccharides, with or without ⁇ - ⁇ , ⁇ -glucose side chains that are found in the cell walls of a variety of plants, yeasts, fungi and bacteria
  • ⁇ - 1 ,3;1,6-glucans are those containing glucose units with (1,3) links having side chains attached at the (1,6) position(s).
  • ⁇ -1 ,3;1,6 glucans are a heterogeneous group of glucose polymers that share structural commonalities, including a backbone of straight chain glucose units linked by a ⁇ -1,3 bond with ⁇ - ⁇ , ⁇ -linked glucose branches extending from this backbone.
  • yeast ⁇ -glucans have additional regions of ⁇ (1 ,3) branching extending from the ⁇ (1 , ⁇ ) branches, which add further complexity to their respective structures.
  • ⁇ -glucans derived from baker's yeast, Saccharomyces cerevislae are made up of chains of D-glucose molecules connected at the 1 and 3 positions, having side chains of glucose attached at the 1 and 6 positions.
  • Yeast-derived ⁇ -glucan is an insoluble, fiber-like, complex sugar having the general structure of a linear chain of glucose units with a ⁇ -1,3 backbone interspersed with ⁇ -1,6 side chains that are generally 6-8 glucose units in length. More specifically, ⁇ -glucan derived from baker's yeast is poly-(1,6) ⁇ -D-glucopyranosyl-(1 ,3)- ⁇ -D-glucopyranose.
  • ⁇ -glucans are well tolerated and do not produce or cause excess gas, abdominal distension, bloating or diarrhea in pediatric subjects.
  • Addition of ⁇ -glucan to a nutritional composition for a pediatric subject, such as an infant formula, a growing-up milk or another children's nutritional product, will improve the subject's immune response by increasing resistance against invading pathogens and therefore maintaining or improving overall health.
  • the ⁇ -glucan is -1,3;1,6-glucan.
  • the ⁇ - 1,3;1,6-glucan is derived from baker's yeast.
  • the nutritional composition may comprise whole glucan particle ⁇ -glucan, particulate ⁇ -glucan, PGG-glucan ( ⁇ - ⁇ , ⁇ - ⁇ -D- glucopyranosyl-1,3 ⁇ -D-glucopyranose) or any mixture thereof.
  • the amount of ⁇ -glucan in the nutritional composition is between about 3 mg and about 17 mg per 100 Kcal. In another embodiment the amount of ⁇ -glucan is between about 6 mg and about 17 mg per 100 Kcal.
  • the disclosed nutritional composition described herein can, in some embodiments, also comprise a source of probiotic.
  • probiotic means a microorganism that exerts beneficial effects on the health of the host. Any probiotic known in the art may be acceptable in this embodiment.
  • the probiotic may be selected from any Lactobacillus species, Lactobacillus rhamnosus GG (ATCC number 53103),
  • Bifidobacterium species Bifidobacterium longum BB536 (BL999, ATCC: BAA-999),
  • Bifidobacterium longum AH 1206 (NCIMB: 41382), Bifidobacterium breve AH 1205 (NCIMB: 41387), Bifidobacterium infantis 35624 (NCIMB: 41003), and Bifidobacterium animalis subsp. lactis BB-12 (DSM No. 10140) or any combination thereof.
  • the nutritional composition may comprise between about 1 x 10 4 to about 1.5 x 10 10 cfu of probiotics per 100 Kcal, more preferably from about 1 x 10 6 to about 1 x 10 9 cfu of probiotics per 100 Kcal.
  • the probiotic(s) may be viable or non-viable.
  • viable refers to live microorganisms.
  • non-viable or non-viable probiotic means non-living probiotic microorganisms, their cellular components and/or metabolites thereof. Such non-viable probiotics may have been heat-killed or otherwise inactivated, but they retain the ability to favorably influence the health of the host.
  • the probiotics useful in the present disclosure may be naturally-occurring, synthetic or developed through the genetic manipulation of organisms, whether such new source is now known or later developed.
  • the disclosed nutritional composition described herein can, in some embodiments also comprise an effective amount of iron.
  • the iron may comprise encapsulated iron forms, such as encapsulated ferrous f umarate or encapsulated ferrous sulfate or less reactive iron forms, such as ferric pyrophosphate or ferric orthophosphate.
