Food-grade butyrate

Abstract

This invention provides compounds that are edible sources of butyrate, as well as compounds with improved functional properties. [Solution] A nutritional composition for providing a source of butyrate or butyric acid, wherein the formula TIFF2026071301000024.tif35147 [In the formula, R 6 A nutritional composition comprising a compound having a long-chain fatty acid with 16 to 20 carbon atoms.

Description

[Technical Field]

[0001] This invention relates to a dietary source of butyrate. [Background technology]

[0002] Butyric acid salts and esters are called butyrates or butanoates. Butyric acid in ester form is found in many foods, such as milk, especially the milk of goats, sheep, cows, camels, and buffaloes, as well as milk-derived products, such as butter and cheese, such as Parmesan cheese. Butyric acid is also a product of anaerobic fermentation, such as a fermentation product produced by the gut microbiota.

[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 oxidation, enhances intestinal barrier function, and influences visceral sensitivity and intestinal motility.

[0004] Butyrates have 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 to reduce the proliferation of colon cancer cells in human cell lines (Lupton, J Nutr., 2004;134(2):479-482). The role of dietary fiber in colon cancer may be due to the production of volatile fatty acids such as butyric acid 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, but not limited to, include acetic acid, propionic acid, and butyric acid. SCFAs, particularly butyrate, inhibit histone deacetylases at the Foxp3 locus, promoting the generation of regulatory T cells in the colon (Furusawa Y, et al., Nature 2013;504(7480):446-450). Oral supplementation of butyrate enhances the antibacterial activity of intestinal macrophages, limiting the spread of bacteria across the intestinal barrier. Butyrate also benefits colon cells 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 promote small intestinal development in newborn piglets (Kotunia et al., J Physiol Pharmacol. 2004;55(2):59-68).

[0005] Tributyline is a triglyceride consisting of three ester functional groups, each having three butyrate moieties, and a glycerol skeleton. Under hydrolytic conditions, such as those occurring during digestion, tributyline can be a source of 3 moles of butyric acid per mole of tributyline. However, the effectiveness of tributyline may be limited by rapid lipolysis in the stomach.

[0006] Butyric acid and triptyline are both generally considered 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 has negative sensory qualities, such as vomit-like, fecal-like, and cheese-like odor characteristics. Triptyline also has negative sensory qualities, particularly a high degree of bitterness. These unpleasant taste and odor characteristics can make oral administration of compositions containing these compounds particularly difficult, especially in child populations.

[0007] Therefore, it is beneficial to provide a source of food-grade butyrate with improved properties compared to available solutions. The liquid form offers further advantages due to its ease of formulation and reduced problems of dissolution and homogenization. [Overview of the Initiative]

[0008] The present invention provides a compound that is a food source of butyrate. The present invention provides a compound having improved functional properties. In particular, the compound has improved odor and / or taste compared to butyric acid, butyrate salts, and triptyline. The compound can be used as a food source of butyric acid. The compound can be used in nutritional compositions for human or animal consumption, such as dietary supplements, medical foods, special medical foods, fortified foods, infant formulas, and follow-on formulas.

[0009] Advantageously, the compounds of the present invention can result in effective delivery of butyric acid to the intestines.

[0010] According to a first aspect of the present invention, a nutritional composition for providing a dietary source of butyric acid or butyrate with improved functional properties, comprising: [ka] [In the formula, R 6 Compounds having long-chain fatty acids with 16 to 20 carbon atoms. Use is provided.

[0011] The compound of formula (1) may be present in nutritional compositions such as nutritional prescriptions, 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 characteristic is an improved odor. In one embodiment, the improved sensory characteristic is an improved taste. In one embodiment, the improved sensory characteristic is an improved odor and an improved taste. In one embodiment, the improved taste is a reduced bitterness.

[0013] According to one aspect of the present invention, a nutritional composition for providing a source of butyrate or butyric acid, comprising the formula [ka] [In the formula, R 6 A nutritional composition is provided which contains a compound having a long-chain fatty acid with 16 to 20 carbon atoms as the main butyrate-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) can provide at least 20 wt%, at least 30 wt%, at least 40 wt%, at least 50 wt%, or at least 60 wt%, at least 70 wt%, at least 80 wt%, or at least 90 wt% of the butyrate - containing triglycerides in the nutritional composition.

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

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

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

[0020] In another preferred embodiment, the compound having formula (1) constitutes at least 60 wt% of the total amount of butyrate - containing triglycerides in the composition.

