Food Grade Butyrate

Abstract

1. A nutritional composition for providing a source of butyrate or butyric acid, comprising: formula [Formula 1] TIFF2023504349000025.tif35147 [In the formula, R 6 A nutritional composition comprising a compound having the formula:

Description

[Technical Field]

[0001] The present invention relates to dietary sources of butyrate. [Background technology]

[0002] The salts and esters of butyric acid are called butyrate or butanoate.Ester form of butyric acid is found in many foods, for example, milk, especially goat, sheep, cow, camel and buffalo milk, and milk-derived products, for example, butter, and cheese, for example, Parmesan cheese.Butyric acid is also the product of anaerobic fermentation, for example, the fermentation product produced by intestinal flora.

[0003] The multiple beneficial effects of butyrate are well documented in mammals and livestock: at intestinal concentrations, butyrate acts to modulate transepithelial fluid transport, mucosal inflammation, and oxidative status, enhances intestinal barrier function, and influences visceral sensitivity and intestinal motility.

[0004] Butyrate has been shown to improve intestinal structure in piglets with short bowel syndrome (Bartholome et al., J of Parenter Enteral Nutr. 2004;28(4):210-222) and reduce colon cancer cell growth in human cell lines (Lupton, J Nutr., 2004;134(2):479-482). The role of dietary fiber in colon (large intestine) cancer may be due to the production of volatile fatty acids, such as butyrate, from fermentable fiber (Lupton, The Journal of Nutrition. 134(2):479-82). Bacteria in the large intestine that feed on or ferment non-digestible fiber and / or prebiotics produce short-chain fatty acids (SCFAs). Examples of SCFAs include, but are not limited to, acetate, propionate, and butyrate. SCFAs, most notably butyrate, inhibit histone deacetylase at the Foxp3 locus and promote the generation of regulatory T cells in the colon (Furusawa Y, et al., Nature 2013;504(7480):446-450). Oral supplementation with butyrate enhances the antibacterial activity of intestinal macrophages and limits the spread of bacteria across the intestinal barrier. Butyrate also benefits colonocytes by increasing energy production. Furthermore, butyrate has been shown to reduce the incidence of diarrhea (Berni Canani et al., Gastroenterol., 2004;127(2):630-634), improve gastrointestinal symptoms in individuals with diarrhea-predominant irritable bowel syndrome (Scarpellini et al., Dig Liver Dis., 2007;1(1):19-22), and enhance small intestinal development in newborn piglets (Kotunia et al., J Physiol Pharmacol. 2004;55(2):59-68).

[0005] Tributyrin is a triglyceride consisting of three ester functional groups with three butyrate moieties and a glycerol backbone. Under hydrolysis conditions, such as those encountered during digestion, tributyrin can provide a source of three moles of butyric acid per mole of tributyrin. However, the effectiveness of tributyrin can be limited by rapid lipolysis in the stomach.

[0006] Both butyric acid and tributyrin are generally regarded as safe (GRAS) food additives (21 CFR 582.60 and 21 CFR 184.1903, respectively) and are natural components of many dairy products. However, butyric acid is associated with negative organoleptic qualities, such as vomit-, fecal-, and cheese-like odor characteristics. Tributyrin also has negative organoleptic qualities, particularly a highly bitter taste. These unpleasant taste and odor characteristics can make oral administration of compositions containing these compounds particularly difficult, especially in pediatric populations.

[0007] Therefore, it would be beneficial to provide a food-grade source of butyrate with improved properties compared to available solutions. A liquid format would offer additional benefits due to ease of formulation and reduced dissolution and homogenization issues. Summary of the Invention

[0008] The present invention provides compounds that are dietary sources of butyrate. The present invention provides compounds with improved organoleptic properties. In particular, the compounds have improved odor and / or taste compared to butyric acid, butyrate salts, and tributyrin. The compounds can be used as dietary sources of butyric acid. The compounds can be used in nutritional compositions for human or animal consumption, such as dietary supplements, medical foods, foods for special medical purposes, fortified foods, infant formulas, and follow-on formulas.

[0009] Advantageously, the compounds of the present invention can provide effective delivery of butyric acid to the intestinal region.

[0010] According to a first aspect of the present invention, there is provided a method for preparing a dietary source of butyric acid or butyrate having improved organoleptic properties, comprising the step of: [ka] [In the formula, R 6 is a long-chain fatty acid having 16 to 20 carbon atoms. Use is provided.

[0011] The compounds of formula (1) may be present in nutritional compositions such as, for example, nutritional formulations, fortified foods, medical foods or foods for special medical purposes, dietary supplements, infant formulas, or follow-on formulas.

[0012] In one embodiment, the improved sensory attribute is improved odor. In one embodiment, the improved sensory attribute is improved taste. In one embodiment, the improved sensory attribute is improved odor and improved taste. In one embodiment, the improved taste is reduced bitterness.

[0013] According to one aspect of the present invention, there is provided a nutritional composition for providing a source of butyrate or butyric acid, the composition comprising: [ka] [In the formula, R 6 is a long-chain fatty acid having 16 to 20 carbons] as the major butyrate moiety-containing triglyceride in the nutritional composition.

[0014] In a preferred embodiment, the compound of formula (1) is the primary source of butyrate or butyric acid in the nutritional composition.

[0015] In one embodiment, the compound of formula (1) may provide at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%, at least 70%, at least 80%, or at least 90% of the butyrate or butyric acid provided by the nutritional composition.