  • vitamins and/or minerals may also be added in to the nutritional composition in amounts sufficient to supply the daily nutritional requirements of a subject. It is to be understood by one of ordinary skill in the art that vitamin and mineral requirements will vary, for example, based on the age of the child. For instance, an infant may have different vitamin and mineral requirements than a child between the ages of one and thirteen years. Thus, the embodiments are not intended to limit the nutritional composition to a particular age group but, rather, to provide a range of acceptable vitamin and mineral components.
  • the composition may optionally include, but is not limited to, one or more of the following vitamins or derivations thereof: vitamin Bi (thiamin, thiamin pyrophosphate, TPP, thiamin triphosphate, " FTP, thiamin hydrochloride, thiamin mononitrate), vitamin B 2 (riboflavin, flavin mononucleotide, FMN, flavin adenine dinucleotide, FAD, lactoflavin, ovoflavin), vitamin B3 (niacin, nicotinic acid, nicotinamide, niacinamide, nicotinamide adenine dinucleotide, NAD, nicotinic acid
  • vitamins or derivations thereof include, but is not limited to, one or more of the following vitamins or derivations thereof: vitamin Bi (thiamin, thiamin pyrophosphate, TPP, thiamin triphosphate, " FTP, thiamin hydrochloride
  • vitamin B12 mononucleotide, NicMN, pyridine-3-carboxylic acid), vitamin B3-precursor tryptophan, vitamin 6 (pyridoxine, pyridoxal, pyridoxamine, pyridoxine hydrochloride), pantothenic acid (pantothenate, panthenol), folate (folic acid, folacin, pteroylg!utamic acid), vitamin B12
  • vitamin C (ascorbic acid), vitamin A (retinol, retinyl acetate, retinyl palmitate, retinyl esters with other long-chain fatty acids, retinal, retinoic acid, retinol esters), vitamin D (calciferol, cholecalciferol, vitamin D 3 , 1,25,-dihydroxyvitamin D), vitamin E (a- tocopherol, a-tocopherol acetate, a-tocopherol succinate, ⁇ -tocopherol nicotinate, a- tocopherol), vitamin K (vitamin Ki, phylloquinone, naphthoquinone, vitamin 2, menaquinone- 7, vitamin K3, menaquinone-4, menadione, menaquinone
  • the composition may optionally include, but is not limited to, one or more of the following minerals or derivations thereof: boron, calcium, calcium acetate, calcium gluconate, calcium chloride, calcium lactate, calcium phosphate, calcium sulfate, chloride, chromium, chromium chloride, chromium picolonate, copper, copper sulfate, copper gluconate, cupric sulfate, fluoride, iron, carbonyl iron, ferric iron, ferrous fumarate, ferric orthophosphate, iron trituration, polysaccharide iron, iodide, iodine, magnesium, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium stearate, magnesium sulfate.
  • minerals or derivations thereof boron, calcium, calcium acetate, calcium gluconate, calcium chloride, calcium lactate, calcium phosphate, calcium sulfate, chloride, chromium, chromium chloride, chromium picolo
  • Non-limiting exemplary derivatives of mineral compounds include salts, alkaline salts, esters and chelates of any mineral compound.
  • the minerals can be added to growing-up milks or to other children's nutritional compositions in the form of salts such as calcium phosphate, calcium glycerol phosphate, sodium citrate, potassium chloride, potassium phosphate, magnesium phosphate, ferrous sulfate, zinc sulfate, cupric sulfate, manganese sulfate, and sodium selenite. Additional vitamins and minerals can be added as known within the art.
  • the nutritional compositions of the present disclosure may optionally include one or more of the following flavoring agents, including, but not limited to, flavored extracts, volatile oils, cocoa or chocolate flavorings, peanut butter flavoring, cookie crumbs, vanilla or any commercially available flavoring.
  • flavoring agents including, but not limited to, flavored extracts, volatile oils, cocoa or chocolate flavorings, peanut butter flavoring, cookie crumbs, vanilla or any commercially available flavoring.
  • useful flavorings include, but are not limited to, pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, honey, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or vanilla extract; or volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, cherry oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch, toffee, and mixtures thereof.
  • the amounts of flavoring agent can vary greatly depending upon the flavoring agent used. The type and amount of flavoring agent can be selected as is known in the art.