[0021] In one embodiment, the compound having formula (1) constitutes at least 70 wt% of the total amount of butyrate - containing triglycerides in the composition.

[0022] In one embodiment, the compound having formula (1) constitutes at least 80 wt% of the total amount of butyrate - containing triglycerides in the composition.

[0023] In one embodiment, the compound having formula (1) constitutes at least 90 wt% of the total amount of butyrate - containing triglycerides in the composition.

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

[0025] According to one aspect of the present invention, a nutritional composition for providing a source of butyrate or butyric acid, comprising the formula [ka] [In the formula, R 6 Compounds having long-chain fatty acids with 16 to 20 carbon atoms, and optionally, formula [ka] [In the formula, R 1 A nutritional composition is provided, comprising a compound having a long-chain fatty acid having 16 to 20 carbon atoms, wherein the compound of formula (1) is optionally present in combination with the compound of formula (2) in an amount of at least 30% by weight, preferably at least 40% by weight, and more preferably at least 50% by weight of the total butyrate-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), and the combination of the compound having formula (1) and the compound having formula (2) is present in an amount of at least 50% by weight, preferably at least 60% by weight, of the total butyrate-containing triglycerides in the composition, as defined herein.

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

[0028] In one embodiment, the nutritional composition contains less than 15 wt%, preferably less than 10 wt%, of the total amount of butyrate-containing triglycerides in the composition of the compound having the formula

Chemical formula

Chemical formula

Chemical formula

[0029] In one embodiment, the nutritional composition contains less than 8 wt%, preferably less than 5 wt%, or less than 2 wt% of the total amount of butyrate-containing triglycerides in the composition of the compound having the 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), in an amount of less than 15% by weight of the total butyrate-containing triglycerides in the composition.

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

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

[0033] In one embodiment, the nutritional composition may be selected from dietary supplements, fortified foods, medical foods or foods for special medical purposes, infant formulas, and follow-on formulas.

[0034] According to one aspect of the present invention, a dietary supplement for providing a source of butyrate or butyric acid, comprising the formula [ka] [In the formula, R 6 A dietary supplement is provided which contains a compound having a long-chain fatty acid with 16 to 20 carbon atoms as the main source of butyrate or butyric acid in the dietary supplement.

[0035] Dietary supplements may be in the form of, for example, capsules, tablets, sachets, liquids / oils, or powders.

[0036] According to another aspect of the present invention, an infant formula or follow-on formula, which is formula [ka] [In the formula, R 6An infant formula or follow-on formula is provided, which independently contains a compound having a long-chain fatty acid with 16 to 20 carbon atoms as the primary source of butyrate or butyric acid in the infant formula or follow-on formula.

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

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

[0039] According to another aspect of the present invention, a method for improving or maintaining the health of a patient, comprising the formula [ka] [In the formula, R 6 A method is provided which includes the step of administering to the patient an effective amount of a nutritional composition containing a compound having 16 to 20 carbon atoms as the primary source of butyrate or butyric acid in the nutritional composition.

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

[0041] In one embodiment, formula (1) is used as defined herein or present in a composition (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula) as defined herein. Preferably, the compound having formula (1) is present in the composition 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.

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

[0043] In one embodiment, the compound having formula (1) is used as defined herein or present in a composition as defined herein (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), in which case 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 present in a composition as defined herein (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), in which case the compound having formula (1) is present in an amount of at least 30% by weight, at least 40% by weight, or preferably at least 50% by weight of the total butyrate-containing triglycerides in the composition.

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

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

[0047] In one embodiment, R as defined herein 6 These are unsaturated fatty acids, preferably monounsaturated.

[0048] In one embodiment, R as defined herein 6 This 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 It is oleic acid.

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

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

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

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

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

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

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

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

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

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

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

[0061] In one embodiment, the compound having formula (5) constitutes about 20% to about 95% by weight of the total butyrate-containing triglycerides in the composition, about 30% to about 95% by weight, about 40% to about 90% by weight, about 50% to about 90% by weight, or 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) constitutes about 40% to about 80% by weight of the total butyrate-containing triglycerides in the composition, for example, 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) constitutes about 50% to about 90% by weight of the total butyrate-containing triglycerides in the composition, for example, 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, a nutritional composition for providing a source of butyrate or butyric acid, comprising the formula [ka] Compounds having the formula, and optionally, [ka] A nutritional composition is provided, comprising a compound having and a compound of formula (5), wherein the compound of formula (5) is optionally present in combination with the compound of formula (6) in an amount of at least 30% by weight, preferably at least 40% by weight, and more preferably at least 50% by weight of the total 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), and the combination of the compound having formula (5) and the compound having formula (6) is present in an amount of at least 50% by weight, preferably at least 60% by weight, of the total butyrate-containing triglycerides in the composition, as defined herein.