[0016] In one embodiment, the compound of formula (1) may provide at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%, at least 70%, at least 80%, or at least 90% by weight of the butyrate moiety-containing triglycerides in the nutritional composition.

[0017] In another embodiment, the compound of formula (1) provides at least 95% by weight, or substantially all, of the butyrate moiety-containing triglycerides in the nutritional composition.

[0018] In one embodiment, the compound having formula (1) comprises at least 30% by weight, preferably at least 40% by weight, of the total butyrate moiety-containing triglycerides in the composition.

[0019] In a preferred embodiment, the compound having formula (1) comprises at least 50% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0020] In another preferred embodiment, the compounds having formula (1) comprise at least 60% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0021] In one embodiment, the compound having formula (1) comprises at least 70% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0022] In one embodiment, the compounds having formula (1) comprise at least 80% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0023] In one embodiment, the compound having formula (1) comprises at least 90% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0024] In one embodiment, the compound having formula (1) comprises at least 95% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0025] According to one aspect of the present invention, there is provided a nutritional composition for providing a source of butyrate or butyric acid, the composition comprising: [ka] [In the formula, R 6 is a long chain fatty acid having 16 to 20 carbons; and optionally a compound having the formula [ka] [In the formula, R 1 is a long chain fatty acid having 16 to 20 carbons, wherein the compound of formula (1), optionally in combination with a compound of formula (2), is present in an amount of at least 30%, preferably at least 40%, and more preferably at least 50% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0026] In one embodiment, a compound having formula (1) and a compound having formula (2) are present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula) wherein the combination of compound having formula (1) and compound having formula (2), as defined herein, is present in an amount of at least 50% by weight, preferably at least 60% by weight, of the total amount of butyrate-containing triglycerides in the composition.

[0027] In another embodiment, a compound having Formula (1) and a compound having Formula (2) are present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), wherein the combination of the compound having Formula (1) and the compound having Formula (2), as defined herein, is present in an amount of at least 60%, at least 70%, at least 80%, or at least 90% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

[0028] In one embodiment, the nutritional composition comprises less than 15%, preferably less than 10%, by weight of the total butyrate moiety-containing triglycerides in the composition, of the formula [ka] a compound having Less than 10% by weight of the total amount of butyrate moiety-containing triglycerides in the composition, of the formula [ka] and / or Less than 10% by weight of the total amount of butyrate moiety-containing triglycerides in the composition, of the formula [ka] and a compound having the formula: In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are each independently a long-chain fatty acid having 16 to 20 carbon atoms.

[0029] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of the total amount of butyrate moiety-containing triglycerides in the composition of a compound having formula (2).

[0030] In a preferred embodiment, the nutritional composition comprises a combination of a compound having formula (3) and a compound having formula (4) at less than 15% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

[0031] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of the compound having formula (3) of the total amount of butyrate-containing triglycerides in the composition.

[0032] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of the compound having formula (4) of the total amount of butyrate-containing triglycerides in the composition.

[0033] In one embodiment, the nutritional composition may be selected from a dietary supplement, a fortified food, a medical food or a food for special medical purposes, an infant formula, a follow-on formula.

[0034] According to one aspect of the present invention, there is provided a dietary supplement for providing a source of butyrate or butyric acid, the dietary supplement comprising: [ka] [In the formula, R 6 is a long-chain fatty acid having 16 to 20 carbons] as the primary source of butyrate or butyric acid in the dietary supplement.

[0035] The dietary supplement may be in the form of, for example, a capsule, tablet, sachet, liquid / oil, or powder.

[0036] According to another aspect of the invention, there is provided an infant formula or follow-on formula comprising a compound of formula [ka] [In the formula, R 6are independently long-chain fatty acids having 16 to 20 carbons] as a primary source of butyrate or butyric acid in the infant formula or follow-on formula.

[0037] According to another aspect of the present invention there is provided the use of an infant formula or follow-on formula of the present invention to provide a source of butyrate or butyric acid having improved organoleptic properties.

[0038] According to another aspect of the present invention there is provided a nutritional composition for use in improving or maintaining gastrointestinal (GI) health, comprising the formula [ka] [In the formula, R 6 is a long-chain fatty acid having 16 to 20 carbons] as a primary source of butyrate or butyric acid in the nutritional composition.

[0039] According to another aspect of the present invention, there is provided a method of improving or maintaining GI health in a patient, comprising administering to a subject an amount of an active ingredient of formula [ka] [In the formula, R 6 is a long-chain fatty acid having 16 to 20 carbons] as the primary source of butyrate or butyric acid in the nutritional composition.

[0040] In a preferred embodiment, the compound of formula (1) is the major butyrate-containing triglyceride component in the nutritional composition.

[0041] In one embodiment, the compound having formula (1) is used as defined herein or is present in a composition as defined herein (e.g., a nutritional composition, dietary supplement, infant formula, or follow-on formula). Preferably, the compound having formula (1) is present in an amount of at least 2% by weight, preferably at least 3% by weight, for example about 3-6% by weight, of the total triglycerides in the composition.

[0042] In one embodiment, the compound having formula (1), for use as defined herein, or in a dietary supplement as defined herein, is present in an amount of at least 5% by weight of the total triglycerides in the composition, as defined herein, preferably at least 10% by weight, such as at least 15% by weight, or at least 20% by weight.