  • the nutritional compositions of the present disclosure may optionally include one or more emulsifiers that may be added for stability of the final product.
  • suitable emulsifiers include, but are not limited to, lecithin ⁇ e.g., from egg or soy), alpha lactalbumin and/or mono- and di-glycerides, and mixtures thereof.
  • Other emulsifiers are readily apparent to the skilled artisan and selection of suitable emulsifier(s) will depend, in part, upon the formulation and final product.
  • the nutritional compositions of the present disclosure may optionally include one or more preservatives that may also be added to extend product shelf life.
  • Suitable preservatives include, but are not limited to, potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate, calcium disodium EDTA, and mixtures thereof.
  • the nutritional compositions of the present disclosure may optionally include one or more stabilizers.
  • Suitable stabilizers for use in practicing the nutritional composition of the present disclosure include, but are not limited to, gum arabic, gum ghatti, gum karaya, gum tragacanth, agar, furcellaran, guar gum, gellan gum, locust bean gum, pectin, low methoxyl pectin, gelatin, microcrystalline cellulose, CMC (sodium carboxymethylcellulose), methylcellulose hydroxypropyl methyl cellulose, hydroxypropyl cellulose, DATEM (diacetyl tartaric acid esters of mono- and diglycerides), dextran, carrageenans, and mixtures thereof.
  • the nutritional compositions of the disclosure may provide minimal, partial or total nutritional support.
  • the compositions may be nutritional supplements or meal replacements.
  • the compositions may, but need not, be nutritionally complete.
  • the nutritional composition of the disclosure is nutritionally complete and contains suitable types and amounts of lipid, carbohydrate, protein, vitamins and minerals.
  • the amount of lipid or fat typically can vary from about 1 to about 25 g/100 Kcal.
  • the amount of protein typically can vary from about 1 to about 7 g/100 Kcal.
  • the amount of carbohydrate typically can vary from about 6 to about 22 g/100 Kcal.
  • the children's nutritional composition may contain between about 10 and about 50% of the maximum dietary recommendation for any given country, or between about 10 and about 50% of the average dietary recommendation for a group of countries, per serving of vitamins A, C, and E, zinc, iron, iodine, selenium, and choline.
  • the children's nutritional composition may supply about 10 - 30% of the maximum dietary recommendation for any given country, or about 10 - 30% of the average dietary recommendation for a group of countries, per serving of B-vitamins.
  • the levels of vitamin D, calcium, magnesium, phosphorus, and potassium in the children's nutritional product may correspond with the average levels found in milk.
  • other nutrients in the children's nutritional composition may be present at about 20% of the maximum dietary recommendation for any given country, or about 20% of the average dietary recommendation for a group of countries, per serving.
  • the nutritional composition is an infant formula.
  • Infant formulas are fortified nutritional compositions for an infant.
  • the content of an infant formula is dictated by federal regulations, which define macronutrient, vitamin, mineral, and other ingredient levels in an effort to simulate the nutritional and other properties of human breast milk.
  • Infant formulas are designed to support overall health and development in a pediatric human subject, such as an infant or a child.
  • the nutritional composition of the present disclosure is a growing-up milk.
  • Growing-up milks are fortified milk-based beverages intended for children over 1 year of age (typically from 1-3 years of age, from 4-6 years of age or from 1-6 years of age). They are not medical foods and are not intended as a meal replacement or a supplement to address a particular nutritional deficiency. Instead, growing-up milks are designed with the intent to serve as a complement to a diverse diet to provide additional insurance that a child achieves continual, daily intake of all essential vitamins and minerals, macronutrients plus additional functional dietary components, such as non-essential nutrients that have purported health-promoting properties.
  • composition of a growing-up milk or other nutritional composition according to the present disclosure can vary from market-to-market, depending on local regulations and dietary intake information of the population of interest.
  • nutritional compositions according to the disclosure consist of a milk protein source, such as whole or skim milk, plus added sugar and sweeteners to achieve desired sensory properties, and added vitamins and minerals.
  • the fat composition includes an enriched lipid fraction derived from milk.
  • Total protein can be targeted to match that of human milk, cow milk or a lower value.