[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), and the combination of the compound having formula (5) and the compound having formula (6) is present in an amount of at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of the total butyrate-containing triglycerides in the composition.

[0067] In one embodiment, the composition contains less than 10% by weight of the total amount of butyrate-containing triglycerides in the composition, and is formulated as follows: [ka] It contains compounds that have the following properties.

[0068] According to one embodiment, the composition contains less than 10% by weight of the total amount of butyrate-containing triglycerides in the composition, and is of the formula [ka] It contains compounds that have the following properties.

[0069] According to one embodiment, the composition contains less than 10% by weight of the total amount of butyrate-containing triglycerides in the composition, and is of the formula [ka] It contains compounds that have the following properties.

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

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

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

[0074] The compositions of the present invention are 1,3-dibutylyl-2-linoleoylglycerol, 1,3-dibutylyl-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-oleoylglycerol, 1-butyryl-2-linoleoyl-3-oleoylglycerol , may further contain 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 composition of the present invention may preferably be in the form of a nutritional composition.

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

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

[0078] According to another aspect of the present invention, the use of compositions defined herein is provided for providing a source of butyrate or butyric acid with improved functional properties.

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

[0080] According to another aspect of the present invention, compositions defined herein are provided for improving or maintaining gastrointestinal health.

[0081] According to another aspect of the present invention, a method is provided for improving or maintaining gastrointestinal health in a subject, comprising the step of administering an effective amount of a composition as defined herein to the subject. [Modes for carrying out the invention]

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

[0083] Fatty acids are carboxylic acids that have a long tail (chain). Fatty acids can be either unsaturated or saturated. Fatty acids that are not bound to other molecules are called free fatty acids (FFAs).

[0084] The term "fatty acid portion" refers to the portion of the triglyceride derived from fatty acids in the esterification reaction with glycerol. The triglyceride used in this invention includes two butyric acid portions (also called "butyrate portions") and one long-chain fatty acid portion.

[0085] Advantageously, the compounds and compositions of the present invention can exhibit improved functional properties compared to triptyline, and provide a high butyric acid content, through the optimization of the butyric acid content of the triglycerides.

[0086] The long-chain fatty acids preferred for use in this invention are fatty acids having 16 to 20 carbon atoms.

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

[0088] The preferred long-chain fatty acid for use in this invention is oleic acid. Oleic acid is the main fatty acid present in breast milk.

[0089] The triglycerides of the present invention can be synthesized, for example, by the esterification reaction of long-chain fatty acid monoacylglycerols (MAGs) with butyric acid.

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

[0091] Water removal can be carried out by conventional methods determined by those skilled in the art as part of the usual procedure.

[0092] Advantageously, such synthesis methods avoid the use of triptyline as a raw material.

[0093] Alternative methods for triglyceride synthesis can be determined by those skilled in the art as part of a standard procedure.

[0094] In one embodiment, sunflower oil is a source of monoolein as a monoacylglycerol. This produces a triglyceride mainly containing a butyrate moiety and an oleate moiety.

[0095] This compound is free of dairy components, cholesterol, and animal-derived components. Fatty acids are detached from triglycerides by naturally occurring lipases in the gastrointestinal tract. Compared to butyrate salts, this compound does not require the addition of further mineral salts to the final formulation.

[0096] A single butyrate-partially-containing triglyceride may be used herein. Alternatively, a mixture of different butyrate-partially-containing triglycerides may 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, such as steps conventionally used in the production of vegetable oils.

[0098] composition The present invention provides compositions comprising butyrate-containing triglycerides as referred to herein. The compositions may be nutritional compositions such as fortified foods, medicinal foods or foods for special medical purposes, dietary supplements, infant formulas or follow-on formulas.

[0099] The expression "nutritional composition" means a composition that provides nutrition to a subject. This nutritional composition is preferably taken orally and may contain a lipid source 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 source 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 all of these.

[0100] In some specific 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 a particular physical or physiological condition and / or a particular disease and disorder (e.g., Codex STAN 146-1985, section 2.1).