[0043] In one embodiment, a compound having formula (1) is present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula) used as defined herein or defined herein, wherein the compound having formula (1) is present in an amount of at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0044] In preferred embodiments, the compound having formula (1) is used as defined herein or is present in a composition defined herein (e.g., a nutritional composition, dietary supplement, infant formula, or follow-on formula), wherein the compound having formula (1) is present in an amount of at least 30%, at least 40%, or preferably at least 50% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0045] In another embodiment, the compound having formula (1) is present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula) used as defined herein or defined herein, wherein the compound having formula (1) is present in an amount of at least 60%, at least 70%, at least 80%, or at least 90% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0046] In another embodiment, the compound having formula (1) is present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula) used as defined herein or defined herein, wherein the compound having formula (1) is present in an amount of at least 95% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0047] In one embodiment, R as defined herein 6 is an unsaturated fatty acid, preferably monounsaturated.

[0048] In one embodiment, R as defined herein 6 is selected from the group consisting of oleic acid, palmitic acid, stearic acid, or linoleic acid.

[0049] In a preferred embodiment, R as defined herein 6 is oleic acid.

[0050] In one embodiment, the compound having formula (1) is:

[0051] [ka] According to another aspect of the present invention, [ka] wherein the compound having formula (5) comprises at least 2%, at least 3%, at least 5%, or at least 10% by weight of the total triglycerides in the composition.

[0052] In one embodiment, the compound having formula (5) comprises at least 20% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0053] In one embodiment, the compound having formula (5) comprises at least 30% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0054] In one embodiment, the compound having formula (5) comprises at least 40% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0055] In one embodiment, the compound having formula (5) comprises at least 50% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0056] In one embodiment, the compound having formula (5) comprises at least 60% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0057] In one embodiment, the compound having formula (5) comprises at least 70% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0058] In one embodiment, the compound having formula (5) comprises at least 80% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0059] In one embodiment, the compound having formula (5) comprises at least 90% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0060] In one embodiment, the compound having formula (5) comprises at least 95% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0061] In one embodiment, the compound having formula (5) comprises from about 20% to about 95% by weight of the total butyrate-containing triglycerides in the composition, from about 30% to about 95% by weight, from about 40% to about 90% by weight, from about 50% to about 90% by weight, or from about 60% to about 95% by weight of the total butyrate-containing triglycerides in the composition.

[0062] In one embodiment, the compound having formula (5) comprises from about 40% to about 80% by weight of the total butyrate-containing triglycerides in the composition, e.g., from about 50% to about 70% by weight of the total butyrate-containing triglycerides in the composition.

[0063] In one embodiment, the compound having formula (5) comprises from about 50% to about 90% by weight of the total butyrate-containing triglycerides in the composition, e.g., from about 60% to about 80% by weight of the total butyrate-containing triglycerides in the composition.

[0064] According to one aspect of the present invention, there is provided a nutritional composition for providing a source of butyrate or butyric acid, the composition comprising: [ka] and optionally a compound having the formula [ka] and a compound having the formula (5), optionally in combination with a compound of formula (6), wherein the compound of formula (5) is present in an amount of at least 30%, preferably at least 40%, more preferably at least 50% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0065] In one embodiment, a compound having formula (5) and a compound having formula (6) are present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), wherein the combination of the compound having formula (5) and the compound having formula (6), as defined herein, is present in an amount of at least 50% by weight, preferably at least 60% by weight, of the total amount of butyrate-containing triglycerides in the composition.

[0066] In another embodiment, a compound having Formula (5) and a compound having Formula (6) are present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), wherein the combination of the compound having Formula (5) and the compound having Formula (6), as defined herein, is present in an amount of at least 60%, at least 70%, at least 80%, or at least 90% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0067] In one embodiment, the composition comprises less than 10% by weight of the total butyrate moiety-containing triglycerides in the composition, of the formula [ka] The compound includes compounds having the formula:

[0068] According to one embodiment, the composition comprises less than 10% by weight of the total butyrate moiety-containing triglycerides in the composition, of the formula [ka] The compound includes compounds having the formula:

[0069] According to one embodiment, the composition comprises less than 10% by weight of the total butyrate moiety-containing triglycerides in the composition, of the formula [ka] The compound includes compounds having the formula:

[0070] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of the compound having formula (6) of the total amount of butyrate-containing triglycerides in the composition.

[0071] In a preferred embodiment, the nutritional composition comprises a combination of a compound having formula (7) and a compound having formula (8) in an amount of less than 15% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

[0072] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of the compound having formula (7) of the total amount of butyrate-containing triglycerides in the composition.

[0073] In one embodiment, the nutritional composition comprises less than 8%, preferably less than 5%, or less than 2% by weight of a compound having formula (8) of the total amount of butyrate-containing triglycerides in the composition.

[0074] The composition of the present invention includes 1,3-dibutyryl-2-linoleoylglycerol, 1,3-dibutyryl-2-stearoylglycerol, 1-butyryl-2-oleoyl-3-palmitoylglycerol, 1-palmitoyl-2-oleoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-linoleoylglycerol, 1-linoleoyl-2-oleoyl-3-butyrylglycerol, 1-oleoyl-2-butyryl-3-linoleoylglycerol, 1-linoleoyl-2-butyryl-3-oleoylglycerol, 1-butyryl-2-linoleoyl-3-oleoylglycerol , 1-oleoyl-2-linoleoyl-3-butyrylglycerol, 1-butyryl-2-stearoyl-3-oleoylglycerol, 1-oleoyl-2-stearoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-stearoylglycerol, 1-stearoyl-2-oleoyl-3-butyrylglycerol, 1,2-dioleoyl-3-palmitoylglycerol, 1-palmitoyl-2,3-dioleoylglycerol, 1,2-dioleoyl-3-linoleoylglycerol, and / or 1-linoleoyl-2,3-dioleoylglycerol.