  • Total carbohydrate is usually targeted to provide as little added sugar, such as sucrose or fructose, as possible to achieve an acceptable taste.
  • Vitamin A, calcium and Vitamin D are added at levels to match the nutrient contribution of regional cow milk.
  • vitamins and minerals can be added at levels that provide approximately 20% of the dietary reference intake (DRI) or 20% of the Daily Value (DV) per serving.
  • nutrient values can vary between markets depending on the identified nutritional needs of the intended population, raw material contributions and regional regulations.
  • the disclosed nutritional composition(s) may be provided in any form known in the art, such as a powder, a gel, a suspension, a paste, a solid, a liquid, a liquid concentrate, a reconstituteable powdered milk substitute or a ready-to-use product.
  • the nutritional composition may, in certain embodiments, comprise a nutritional supplement, children's nutritional product, infant formula, human milk fortifier, growing-up milk or any other nutritional composition designed for an infant or a pediatric subject.
  • compositions of the present disclosure include, for example, orally-ingestible, health- promoting substances including, for example, foods, beverages, tablets, capsules and powders.
  • the nutritional composition of the present disclosure may be standardized to a specific caloric content, it may be provided as a ready-to-use product, or it may be provided in a concentrated form.
  • the nutritional composition is in powder form with a particle size in the range of 5 ⁇ to 1500 m, more preferably in the range of 10 ⁇ to 300 ⁇ .
  • the nutritional compositions of the present disclosure may be provided in a suitable container system.
  • suitable container systems include plastic containers, metal containers, foil pouches, plastic pouches, multi-layered pouches, and combinations thereof.
  • the nutritional composition may be a powdered composition that is contained within a plastic container.
  • the nutritional composition may be contained within a plastic pouch located inside a plastic container.
  • the nutritional compositions described herein advantageously reduce the incidence of allergic reaction and improve tolerance to cow's milk allergy in a subject. Further, in some embodiments, the nutritional compositions advantageously reduce the inflammatory response caused by allergy in a subject. Accordingly, the disclosure relates to methods of improving tolerance to cow's milk allergy in a subject. Further, the disclosure relates to methods of reducing the incidence of allergic reaction and reducing the inflammatory response caused by allergy in a subject via administration of the nutritional compositions including PDX GOS and dietary butyrate as disclosed herein.
  • the method comprises the step of subjecting the target subject to cow's milk and then providing the nutritional composition disclosed herein including PDX/GOS and dietary butyrate to the target subject.
  • the target subject may be provided with a nutritional composition that includes PDX/GOS and dietary butyrate and a protein equivalent source as disclosed herein.
  • the target subject after being exposed to cow's milk or other allergen, may be administered a nutritional composition comprising PDX/GOS and dietary butyrate, and a protein equivalent source.
  • the protein equivalent source may be substantially free of whole and/or intact protein.
  • the protein equivalent source may comprise hydrolyzed protein, amino acids, the peptide component disclosed herein, and combinations thereof.
  • the nutritional composition includes a protein equivalent source includes amino acids and no hydrolyzed or whole/intact protein.
  • the target subject is not subjected to cow's milk or an allergen prior to administration of the nutritional composition.
  • the method is directed to reducing allergic response in a target subject via providing the nutritional compositions disclosed herein including dietary butyrate to the target subject, and subsequently exposing the target subject to cow's milk or other allergen.
  • the nutritional compositions described herein advantageously reduce the inflammatory response in a subject. Accordingly, the disclosure relates to methods of reducing a proinflammatory response in a subject by administering to a subject a nutritional composition containing the protein equivalent source described herein in combination with PDX/GOS and dietary butyrate. For example, the present methods may reduce the production of proinflammatory cytokines in a subject.
  • the method for reducing an inflammatory response in a subject comprises administering to a subject a nutritional composition comprising a carbohydrate source, a protein equivalent source, fat source, PDX/GOS and dietary butryate, wherein the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21 , SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63.
  • the peptide component may comprise additional peptides disclosed in Table 1.
  • the composition may include at least 10 additional peptides disclosed in Table 1.
  • 20% to 80% of the protein equivalent source comprises the peptide component
  • 20% to 80% of the protein equivalent source comprises an intact protein, a partially hydrolyzed protein, and combinations thereof.
