EP3373747A1 - Nutritional compositions comprising lactobacillus rhamnosus gg, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrate - Google Patents
Nutritional compositions comprising lactobacillus rhamnosus gg, as well as dietary butyrate and/or a compound for stimulating formation of endogenous butyrateInfo
- Publication number
- EP3373747A1 EP3373747A1 EP16790818.5A EP16790818A EP3373747A1 EP 3373747 A1 EP3373747 A1 EP 3373747A1 EP 16790818 A EP16790818 A EP 16790818A EP 3373747 A1 EP3373747 A1 EP 3373747A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nutritional composition
- seq
- butyrate
- protein
- milk
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 title claims abstract description 101
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- 239000011655 sodium selenate Substances 0.000 description 1
- 235000018716 sodium selenate Nutrition 0.000 description 1
- 229960001881 sodium selenate Drugs 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019710 soybean protein Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 235000019722 synbiotics Nutrition 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 235000008170 thiamine pyrophosphate Nutrition 0.000 description 1
- YXVCLPJQTZXJLH-UHFFFAOYSA-N thiamine(1+) diphosphate chloride Chemical compound [Cl-].CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N YXVCLPJQTZXJLH-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 235000015149 toffees Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000014393 valine Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019160 vitamin B3 Nutrition 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940045999 vitamin b 12 Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 229940041603 vitamin k 3 Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 235000020255 yak milk Nutrition 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000021241 α-lactalbumin Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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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
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- 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
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- 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 LACTOBACILLUS RHAMNOSUS GG, AS WELL AS DIETARY BUTYRATE AND/OR A COMPOUND FOR STIMULATING
- the present disclosure relates generally to nutritional compositions comprising a combination of polydextrose (“PDX”), galacto-o!igosaccharides (“GOS”), and
- Lactobacillus rhamnosus GG (“LGG”) or compositions comprising LGG and a source of dietary butyrate.
- the nutritional compositions are suitable for administration to pediatric subjects. Further, disclosed are methods for reducing risk for allergic
- compositions disclosed herein may provide additive and or/synergis ⁇ ic beneficial health effects.
- Food allergies such as allergy to cow's milk protein, soy protein, rice protein and peanuts, are being recognized as an increasing problem.
- Cow's milk protein allergy (“CMA”) is the most common food allergy in early childhood and affects 2-3% of young children with a range of immunoglobulin (Ig-E) and non Ig-E mediated syndromes.
- Food allergies continue to be a growing health concern with an increasing prevalence and severity, potential increase of atopic disease in later life, risk of persistence, and functional gastrointestinal disorders. Thus, there is a strong need to develop effective methods for supporting resistance to such allergies.
- the first step of treatment of CMA is the rapid resolution of symptoms, with elimination of cow's milk protein from the diet being the only proven treatment. While certain hydrolyzed protein formulas have been used to avoid CMA, there is a need for nutritional compositions, especially for infants, including components that are capable of further accelerating tolerance acquisition to cow's milk.
- compositions that accelerate tolerance to cow's milk allergy. Further provided are compositions for the dietary management of food allergies.
- the present disclosure is directed, in an embodiment, to a nutritional composition that includes a synbiotic combination of a prebiotic composition comprising PDX and GOS in combination with LGG. Additionally, the disclosure provides, in an embodiment, a nutritional composition comprising dietary butyrate and LGG.
- the nutritional compositions include a component which can stimulate the production of endogenous short chain fatty acid ("SCFA") including butyrate in the human gut.
- SCFA short chain fatty acid
- the dietary butyrate may be provided directly by nutrition in the form of encapsulated butyrate or enriched lipid fractions from milk.
- the present disclosure further provides methods for accelerating tolerance to cow's milk allergy in a target subject via administering the nutritional compositions disclosed herein to the target subject. Further provided are methods for the dietary management of allergy, such as cow's milk allergy, via administering the nutritional composition disclosed herein to the target subject.
- the present disclosure reiates generaiiy to nutritional compositions comprising dietary butyrate and a probiotic comprising LGG.