[0075] The compositions of the present invention may preferably be in the form of a nutritional composition.

[0076] The compositions of the present invention may be in the form of an infant formula or a follow-on formula.

[0077] The compositions of the present invention may be in the form of a dietary supplement.

[0078] According to another aspect of the present invention there is provided the use of a composition as defined herein to provide a source of butyrate or butyric acid having improved organoleptic properties.

[0079] According to another aspect of the present invention, there is provided a method of providing a source of butyric acid having improved organoleptic properties to a subject, the method comprising the step of administering to said subject an effective amount of a composition as defined herein.

[0080] According to another aspect of the present invention there is provided a composition as defined herein for improving or maintaining gastrointestinal health.

[0081] According to another aspect of the present invention, there is provided a method of improving or maintaining gastrointestinal health in a subject, the method comprising administering to the subject an effective amount of a composition as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0082] triglycerides Triglycerides (also called triacylglycerols) are triesters derived from glycerol and three fatty acids.

[0083] Fatty acids are carboxylic acids with long tails (chains). Fatty acids can be either unsaturated or saturated. Fatty acids that are not bound to other molecules are called free fatty acids (FFA).

[0084] The term "fatty acid moiety" refers to the portion of a triglyceride derived from a fatty acid in an esterification reaction with glycerol. The triglycerides used in the present invention contain two butyric acid moieties (also called "butyrate moieties") and one long-chain fatty acid moiety.

[0085] Advantageously, the compounds and compositions of the present invention can provide a high butyric acid content while exhibiting improved organoleptic properties compared to tributyrin through optimization of the butyric acid content of the triglycerides.

[0086] Preferred long chain fatty acids for use in the present invention are those having 16 to 20 carbon atoms.

[0087] Examples of long chain fatty acids include oleic acid, palmitic acid, stearic acid, and linoleic acid.

[0088] A preferred long chain fatty acid for use in the present invention is oleic acid, which is the predominant fatty acid present in breast milk.

[0089] The triglyceride of the present invention can be synthesized, for example, by an esterification reaction between a long-chain fatty acid monoacylglycerol (MAG) and butyric acid.

[0090] The triglycerides of the present invention can be synthesized, for example, by the esterification reaction of long-chain fatty acid monoacylglycerol (MAG) with butyric acid, with the removal of water. As an example, the method for obtaining 1,2-dibutyryl-3-oleoylglycerol is shown below: [ka] The esterification reaction is preferably carried out at a butyric acid (BA):monoacylglycerol (MAG) molar ratio of 2 or greater, ie, a molar excess of butyric acid, for example, a BA:MAG molar ratio of about 3.

[0091] Water removal can be carried out by conventional methods as determined by one skilled in the art as part of routine procedures.

[0092] Advantageously, such a synthesis method avoids the use of tributyrin as a raw material.

[0093] Alternative methods of triglyceride synthesis can be determined as part of routine procedures by those skilled in the art.

[0094] In one embodiment, sunflower oil is the source of monoolein as the monoacylglycerol, creating a triglyceride containing primarily butyrate and oleate moieties.

[0095] This compound is dairy-free, cholesterol-free, and animal-derived free. The fatty acids are released from triglycerides by naturally occurring lipases in the gastrointestinal tract. Compared to butyrate salts, this compound does not add additional mineral salts to the final formulation.

[0096] A single butyrate moiety-containing triglyceride can be used herein, or a mixture of different butyrate moiety-containing triglycerides can be used.

[0097] The triglycerides may be further subjected to decolorization and / or deodorization steps that are conventional in the art and well known to those skilled in the art, for example, steps that are conventionally used in the production of vegetable oils.

[0098] composition The present invention provides a composition comprising the butyrate-containing triglycerides referred to herein. The composition may be, for example, a nutritional composition such as a fortified food, a medical food or a food for special medical purposes, a dietary supplement, an infant formula, or a follow-on formula.

[0099] The expression "nutritional composition" refers to a composition that provides nutrition to a subject. This nutritional composition is preferably taken orally and may comprise a lipid or fat source and a protein source. Such a composition may also contain a carbohydrate source. In one embodiment, the nutritional composition contains only a lipid or fat source. In other specific embodiments, the nutritional composition contains a lipid (or fat) source together with a protein source, a carbohydrate source, or both.

[0100] In some particular embodiments, the nutritional compositions according to the present invention are foods for special dietary uses (FSDUs). As used herein, the expression "foods for special dietary uses" refers to foods that are specially formulated to meet specific dietary requirements arising from specific physical or physiological conditions and / or specific diseases and disorders (e.g., Codex STAN146-1985, section 2.1).

[0101] In some specific embodiments, the nutritional composition according to the present invention is a medical food or a food for special medical purposes (FSMP). As used herein, "medical food" or "food for special medical purposes" refers to a food that is specially formulated for and intended for the dietary management of a disease. In the United States, "medical food" is defined in section 5(b) of the Food and Drug Administration's 1988 Orphan Drug Act (21 USC 360ee(b)(3)). In Europe, "medical foods" are referred to as "foods for special medical purposes" (e.g., as defined in European Commission Delegated Regulation (EU) 2016 / 128 of September 25, 2015). The terms "medical food" and "food for special medical purposes" are used interchangeably herein.