  • the method comprises administering to a subject a nutritional composition, wherein 20% to 80% of the protein equivalent source includes a peptide component comprising at least 3 peptides selected from the group consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63, and at least 5 additional peptides selected from Table 1; and wherein 20% to 80% of the protein equivalent source comprises an intact protein, a partially hydrolyzed protein, or combinations thereof.
  • the protein equivalent source includes a peptide component comprising at least 3 peptides selected from the group consisting of SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO
  • the method for reducing the inflammatory response includes providing a nutritional composition comprising a peptide component from Table 1, wherein the peptide component is derived from a casein hydrolysate having a molar mass distribution of greater than 500 Daltons. In some embodiments, the molar mass distribution of the casein hydrolysate is in a range of 500 to 2000 Daltons. In other embodiments, the method for reducing the inflammatory response includes providing a nutritional composition comprising the peptide component described herein, wherein the peptide component is derived from a casein hydrolysate that does not include peptides having a molar mass distribution of less than 200 Daltons.
  • the target subject may be a pediatric subject.
  • the nutritional composition provided to the pediatric subject may be an infant formula.
  • the peptide component identified herein, PDX/GOS and dietary butyrate as disclosed herein may be added to the infant formula and, further, each may be selected from a specific source and concentrations thereof may be adjusted to maximize health benefits.
  • the nutritional composition comprising the peptide component disclosed herein, PDX/GOS and dietary butyrate is a growing up milk.
  • the nutritional composition is an infant formula
  • composition may advantageously reduce a pro-inflammatory response in the infant, and thereby reduce the incidence of inflammatory disease. Moreover, the reduction in inflammatory disease may last throughout childhood and into adulthood. Similarly, when the nutritional composition is a growing-up milk, a child who ingests the growing-up milk may experience a reduction in the incidence of inflammatory disease in adulthood, as well as during childhood.
  • the disclosure is directed to a method for improving the absorption of butyrate in a target subject by providing or administering the nutritional compositions disclosed herein including PDX/GOS and dietary butyrate to the target subject.
  • the target subject is a pediatric subject or an infant.
  • the nutritional composition is an infant formula or a growing-up milk.
  • compositions of the present disclosure can comprise, consist of, or consist essentially of the essential elements and limitations of the embodiments described herein, as well as any additional or optional ingredients, components or limitations described herein or otherwise useful in nutritional compositions.
  • Table 3 provides an example embodiment of a peptide component including 8 peptides from Tablel .
  • Table 4 provides an example embodiment of a peptide component including certain peptides from Table 1.
  • Table 2 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 2 are based on a weight-to-weight percentage based on the total amino acids in the protein equivalent source.
  • Table 2 Example protein equivalent source
  • Table 3 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 3 are based on a weight-to-weight percentage based on the total amino acids in the protein equivalent source.
  • Table 4 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 4 are based on grams per 100 Kcal of the nutritional composition.
  • Table 5 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 5 are based on grams per 100 Kcal of the nutritional composition.
  • Table 6 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 6 are based on grams per 100 Kcal of the nutritional composition.
  • Table 7 provides an example embodiment of a protein equivalent source that may be included in the nutritional compositions disclosed herein.
  • the amounts of amino acids disclosed in Table 7 are based on grams per 100 Kcal of the nutritional composition.
  • Table 8 illustrated below, provides an example embodiment of the nutritional profile of a nutritional composition including PDX/GOS and dietary butyrate and describes the amount of each ingredient to be included per 100 Kcal serving of nutritional composition.
  • Table 8 Nutrition profile of an example nutritional composition including dietary butyrate
  • Lactobacillus rhamnosus GG (cf u) 1x10 4 1.5x10 12
  • Vitamin A 9.60 x TO 5 3.80 x 10 8

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Abstract

L'invention concerne des compositions nutritionnelles comprenant un composant destiné à stimuler la production de butyrate dans l'intestin humain et/ou un butyrate alimentaire. L'invention concerne en outre des procédés de réduction de réaction allergique et d'augmentation de la tolérance à l'allergie au lait de vache chez un sujet pédiatrique par apport desdites compositions nutritionnelles à un sujet cible.