- nutritional compositions comprising a prebiotic comprising PDX and GOS and LGG. Additionally, the disclosure reiates to methods for accelerating tolerance to cow's milk allergy or methods for the dietary management of allergy in target subjects.
- ''Allergy as used herein is defined as an "abnormal hypersensitivity to a substance which is normally tolerated and generally considered harmless.”
- the first stage involves the development of the early phase of an immediate-type hypersensitivity response to allergens. The first time an aliergen meets the immune system, no allergic reaction occurs. Instead, the immune system prepares itself for future encounters with the allergen. Macrophages, which are scavenger ceils, surround and break up the invading allergen. The macrophages then display the allergen fragments on their ceil wails to T lymphocytes, which are the main orchestrators of the body's immune reaction. This cognitive signai plus several non-cognitive signals (e.g.
- cytokines activate the ndf ' ve T-ceiis and instruct the T-celi differentiation into T-ceil effector subpopulations.
- the key players in the allergic cascade are T-ceils of the Th-2 phenotype (TH-2).
- TH-2 type T-cells are characterized by the secretion of several cytokines including in ⁇ erleukin-4 (!L-4), IL-5 and IL-13.
- the cytokines IL-4 and IL-13 then activate B lymphocytes which produce antibodies of the subclass E (IgE).
- IgE antibodies are directed against the particular aliergen.
- the interaction of specific !gE antibodies on the surface of effector cells (mast cells and basophils) with an allergen triggers the early phase of immediate type hypersensitivity responses.
- This mast cell activation usually occurs within minutes after the second exposure to an allergen.
- IgE antibodies on mast ceils constructed during the sensitization phase, recognize the allergen and bind to the invader. Once the aiiergen is bound to the receptor, granules in the mast cells release their contents.
- These contents, or mediators are proinflammatory substances such as histamine, platelet-activating factor, prostagiandins, cytokines and ieukotrienes. These mediators actually trigger the allergy attack. Histamine stimulates mucus production and causes redness, swelling, and inflammation. Prostaglandins constrict airways and enlarge blood vessels.
- the second phase of the allergic immune response is characterized by infiltration of inflammatory cells, such as eosinophils, into the airways after an aliergen exposure.
- inflammatory cells such as eosinophils
- An important linkage between sensitization and inflammation is represented by T-celis that secrete mediators not only involved in IgE synthesis, but also responsible for eosinophil recruitment, activation and survival.
- the tissue mast cells and neighboring cells produce chemical messengers that signal circulating basophils, eosinophils, and other cells to migrate into that tissue and help fight the foreign material.
- Eosinophils secrete chemicals of their own that sustain inflammation, cause tissue damage, and recruit yet more immune cells.
- This phase can occur anywhere between several hours and several days after the allergen exposure and can last for hours and even days.
- 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.
- 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 fuilterm) 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 ] 2 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 bom before the end of the 37 th week of gestation.
- Full term means an infant born after the end of the 37 ih 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 seienocysteine.
- peptide may also refer to naturally modified peptides where the modification is effected, for example, by giycosylation, 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, in certain other embodiments, 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 fractionation, supercritical fluid fractionation and/or combinations thereof.
- 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. Additionally, “milk fat globule membrane” may include phospholipids, cerebrosides, gangiiosides, sphingomyelins, and/or cholesterol.
- milk fat globule membrane may include phospholipids, cerebrosides, gangiiosides, sphingomyelins, and/or cholesterol.
- growing-up milk refers to a broad category of nutritional
- “Milk” means a component that has been drawn or extracted from the mammary giand 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.
- 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
- 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 (GE D),
- Probiotic means a microorganism with low or no pathogenicity that exerts a beneficial effect on the health of the host.
- non-viable probiotic means a probiotic wherein the metabolic activity or reproductive ability of the referenced probiotic has been reduced or destroyed. More specifically, “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.