[0102] In some particular embodiments, the nutritional compositions according to the present invention are "enteral nutritional compositions," i.e., foodstuffs in which administration of the composition involves the gastrointestinal tract. Introduction to the stomach may involve the use of a tube passed through the oral / nasal cavity or a tube directly into the stomach in the abdomen. Such a tube may be used, particularly in a hospital or clinic.

[0103] The composition according to the invention may be an infant formula (e.g. an infant starter formula), a follow-up or follow-on formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a breast milk fortifier, or a nutritional supplement.

[0104] As used herein, the expression "infant formula" refers to a food product intended for the specific nutritional supplementation of infants during the first month of life, where the milk itself meets the nutritional requirements of infants falling within this category (e.g., Article 2(c) of the European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 on infant and follow-on formulas).

[0105] Generally, starter formulas are breast milk substitutes for infants from birth onwards. Follow-up or follow-on formulas are offered from the sixth month onwards. These formulas constitute the main liquid component of the increasingly varied diet of infants in this category. "Growing-up milk" (or GUM) is offered from the first year onwards. This milk is generally a dairy-based drink specifically tailored to the nutritional needs of children.

[0106] The term "fortifier" refers to a liquid or solid nutritional composition suitable for mixing with breast milk (human milk) or infant formula. The term "breast milk" is to be understood as mother's milk or mother's colostrum, or donor's milk or the colostrum of donor's milk.

[0107] The term "dietary supplement" can be used to supplement an individual's nutrition (typically for nutritional supplementation, but can also be added to any type of composition intended for ingestion). It can be in the form of, for example, a tablet, capsule, lozenge, or liquid. Dietary supplements can also contain protective hydrocolloids (gums, proteins, modified starches, etc.), binders, film-forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste-masking agents, bulking agents, jellifying agents, and gel-forming agents. Dietary supplements may also contain conventional pharmaceutical excipients and adjuvants, additives, and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugar, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, coloring agents, humectants, fillers, and the like.

[0108] In another particular embodiment, the nutritional composition of the present invention is a fortifier. The fortifier may be a breast milk fortifier or a formula fortifier, such as an infant formula fortifier. Thus, a fortifier is a particularly advantageous embodiment when the infant or toddler is premature.

[0109] When the composition is a nutritional supplement, it may be provided in unit dose form.

[0110] The nutritional compositions of the present invention, particularly infant formulas, generally contain a protein source, a carbohydrate source, and a lipid source, although in some embodiments, particularly when the nutritional composition of the present invention is a nutritional supplement or fortifier, only lipid (or a lipid source) may be present.

[0111] The nutritional compositions according to the present invention may contain a protein source. The protein may be in an amount of 1.6-3 g / 100 kcal. In some embodiments, particularly when the composition is intended for premature infants / toddlers, the protein amount may be 2.4-4 g / 100 kcal, or greater than 3.6 g / 100 kcal. In some other embodiments, the protein amount may be less than 2.0 g / 100 kcal, for example, 1.8-2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0112] For example, protein sources based on whey, casein, and mixtures thereof can be used, as well as vegetable protein sources, such as soybean-based protein sources. With regard to whey protein, the protein source can be based on acid whey or sweet whey, or a mixture thereof, and can contain α-lactalbumin and β-lactoglobulin in any desired proportion. In some embodiments, the primary protein source is whey (i.e., more than 50%, e.g., more than 60% or more than 70% of the protein is derived from whey protein). The protein can be an intact protein, a hydrolyzed protein, or a mixture of intact and hydrolyzed protein. The term "intact" means that the majority of the protein is intact, i.e., the molecular structure is unchanged, e.g., at least 80% of the protein is unchanged, e.g., at least 85% of the protein is unchanged, preferably at least 90% of the protein is unchanged, and even more preferably, at least 95% of the protein is unchanged, e.g., at least 98% of the protein is unchanged. In certain embodiments, the protein is completely unchanged.

[0113] The term "hydrolyzed" in the context of the present invention means that a protein has been hydrolyzed or broken down into its constituent amino acids.

[0114] Protein can be either completely hydrolyzed or partially hydrolyzed. When hydrolyzed protein is required, the hydrolysis process can be carried out as desired as known in the art. For example, whey protein hydrolysate can be prepared by enzymatically hydrolyzing whey fraction in one or more steps. It has been found that if the whey fraction used as starting material is substantially lactose-free, the protein undergoes significantly less lysine blackage during the hydrolysis process. This can reduce the degree of lysine blackage from about 15% by weight of the total lysine to less than about 10% by weight, for example, about 7% by weight of lysine, which significantly improves the nutritional value of the protein source.

[0115] In a particular embodiment, the protein of the composition is hydrolyzed, fully hydrolyzed, or partially hydrolyzed. The degree of hydrolysis (DH) of the protein may be 2 to 20, or 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, or greater than 90. For example, nutritional compositions containing hydrolysates having a degree of hydrolysis of less than about 15% are commercially available from the Nestle Company under the trade name Peptamen®.