PCT/US2016/057646 2015-11-09 2016-10-19 Compositions nutritionnelles comprenant un hydrolysat de caséine, ainsi que du butyrate alimentaire et/ou un composé pour stimuler la formation de butyrate endogène WO2017083069A1 (fr)

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SG11201803123PA SG11201803123PA (en) 2015-11-09 2016-10-19 Nutritional compositions comprising a casein hydrolysate, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrate
CA3004740A CA3004740A1 (fr) 2015-11-09 2016-10-19 Compositions nutritionnelles comprenant un hydrolysat de caseine, ainsi que du butyrate alimentaire et/ou un compose pour stimuler la formation de butyrate endogene
CN201680065416.9A CN108347984A (zh) 2015-11-09 2016-10-19 包含酪蛋白水解物以及膳食丁酸和/或用于刺激内源性丁酸形成的化合物的营养组合物
AU2016351456A AU2016351456B2 (en) 2015-11-09 2016-10-19 Nutritional compositions comprising a casein hydrolysate, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrate
JP2018523445A JP2018537084A (ja) 2015-11-09 2016-10-19 カゼイン加水分解物並びに食品酪酸塩および／または内因性酪酸塩の形成を刺激するための化合物を含む栄養組成物
BR112018008040A BR112018008040A2 (pt) 2015-11-09 2016-10-19 composição nutricional compreendendo um hidrolisado de caseína, bem como um butirato dietético e/ou um composto para estimular a formação de butirato endógeno
EP16790819.3A EP3373748A1 (fr) 2015-11-09 2016-10-19 Compositions nutritionnelles comprenant un hydrolysat de caséine, ainsi que du butyrate alimentaire et/ou un composé pour stimuler la formation de butyrate endogène
MX2018005663A MX2018005663A (es) 2015-11-09 2016-10-19 Composiciones nutricionales que comprenden un hidrolizado de caseina, asi como butirato alimenticio y/o un compuesto para estimular la formacion de butirato endogeno.
PH12018500992A PH12018500992A1 (en) 2015-11-09 2018-05-08 Nutritional compositions comprising a casein hydrolysate, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrate
HK18115346.9A HK1256282A1 (zh) 2015-11-09 2018-11-30 包含酪蛋白水解物以及膳食丁酸和/或用於刺激內源性丁酸形成的化合物的營養組合物
AU2020257046A AU2020257046B2 (en) 2015-11-09 2020-10-20 Nutritional compositions comprising a casein hydrolysate, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrate

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US14/936,014 US20170127693A1 (en) 2015-11-09 2015-11-09 Nutritional compositions containing butyrate and uses thereof
US14/936,014 2015-11-09
US14/959,107 US10034937B2 (en) 2015-12-04 2015-12-04 Synergistic nutritional compositions and uses thereof
US14/959,107 2015-12-04
US15/011,797 2016-02-01
US15/011,797 US20170215464A1 (en) 2016-02-01 2016-02-01 Nutritional compositions containing dietary butyrate and uses thereof

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PCT/US2016/057641 WO2017083067A1 (fr) 2015-11-09 2016-10-19 Compositions nutritionnelles contenant du butyrate et utilisations de celles-ci
PCT/US2016/057646 WO2017083069A1 (fr) 2015-11-09 2016-10-19 Compositions nutritionnelles comprenant un hydrolysat de caséine, ainsi que du butyrate alimentaire et/ou un composé pour stimuler la formation de butyrate endogène

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PCT/US2016/057641 WO2017083067A1 (fr) 2015-11-09 2016-10-19 Compositions nutritionnelles contenant du butyrate et utilisations de celles-ci

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RU2809650C2 (ru) * 2018-12-21 2023-12-14 Сосьете Де Продюи Нестле С.А. Пищевой бутират для лечения или профилактики аллергического расстройства

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JP2018537441A (ja) 2018-12-20
PH12018500993A1 (en) 2018-11-12
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AU2016351456B2 (en) 2020-09-17
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CN108347986A (zh) 2018-07-31
BR112018008726A2 (pt) 2018-10-30
CN108347985A (zh) 2018-07-31
WO2017083068A1 (fr) 2017-05-18
BR112018008833A2 (pt) 2018-11-06
CN108347984A (zh) 2018-07-31
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AU2016351455A1 (en) 2018-05-10
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EP3373747A1 (fr) 2018-09-19
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