- the "nonviable probiotic” does, however, still retain, at the cellular level, its ceil structure or other structure associated with the cell, for example exopolysaccharide and at least a portion its biological glycol-protein and DNA/RNA structure and thus retains the ability to favorably influence the health of the host. Contrariwise, the term “viable” refers to live microorganisms. As used herein, the term “non-viable” is synonymous with
- Prebiotic means a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the digestive tract that can improve the health of the host.
- 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, glycerol esters of butyric acid, and combinations thereof.
- 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.
- LGG Lactobacillus r amnoses GG
- 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/ 00 kcal. In some embodiments, the nutritional composition includes a source of dietary butyrate that is present in an amount of from about 1 5 g/ 00 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 cal 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
- 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
- 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.
- 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
- 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
- the dietary butyrate is synthetically produced, in embodiments where 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. In certain embodiments, 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.
- 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; plant, animal and microbial derived proteins and hydrocolloids, such as starches, maltodextrins, gelatin, pectins, glucans, caseins, soy proteins, and/or whey proteins 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 alkyl, and or 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 combinations thereof.
- the use of selected dietary butyrate salts may improve intestinal health when provided to target subjects.
- 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 cyciodextrins.
- cyciodextrins are cyclic oligosaccharides composed of six (a-cyc!odex ⁇ rin), seven ( ⁇ -cyclodextrin), or eight (gamma- cyclodextrin) units of a- l ,4-glucopyranose. Cyciodextrins 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 compounds in complex form with one or more cyciodextrins. Further, cyciodextrins are bulky hydrophobic molecules that are resistant to stomach acid as well as gastrointestinal enzymes, thus
- 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 miik 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 miik 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.
- the milk mixture used to create the enriched lipid fraction is bovine miik.
- 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 linoieic acid (“CLA”); monounsaturated fatty acids;
- the enriched lipid fraction includes, per 100 Kcal, more of the following:
- the following example illustrates a milk fat fraction having an enriched concentration of butyric acid (C4) that may be produced by a fractionation procedure.
- lipid profile of fractionated miik fat produced by su critical carbon extraction fractionation procedure and by melt-fractionation.
- AMF anhydrous milk fat
- SCC02 super-critical carbon dioxide fraction (super olein).
- MeltFrac melt crystallization fraction separated at 10°C.
- the nutritional composition of the present disclosure also includes at least one probiotic; in a preferred embodiment, the probiotic comprises LGG.
- the probiotic may be selected from any other Lactobacillus species.
- Bifidobacterium species Bifidobacterium longum BB536 (BL999, ATCC: BAA-999), Bifidobacterium longum AH 1 206 (NCIMB: 41 382), Bifidobacterium breve AH 1 205 (NCIMB: 41 387), Bifidobacterium infantis 35624 (NCIMB: 41003), and Bifidobacterium animaiis subsp. lactis BB-12 (DSM No. 10140) or any combination thereof.
- the amount of the probiotic may vary from about 1 x 10 4 to about 1 .5 x 10 12 cfu of probiotic(s) per 100 kca!. In some embodiments the amount of probiotic may be from about 1 x 10 6 to about 1 x 10 9 cfu of probiotic (s) per 100 kcal. In certain other embodiments the amount of probiotic may vary from about 1 x 10 7 cfu/ 100 kcal to about 1 x 10 8 cfu of probiotic (s) per 100 kcal.
- the probiotic comprises LGG.
- LGG is a probiotic strain isolated from healthy human intestinal flora. It was disclosed in U.S. Patent No. 5,032,399 to Gorbach, et a/. , which is herein incorporated in its entirety, by reference thereto. LGG is resistant to most antibiotics, stable in the presence of acid and bile, and attaches avidly to mucosal cells of the human intestinal tract. It survives for 1 -3 days in most individuals and up to 7 days in 30% of subjects. In addition to its colonization ability, LGG also beneficially affects mucosa! immune responses. LGG is deposited with the depository authority American Type Culture Collection ("ATCC”) under accession number ATCC 53103.
- ATCC American Type Culture Collection
- the probiotic(s) may be viable or non-viable.