[0116] At least 70%, 80%, 85%, 90%, 95%, or 97% of the protein may be hydrolyzed, hi certain embodiments, 100% of the protein is hydrolyzed.

[0117] In one particular embodiment, the protein of the composition is a vegetable protein.

[0118] The nutritional composition of the present invention may contain a carbohydrate source. It is particularly preferred that the nutritional composition of the present invention is an infant formula. In this case, any carbohydrate source commonly found in infant formula, such as lactose, sucrose, saccharose, maltodextrin, starch, and mixtures thereof, can be used, but lactose is one of the preferred carbohydrate sources for infant formula. The nutritional composition of the present invention may also contain all vitamins and minerals that are considered to be essential in daily diet and in significant amounts for nutrition. Minimum required amounts have been established for certain vitamins and minerals. Examples of minerals, vitamins, and other nutrients optionally present in the compositions of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amount of specific minerals and other vitamins vary depending on the target population. If necessary, the nutritional compositions of the present invention may contain emulsifiers and stabilizers, such as soybeans, lecithin, and citric acid esters of mono- and diglycerides. The nutritional compositions of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGF-β, slgA, glutamine, nucleotides, and nucleosides.

[0119] The compositions of the present invention may further comprise at least one indigestible oligosaccharide (eg, a prebiotic), typically in an amount of 0.3 to 10% by weight of the composition.

[0120] Prebiotics are typically indigestible, meaning they are not broken down or absorbed in the stomach or small intestine. Thus, they remain intact upon entering the large intestine and are selectively fermented by beneficial bacteria there. Examples of prebiotics include certain oligosaccharides, such as fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, or any mixture thereof. In certain embodiments, the prebiotic may be fructooligosaccharides and / or inulin. In certain embodiments, the prebiotic is a combination of FOS and inulin, such as in the product sold by BENEO-Orafti under the trade name Orafti® Oligofructose (formerly Raftilose®) or the product sold by BENEO-Orafti under the trade name Orafti® Inulin (formerly Raftiline®). Another example is a combination of 70% short-chain fructooligosaccharides and 30% inulin, which is registered by Nestle under the trade name "Prebio1". The nutritional compositions of the present invention may also comprise at least one milk oligosaccharide, which may be BMO (cow's milk oligosaccharide) and / or HMO (human milk oligosaccharide). The compositions of the present invention may further comprise at least one probiotic (i.e., probiotic strain), such as a probiotic strain.

[0121] The most commonly used probiotic microorganisms are bacteria and yeasts, mainly of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0122] In some particular embodiments, the probiotic is a probiotic strain, hi some particular embodiments, the probiotic strain is Bifidobacteria and / or Lactobacilli.

[0123] The nutritional composition according to the present invention may contain, on a dry weight basis, from 10e3 to 10e12 cfu of probiotic strain per gram of composition, more preferably from 10e7 to 10e12 cfu, for example from 10e8 to 10e10 cfu of probiotic strain per gram of composition.

[0124] In one embodiment, the probiotics are live bacteria. In another embodiment, the probiotics are non-replicating or inactivated. The probiotics may also be parts of the probiotic, such as cell wall components or metabolic products of the probiotic. In some other embodiments, both viable and inactivated probiotics may be present. The nutritional composition of the present invention may further comprise at least one phage (bacteriophage) or mixture of phages, preferably against pathogenic streptococci, Haemophilus, Moraxella, and Staphylococcus.

[0125] In one embodiment, the nutritional composition according to the present invention may be a dairy product. A dairy product is a product containing a milk-based product. Dairy products are generally made from a suitable mixture of concentrated milk protein and fat sources. Dairy products can be acidified. Dairy products include ready-to-drink dairy beverages, concentrated milk, evaporated milk, sweetened concentrated milk, milk powder, yogurt, fresh cheese, cheese, ice cream, and dairy spreads, such as spreadable fresh cheese, cottage cheese, quark, crème fraîche, clotted cream, and cream cheese. Milk powder can be produced, for example, by spray drying or freeze drying.

[0126] Depending on the fat content, dairy products can be prepared from full-fat or whole milk, semi-skimmed milk, skimmed milk, or low-fat milk. Skimmed milk is milk containing less than 0.1% milk fat. Semi-skimmed milk is milk containing 1.5% to 2.5% milk fat. Full-fat milk is typically milk containing 3% to 4% fat. The exact fat content of skimmed, semi-skimmed, and full-fat milk varies primarily depending on local food regulations.

[0127] Dairy products are generally made from cow's milk, but can also be made from buffalo milk, yak milk, goat milk, sheep milk, horse milk, donkey milk, camel milk, reindeer milk, moose milk, or combinations thereof.

[0128] Acidified dairy products can be obtained by fermentation with suitable microorganisms. Fermentation provides flavor and sourness to dairy products. Fermentation can also affect the texture of dairy products. In addition, the microorganisms used for fermentation are selected for their ability to ferment milk into edible fermented dairy products. Typically, the microorganisms are known for their beneficial properties. These microorganisms include lactic acid bacteria and yeasts. Some of these microorganisms can be considered probiotics. Examples of lactic acid bacteria include Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, both of which are involved in the production of yogurt, or other lactic acid bacteria belonging to the genera Lactobacillus, Streptococcus, Lactococcus, Leuconostoc, Bifidobacterium, Pediococcus, or any mixture thereof.