- the probiotics useful in the present disclosure may be naturaliy-occurring, synthetic or developed through the genetic manipulation of organisms, whether such source is now known or later developed.
- the nutritional composition may include a source comprising probiotic cell equivalents, which refers to the level of non-viable, non- replicating probiotics equivalent to an equal number of viable cells.
- probiotic cell equivalents refers to the level of non-viable, non- replicating probiotics equivalent to an equal number of viable cells.
- the term ''non- replicating is to be understood as the amount of non-replicating microorganisms obtained from the same amount of replicating bacteria (cfu/g), including inactivated probiotics, fragments of DNA, cell wall or cytoplasmic compounds.
- the quantity of non-living, non-replicating organisms is expressed in terms of cfu as if all the microorganisms were alive, regardless whether they are dead, non-replicating, inactivated, fragmented etc.
- the amount of the probiotic cell equivalents may vary from about 1 x 10 4 to about 1 .5 x 10 so cell equivalents of probiotic(s) per 100 kcai. In some embodiments the amount of probiotic cell equivalents may be from about 1 x 10* to about 1 x 10 9 cell equivalents of probiotic (s) per 100 kcai nutritional composition, in certain other embodiments the amount of probiotic cell equivalents may vary from about 1 x 10 7 to about 1 x T O 8 cell equivalents of probiotic(s) per 100 kcai of nutritional composition.
- the probiotic source incorporated into the nutritional composition may comprise both viable colony-forming units, and non-viable cell- equivalents.
- probiotics may be helpful in pediatric patients, the administration of viable bacteria to pediatric subjects, and particularly preterm infants, with impaired intestinal defenses and immature gut barrier function may not be feasible due to the risk of bacteremia. Therefore, there is a need for compositions that can provide the benefits of probiotics without introducing viable bacteria into the intestinal tract of pediatric subjects
- a culture supernatant from batch cultivation of a probiotic, and in particular embodiments, LGG provides beneficial gastrointestinal benefits. It is further believed that the beneficial effects on gut barrier function can be attributed to the mixture of components (including proteinaceous materials, and possibly including (exo)poiysaccharide materials) that are released into the culture medium at a late stage of the exponential (or "log") phase of batch cultivation of LGG.
- the composition will be hereinafter referred to as "culture supernatant.”
- the nutritional composition includes a culture supernatant from a late-exponential growth phase of a probiotic batch- cultivation process.
- the activity of the culture supernatant can be attributed to the mixture of components (including proteinaceous materials, and possibly including (exo)poiysaccharide materials) as found released into the culture medium at a late stage of the exponential (or "log") phase of batch cultivation of the probiotic.
- culture supernatant includes the mixture of components found in the culture medium. The stages recognized in batch cultivation of bacteria are known to the skilled person.
- a culture supernatant is obtainable by a process comprising the steps of (a) subjecting a probiotic such as LGG to cultivation in a suitable culture medium using a batch process; (b) harvesting the culture supernatant at a late exponential growth phase of the cultivation step, which phase is defined with reference to the second half of the time between the lag phase and the stationary phase of the batch-cultivation process; (c) optionally removing low molecular weight constituents from the supernatant so as to retain molecular weight constituents above 5-6 kiioDaltons (kDa); (d) removing liquid contents from the culture supernatant so as to obtain the composition.
- a probiotic such as LGG
- the culture supernatant may comprise secreted materials that are harvested from a late exponential phase.
- the late exponential phase occurs in time after the mid exponential phase (which is halftime of the duration of the exponential phase, hence the reference to the late exponential phase as being the second half of the time between the lag phase and the stationary phase).
- the term "late exponential phase” is used herein with reference to the latter quarter portion of the time between the lag phase and the stationary phase of the LGG batch-cultivation process.
- the culture supernatant is harvested at a point in time of 75% to 85% of the duration of the exponential phase, and may be harvested at about 5 / ⁇ of the time elapsed in the exponential phase.
- the culture supernatant is believed to contain a mixture of amino acids, oiigo- and polypeptides, and proteins, of various molecular weights.
- the composition is further believed to contain polysaccharide structures and/or nucleotides.
- the culture supernatant of the present disclosure excludes low moiecuiar weight components, generally below 6 kDa, or even below 5 kDa. In these and other embodiments, the culture supernatant does not include lactic acid and/or lactate salts. These lower molecular weight components can be
- the culture supernatant of the present disclosure can be formulated in various ways for administration to pediatric subjects.
- the culture supernatant can be used as such, e.g. incorporated into capsules for oral administration, or in a liquid nutritional composition such as a drink, or it can be processed before further use.
- processing generally involves separating the compounds from the generally liquid continuous phase of the supernatant. This preferably is done by a drying method, such as spray-drying or freeze-drying (iyophilization) . Spray-drying is preferred.
- a carrier material will be added before spray-drying, e.g., maltodextrin DE29.
- the LGG culture supernatant of the present disclosure will generally be administered in an amount effective in promoting gut regeneration, promoting gut maturation and/or protecting gut barrier function.
- the effective amount is preferably equivalent to IxlO 4 to about lxl 0 , 2 cell equivalents of live probiotic bacteria per kg body weight per day, and more preferably 10 s - 0 9 cell equivalents per kg body weight per day.
- the amount of ceil equivalents may vary from about 1 x 10 4 to about 1 .5 x 10'° cell equivalents of probiotic(s ⁇ per 100 Kcal.
- the amount of probiotic cell equivalents may be from about 1 x 10 6 to about 1 x 10 9 cell equivalents of probiotic(s) per 100 Kcal nutritional composition. In certain other embodiments the amount of probiotic cell equivalents may vary from about 1 x 10 7 to about 1 x 10 s cell equivalents of probiotic (s) per 100 Kcai of nutritional composition.
- the disclosed combination of dietary butyrate and probiotic, especially LGG provides a higher potential to bring allergic infants and chiidren to a normal diet, fast management of CMA manifestations, and can accelerate the development of tolerance acquisition in infants affected by CMA.
- the unique combination of nutrients in the disclosed nutritional composition (s) is believed to be capable of providing novel and unexpected benefits for infants and children.
- the benefit of this nutritional composition is believed to be obtained during infancy, and also by including it as part of a diverse diet as the child continues to grow and develop.
- the nutritional composition further comprises a component for stimulating endogenous butyrate production.
- the component for stimulating endogenous butyrate production comprises a microbiota-stimulating component that is a prebiotic including both polydextrose ("PDX") and galacto-oligosaccharides ("GOS").
- PDX polydextrose
- GOS galacto-oligosaccharides
- a prebiotic component including PDX and GOS can enhance butyrate production by microbiota.
- Butyrate has epigenetic (histone deacetylase inhibition activity) that results in regulatory responses such as generation of regulatory T-celis. 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.
- 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 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, PDX powder, lactulose,
- lactosucrose lactosucrose, raffinose, gluco-oligosaccharide, inulin, fructo-oligosaccharide (FOS), isomalto-oligosaccharide, soybean oligosaccharides, lactosucrose, xyio- oligosaccharide (XOS), chito-oligosaccharide, manno-oligosaccharide, aribino- oligosaccharide, siallyl-oligosaccharide, fuco-oligosaccharide, and gentio- oligosaccharides.
- FOS fructo-oligosaccharide
- XOS xyio- oligosaccharide
- chito-oligosaccharide manno-oligosaccharide
- aribino- oligosaccharide siallyl-oligosaccharide
- fuco-oligosaccharide fuco-
- 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 preferabiy, 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 cal ⁇ o about 1 .5 g/100 cai. In certain embodiments, the total amount of prebiotics present in the nutritional composition may be from about 0.15 g/100 Kcai 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 0.015 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 Kcai 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 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.
- 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
- the nutritional composition includes a protein equivalent source, wherein the protein equivalent source includes a peptide component
- the peptide component may comprise
- composition may include at Ieast 10 additional peptides disclosed in Table 1 .