[0129] Another example of a fermented dairy product, also called cultured dairy product or cultured dairy food, or cultured milk, is fermented buttermilk fermented with Lactococcus lactis (Lactococcus lactis subsp. lactis, Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. lactisbiovare diacetylactis) and / or Leuconostoc mesenteroides subsp. cremoris.

[0130] The microorganisms may be live or inactivated.

[0131] Dairy analogs are products made in a similar manner to the dairy products described above, but using a protein source other than dairy (in whole or in part) and / or an edible fat source other than dairy (in whole or in part). Suitable protein sources include vegetable proteins, such as soybeans, potatoes, and peas. Suitable fat sources include oils and fats of plant or marine origin. Fats and oils are used interchangeably. Preparations similar to those described above are meant to include product processing in which the traditional whey separation step is omitted, since the dairy analog formulation of the product allows for the elimination of the separation step.

[0132] The nutritional compositions according to the present invention may be prepared in any suitable manner.

[0133] For example, a formula, such as an infant formula, can be prepared by blending a protein source, a carbohydrate source, and a fat source together in the appropriate proportions. If used, an emulsifier can be included at this point. Vitamins and minerals may be added at this point, but are typically added later to avoid thermal degradation. Any lipophilic vitamins and emulsifiers, etc., can be dissolved in the fat source before blending. Water, preferably treated with reverse osmosis, can then be added to form a liquid mixture. The temperature of the water is suitably in the range of about 50°C to about 80°C to aid in the dispersion of the ingredients. A commercially available liquefaction device can be used to form the liquid mixture.

[0134] Any oligosaccharides may be added at this stage, especially if the final product is in liquid form. If the final product is to be a powder, any oligosaccharides may likewise be added at this stage, if desired.

[0135] The liquid mixture is then homogenized, for example in two stages.

[0136] In one embodiment, the nutritional compositions of the present invention are given to an infant or young child as a composition to complement breast milk.

[0137] Compositions of the present invention may be, for example, in solid (eg, powder), liquid, or gelatinous form.

[0138] The compositions of the present invention may be, for example, tablets, dragees, capsules, gelcaps, powders, granules, solutions, emulsions, suspensions, coated particles, spray-dried particles, or pills.

[0139] The composition may be in the form of a pharmaceutical composition and may comprise one or more suitable pharmaceutically acceptable carriers, diluents and / or excipients.

[0140] Examples of such suitable excipients for the compositions described herein can be found in "Handbook of Pharmaceutical Excipients", 2nd Edition (1994), edited by A Wade and PJ Weller.

[0141] Acceptable carriers or diluents for therapeutic use are known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0142] The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient, or diluent any suitable binder, lubricant, suspending agent, coating agent, and / or solubilizing agent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, fluid lactose, β-lactose, and the like, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0143] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0144] Preservatives, stabilizers, dyes, and even flavoring agents may be included in the composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used.

[0145] Gastrointestinal health The compounds defined herein are sources of butyrate / butyric acid and therefore can be used to improve or maintain gastrointestinal (GI) health.

[0146] In one embodiment, the compounds and compositions defined herein can be used for the treatment of inflammatory bowel disease, for example, Crohn's disease or ulcerative colitis.

[0147] It is well documented that butyrate has multiple beneficial effects on GI health: at intestinal concentrations, butyrate acts to modulate transepithelial fluid transport, mucosal inflammatory and oxidative status, strengthens the epithelial barrier, and modulates visceral sensitivity and intestinal motility.

[0148] Fatty acids, such as butyrate, are the primary energy source for colonic mucosal cells (Reodriger, Gut. 1980;21:793-798), most important for colonocytes in the distal colon. Butyrate's potent trophic effects on the small intestinal mucosa have been observed in experimental animals (Guilteau et al., 2 J Anim Feed Sci 2004;13, Suppl. 1:393-396). A decrease in intestinal butyrate concentration leads to atrophy of the colonic mucosa, which is usually explained by a decrease in substrate availability to colonocytes. On the other hand, administration of butyrate into the colonic lumen induces weight gain, increased DNA synthesis, and increased intestinal crypt depth (Kripke et al., J Parenter Enter Nutr. 1989;13:109-116).

[0149] High concentrations of butyrate, obtained by fermentation of insoluble dietary fiber or after anal administration of butyrate, can inhibit early and late stage colonic tumorigenesis by modulating the transcription, expression, and activation of key proteins in the apoptotic cascade (Avivi-Green et al., J Nutr. 2002;132(7):1812-18).

[0150] Chapman et al. (Gut 1994;35(1):73-76) showed that inflamed colonic mucosa traps much more butyrate than glutamine or glucose. Experiments have shown that infusion of butyrate significantly reduces inflammation and reduces the degree of ulceration in the colon wall in rats (Andoh et al., J Parenter Enter Nutr. 1999;23(5):70-73).

[0151] The effectiveness of butyrate enemas has been demonstrated by clinical observations in patients with ulcerative colitis (Han et al., Gastroenterol Clin North Am. 1999;28:423-443; Scheppach et al., Gastroenterol Suppl. 1997;222:53-57).

[0152] The direct anti-inflammatory activity of butyrate may be related to its inhibition of nuclear factor kappa B (NFκB) translocation and DNA binding, as well as the inhibition of the transcription and production of inflammatory cytokines (Segain et al., Gut. 2000;47:397-403).

[0153] Therefore, the triglyceride compounds used in the present invention are a source of butyrate, which may play a major role in maintaining intestinal homeostasis and GI health.