- the composition may include at Ieast 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 hydroiyzed
- the term additional means selecting different peptides than those enumerated.
- peptide component comprising at ieast 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 ;
- partially hydroiyzed protein or combinations thereof. In some embodiments, 20% to
- 80% of the protein equivalent source includes a peptide component comprising at
- Ieast 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 ieast 5 additional peptides selected from Table 1 ; and wherein 20% to 80% of the protein equivalent source comprises an intact protein, a partially hydroiyzed protein, or combinations thereof.
- Table 1 identifies the amino acid sequences of the peptides that may be included in the peptide component of the present nutritional compositions.
- 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 trom 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 trom 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
- 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 hydro!yzed bovine casein or hydroiyzed 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 hydroiyzed using a proteolytic enzyme, Protease N.
- Protease N "Amano" is commercially available from Amano Enzyme U.S.A. Co., Ltd., Elgin, Hi.
- 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 uni ⁇ s/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, in some embodiments, the protein equivalent source comprises a hydrolyzed protein including peptides having a molar mass distribution ot greater than 500 Daltons. In some embodiments, the hydrolyzed protein comprises peptides having a molar mass distribution in the range ot from about 500 Daltons to about 1 ,500 Daltons. Still, in some embodiments 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, in some embodiments, 30% to 60% of the protein equivalent source comprises the peptide component disclosed herein. In still other embodiments, 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
- 40% to 70% of the protein equivalent source comprises intact proteins, partially hydrolyzed proteins, extensively hydrolyzed protein, or a combination thereof.
- 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%.
- 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 probiotic, such as LGG, dietary butyrate, and the protein equivating source provide synergistic health benefits.
- 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, maitodextrins, 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 ca!. In other
- the amount of carbohydrate is between about 12 g and about 14 g/100 Kcal.
- 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.
- 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
- fructoo!igosaccharides 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 caseinate, calcium caseinate) and any combinations thereof.
- the proteins of the nutritional composition are provided as intact proteins.
- 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.
- the protein source comprises amino acids, in yet another embodiment, the protein source may be supplemented with glutamine-containing peptides.
- the whey:casein ratio of the protein source is similar to that found in human breast milk, in an embodiment, 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 cal. 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 ceil oils; vegetable and plant oiis, such as corn oii, canola oil, sunflower oil, soybean oil, palm olein oil, coconut oil, high oieic sunflower oil, evening primrose oii, rapeseed oii, olive oil, flaxseed (iinseed) oii, cottonseed oii, high oleic safflower oii, palm stearin, palm kernei oii, wheat germ oil; medium chain triglyceride oils and emulsion
- 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 Kcai.
- the fat or lipid source comprises from about 10% to about 35% palm oii 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 1 8% to about 25 % paim oii per the totai amount of fat or lipid.
- the fat or lipid source may be formulated to include from about 2% to about 1 6% 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 iipid. In some embodiments, the fat or Iipid source may be formulated to include from about 6% to about 0% soybean oil based on the total amount of fat or Iipid.
- the fat or Iipid source may be formulated to include from about 2% to about 1 6% coconut oil based on the total amount of fat or Iipid. In some embodiments, the fat or Iipid 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 Iipid source may be formulated to include from about 6% to about 10% coconut oil based on the total amount of fat or Iipid.
- the fat or Iipid source may be formulated to include from about 2% to about 1 6% sunflower oil based on the total amount of fat or lipid. In some embodiments, the fat or Iipid source may be formulated to include from about 4% to about 12% sunflower oil based on the total amount of fat or Iipid. In some embodiments, the fat or iipid source may be formulated to include from about 6% to about 10% sunflower oil based on the total amount of fat or Iipid.
- 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 Iipid source disclosed herein.
- 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 Kcai, and may vary from about 5 mg/100 Kcal to about 100 mg/100 Kcal, more preferably from about 10 mg/100 Kcai to about 50 mg/100 Kcal.
- Non-limiting examples of LCPUFAs include, but are not limited to, DHA, A A, linoleic (18:2 n-6), ⁇ -!ino!enic (18:3 n-6), dihomo- ⁇ -!ino!enic (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 1 7 mg/100 Kcal, and may vary from about 5 mg/100 Kcal to about 75 mg/100 Kcai, more preferabiy from about 10 mg/100 Kcai to about 50 mg/100 Kcai.
- 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 aspects
- Glucans are polysaccharides, specifically polymers of glucose, which are naturally occurring and may be found in ceil walls of bacteria, yeast, fungi, and plants.
- Beta glucans ( ⁇ -g!ucans) 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
- ⁇ -l ,3-glucans are carbohydrate polymers purified from, for example, yeast, mushroom, bacteria, algae, or cereals.
- Stone BA Clarke AE. Chemistry and Biology of ( l -3)-Be ⁇ a-Glucans. London:Por ⁇ land Press Ltd; 1993.
- the chemical structure of ⁇ -1 ,3- glucan depends on the source of the ⁇ -l ,3-glucan.
- various physiochemical parameters such as solubility, primary structure, molecular weight, and branching, play a role in biological activities of ⁇ -l ,3-glucans.
- Yadomae T. Structure and biological activities of fungal beta- l,3-glucans. Yakugaku Zasshi. 2000; 120:413-431 .
- -1 ,3 ⁇ 5 are naturally occurring polysaccharides, with or without ⁇ -1 ,6- giucose side chains that are found in the cell walls of a variety of plants, yeasts, fungi and bacteria.
- ⁇ -1 ,3; 1 , ⁇ 5 are those containing glucose units with (1 ,3) links having side chains attached at the (1 ,6) posi ⁇ ion(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 ⁇ -1 ,6- linked glucose branches extending from this backbone. While this is the basic structure for the presently described class of ⁇ -glucans, some variations may exist. For example, certain yeast ⁇ -giucans have additional regions of ⁇ (1 ,3) branching extending from the ⁇ (1 ,6) branches, which add further complexity to their respective structures.
- ⁇ -giucans derived from baker's yeast, Saccharomyces cerevisiae 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 ⁇ ⁇ -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-(l ,6) ⁇ -D-glucopyranosyi-(l ,3) ⁇ -D-giucopyranose.
- ⁇ -glucans are well tolerated and do not produce or cause excess gas, abdominal distension, bloating or diarrhea in pediatric subjects.
- Addition of ⁇ - giucan 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 , ⁇ .
- the ⁇ -1 ,3; 1 ,6-g!ucan is derived from baker's yeast.
- the nutritional composition may comprise whole giucan particle ⁇ -g!ucan, particulate ⁇ -glucan, PGG-glucan (poly-1 ,6- ⁇ -D-giucopyranosyl-l ,3 ⁇ -D-g!ucopyranose) or any mixture thereof.
- the amount of ⁇ -glucan in the nutritional composition is between about 3 mg and about 17 mg per 100 cal. In another embodiment the amount of ⁇ -glucan is between about 6 mg and about 1 7 mg per 100 Kcal.
- the disclosed nutritional composition described herein can, in some embodiments
- inventions also comprise an effective amount of iron.
- the iron may comprise encapsulated iron forms, such as encapsulated ferrous fumarate 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
- vitamin B2 riboflavin, flavin mononucleotide, FMN, flavin adenine dinucleotide, FAD, iactoflavin, ovoflavin
- vitamin B3 niacin, nicotinic acid, nicotinamide, niacinamide, nicotinamide adenine dinucleotide, NAD, nicotinic acid mononucleotide, NicMN, pyridine-3-carboxylic acid
- vitamin B3-precursor tryptophan vitamin ⁇ (pyridoxine, pyridoxal, pyridoxamine, pyridoxine hydrochioride), pantothenic acid (pantothenate, panthenol), folate (folic acid, folacin, pteroylglutamic acid), vitamin B12 (cobalamin, methylcobaiamin
- menaquinone-8H menaquinone-9, menaquinone-9H, menaquinone-10,
- menaquinone-1 1 menaquinone-12, menaquinone-13
- choline inositol
- ⁇ -carotene any combinations thereof.