[0154] Administration Preferably, the compounds and compositions described herein are administered enterally.

[0155] Enteral administration may be, for example, oral or gastric.

[0156] In general terms, administration of the combinations or compositions described herein may be, for example, by the oral route or by another route to the gastrointestinal tract, for example, administration may be by tube feeding.

[0157] The subject may be a mammal, such as a human, dog, cat, horse, goat, cow, sheep, pig, deer, and primate. Preferably, the subject is a human. [Example]

[0158] Example 1 - Preparation of Triglycerides Containing Butyrate Moieties A composition containing butyrate-containing triglycerides was produced by the esterification reaction of monoolein (derived from sunflower oil) with butyric acid, added in a molar excess (5 equivalents total). These two reagents were mixed together in a flask and heated to reflux (the boiling point of butyric acid is 163.5°C). A condenser ("colorne de Vigreux") was used to remove water. The reaction was monitored by TLC and stopped when all monoacylglycerols were converted to triacylglycerols.

[0159] The components of the resulting oil composition (mainly triglycerides) are shown in Table 1 below. These triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by the lipid number: 4:0 for butyrate, 16:0 for palmitate, 18:0 for stearate, 18:1 for oleate, and 18:2 for linoleate. The central fatty acid is located at the sn-2 position of the triglyceride. As an example, 16:0-4:0-18:1 represents two different triglycerides, both with butyrate at the sn-2 position and palmitate at the sn-1 position and oleate at the sn-3 position, or oleate at the sn-1 position and palmitate at the sn-3 position.

[0160] [Table 1] In this composition, 4:0-4:0-18:1 was identified as the most abundant triglyceride.

[0161] The resulting oil product was then subjected to a decolorization step by the action of bleaching earth and purified by short-path distillation (130°C, 0.001-0.003 mbar) and / or deodorization by injection of steam water (160°C, 2 mbar, 2 h) to remove residual reagents and intermediates, such as butyric acid, MAG, and by-products (e.g., DAG and tributyrin).

[0162] The resulting oil product was evaluated in a descriptive sensory evaluation and it was found that the oil product had a better odor and taste than tributyrin and butyric acid.

Claims

1. 1. A nutritional composition for providing a source of butyrate or butyric acid and for use in improving or maintaining gastrointestinal (GI) health, comprising: 【Chemistry 1】 [In the formula, R ６ is an acyl group of a long-chain fatty acid having 16 to 20 carbon atoms] as the predominant butyrate-containing triglyceride in the nutritional composition, wherein the compound of formula (1) provides at least 50% of the butyrate-containing triglycerides provided by the nutritional composition, and the nutritional composition is selected from a fortified food, a medical food or a food for special medical purposes, a dietary supplement, an infant formula, or a follow-on formula.

2. 2. The nutritional composition of claim 1, wherein the compound of formula (1) is the primary source of the butyrate or butyric acid in the nutritional composition.

3. 3. The nutritional composition of claim 1 or 2, wherein the compound of formula (1) provides at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially all of the butyrate moiety-containing triglycerides provided by the nutritional composition.

4. 4. The nutritional composition of any one of claims 1 to 3, wherein the nutritional composition is a dietary supplement for providing a source of butyrate.

5. 5. The nutritional composition of claim 4 in the form of a capsule, liquid, tablet, sachet, or powder.

6. 1. A method for the preparation of a nutrient composition comprising administering to a subject a subject in need thereof a butyrate or butyric acid source having improved organoleptic properties and for use in improving or maintaining gastrointestinal health, the method comprising administering to a subject ... 【Chemistry 2】 [In the formula, R ６ is an acyl group of a long-chain fatty acid having 16 to 20 carbons, wherein the compound of formula (1) is the majority butyrate-containing triglyceride in the nutritional composition, the compound of formula (1) provides at least 50% of the butyrate-containing triglycerides provided by the nutritional composition, and the nutritional composition is selected from a fortified food, a medical food or a food for special medical purposes, a food for special dietary uses, a dietary supplement, an infant formula, or a follow-on formula.

7. 7. The use according to claim 6, wherein the compound having formula (1) is present in the composition comprising the compound having formula (1) in an amount of at least 3% by weight of the total triglycerides in the composition.

8. 7. The use of claim 6, wherein the compound having formula (1) is present in the composition comprising the compound having formula (1) in an amount of at least 60%, at least 70%, at least 80%, or at least 90% by weight of the total amount of butyrate-containing triglycerides in the composition.

9. R ６ The use according to any one of claims 6 to 8, wherein is an acyl group of a fatty acid selected from the group consisting of oleic acid, palmitic acid, or linoleic acid.

10. formula 【Transformation 3】 1. A nutritional composition comprising a compound having the formula (5), wherein the nutritional composition is an infant formula, a follow-on formula, or a dietary supplement, and the compound having the formula (5) comprises at least 50% by weight of the total triglycerides containing a butyrate moiety in the composition, for use in improving or maintaining gastrointestinal health.

11. 11. The nutritional composition of claim 10, wherein the compound having formula (5) comprises at least 3% by weight of the total triglycerides in the nutritional composition.

12. 12. The nutritional composition of claim 10 or 11, wherein the compound having formula (5) comprises at least 60%, at least 70%, or at least 80% by weight of the total butyrate-containing triglycerides in the composition.

13. Use of a composition according to any one of claims 10 to 12 to provide a source of butyrate having improved organoleptic properties.

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