- 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 chioride, 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, manganese, molybdenum, phosphorus, potassium, potassium phosphate, potassium iodide, potassium chioride, potassium acetate, se
- 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 emuisifiers that may be added for stability of the final product.
- suitable emuisifiers include, but are not limited to, lecithin (e.g., from egg or soy) , alpha lactalbumin and/or mono- and di-glycerides, and mixtures thereof.
- lecithin e.g., from egg or soy
- alpha lactalbumin e.g., from egg or soy
- mono- and di-glycerides e.g., from egg or soy
- Other emuisifiers 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 stabiiizers.
- Suitable stabiiizers 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, gelian gum, locust bean gum, pectin, low methoxyl pectin, gelatin, microcrystalline cellulose, CMC (sodium
- DATEM diacetyl tartaric acid esters of mono-
- 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, in an embodiment, 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/ 00 Kcal.
- the amount of protein typicaliy 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, in another embodiment, the children's nutritionai 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. In yet another embodiment, 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. In other embodiments, 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 nutritionai 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 formuias are designed to support overall health and development in a pediatric human subject, such as an infant or a child.
- the nutritionai 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 nutritionai 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 ail essentia! vitamins and minerals, macronutrients plus additional functional dietary components, such as non-essential nutrients that have purported heaith-promoting properties.
- compositions 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.
- nutritionai 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 iipid fraction derived from miik.
- 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. Otherwise, in some embodiments, vitamins and minerals can be added at levels that provide approximately 20% of the dietary reference intake (DRI j or 20% of the Daily Value (DV) per serving. Moreover, nutrient values can vary between markets depending on the identified nutritional needs of the intended population, raw materia! contributions and regional regulations.
- the disclosed nutritional composition (s) may be provided in any form known in the art, such as a powder, a ge!, 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.
- Nutritional 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 1 500 ⁇ , more preferably in the range of 10 Mm 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, in certain other embodiments, the nutritional composition may be contained within a plastic pouch located inside a plastic container.
- the nutritional compositions advantageously reduce the inflammatory response caused by allergy in a subject. Accordingly, the disclosure reiates to methods of improving tolerance to cow's milk allergy in a subject. Further, the disclosure relates to methods for the dietary management of allergic diseases and/or allergic reaction in a subject via
- the nutritional compositions including a probiotic, such as LGG, and dietary butyrate as disclosed herein.
- a probiotic such as LGG
- 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 a probiotic and dietary butyrate to the target subject.
- the target subject after the target subject has been subjected to cow's milk, the target subject may be provided with a nutritional composition that includes a probiotic 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 probiotic 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 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 probiotic and dietary butyrate.
- 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, probiotic, and dietary bufyrate, wherein the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 1 7, 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 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 1 3, SEQ ID NO 1 7, 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 Tabie 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 1 3, SEQ ID NO 1 7, 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
- the method for reducing the inflammatory response includes providing a nutritional composition comprising a peptide component from Tabie 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, probiotic and dietary bufyrate 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, in another embodiment of this method, the nutritional composition comprising the peptide component disclosed herein, probiotic and dietary butyrate is a growing up milk.
- the 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 probiotic 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 Table 1 .
- Example peptide component
- Table 4 provides an exampie embodiment of a peptide component inciuding certain peptides from Tabie 1 .
- Table 5 illustrated below, provides an example embodiment of the nutritional profile of a nutritional composition inciuding PDX/GOS and dietary butyrate and describes the amount of each ingredient to be included per 00 Kcal serving of nutritional composition.
- Lactobacillus rhamnosus GG (cfu) l xl O 4 1 .5xl 0' 2
- Vitamin A 9.60 x 1 0 5 3.80 x 10 s
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US20220079908A1 (en) * | 2018-12-21 | 2022-03-17 | Societe Des Produits Nestle S.A. | Dietary butyrate for treating or preventing an allergic disorder |
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