[0101] In some specific embodiments, the nutritional compositions according to the present invention are medical foods or foods for special medical purposes (FSMPs). As used herein, “medical foods” or “foods for special medical purposes” refers to foods that are specifically formulated for and intended for the dietary management of a disease. In the United States, “medical foods” are defined in section 5(b) of the Food and Drug Administration’s 1988 Orphan Drug Act (21 USC360ee(b)(3)). In Europe, “medical foods” are referred to as “foods for special medical purposes” (for example, by definition in European Commission Delegated Regulation (EU) 2016 / 128 of 25 September 2015). The terms “medical foods” and “foods for special medical purposes” are used interchangeably herein.

[0102] In some specific embodiments, the nutritional composition according to the present invention is an "enteral nutrition composition," i.e., a food product in which the gastrointestinal tract is involved in the administration of the composition. Introduction into the stomach may involve the use of a tube passing through the oral / nasal cavity or a tube directly connected to the stomach in the abdomen. Such tubes can be used particularly in hospitals or clinics.

[0103] The composition according to the present invention may be an infant formula (e.g., an infant starter formula), a follow-up formula or follow-on formula, growing-up milk, 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 intended for specific nutritional supplementation purposes for infants during the first month of life, which, by its milk itself, satisfies the nutritional requirements for infants in this category (for example, Article 2(c) of the European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 for infant formulas and follow-on formulas).

[0105] Generally, starter formulas are breast milk substitutes for infants from birth. Follow-up or follow-on formulas are given from 6 months of age onward. These formulas constitute the main liquid component of the increasingly diverse diet of infants in this category. "Growing-up milk" (or GUM) is given from the first year onward. This milk is generally a dairy beverage specifically formulated to meet 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" should be understood as the mother's milk or colostrum, or the donor's milk or colostrum from the donor's milk.

[0107] The term “dietary supplement” can be used as a complement to an individual’s nutrition (typically used for nutritional supplementation, but also as an addition to any type of composition intended for ingestion). This may be in the form of, for example, tablets, capsules, lozenges, or liquids. Dietary supplements may further contain protective hydrophilic colloids (such as gums, proteins, and modified starches), binders, film-forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (such as oils, fats, waxes, and lecithins), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flowing agents, taste masking agents, bulking agents, gelling agents, and gel-forming agents. Dietary supplements may also contain conventional pharmaceutical additives and adjuvants, additives, and diluents, including, but not limited to, water, gelatin of any origin, vegetable gum, lignin sulfonate, talc, sugar, starch, gum arabic, vegetable oil, polyalkylene glycol, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, and fillers.

[0108] In another specific 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. Therefore, if the infant or toddler is premature, the fortifier is a particularly advantageous embodiment.

[0109] If the composition is a nutritional supplement, it can be provided in the form of a unit dose.

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

[0111] The nutritional composition according to the present invention may contain a protein source. The amount of protein may be 1.6 to 3 g / 100 kcal. In some embodiments, particularly when the composition is intended for premature infants / toddlers, the amount of protein may be 2.4 to 4 g / 100 kcal, or more than 3.6 g / 100 kcal. In some other embodiments, the amount of protein may be less than 2.0 g / 100 kcal, for example, 1.8 to 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 in the same way as, for example, soy-based plant protein sources. With respect to whey protein, the protein source may be based on acidic whey, sweet whey, or mixtures thereof, and may contain α-lactalbumin and β-lactoglobulin in any desired proportion. In some embodiments, the primary protein source is whey (i.e., more than 50%, for example more than 60% or more than 70% of the protein is derived from whey protein). The protein may be intact protein, hydrolyzed protein, or a mixture of intact and hydrolyzed protein. The term “intact” means that the main part of the protein is intact, i.e., its molecular structure has not changed, for example, at least 80% of the protein has not changed, for example at least 85% of the protein has not changed, preferably at least 90% of the protein has not changed, and more preferably at least 95% of the protein has not changed, for example at least 98% of the protein has not changed. In certain embodiments, the protein is not changed at all.

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

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

[0115] In a particular embodiment, the protein in the composition is hydrolyzed, completely 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, a nutritional composition containing a hydrolysate having a degree of hydrolysis of less than about 15% is commercially available from Nestle Company under the trademark name Peptamen®.

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

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

[0118] The nutritional composition according to the present invention may contain a carbohydrate source. The inclusion of a carbohydrate source is particularly preferred when the nutritional composition of the present invention is an infant formula. In this case, any carbohydrate source commonly found in infant formulas, such as lactose, sucrose, saccharose, maltodextrin, starch, and mixtures thereof, can be used, but one preferred carbohydrate source for infant formulas is lactose. The nutritional composition of the present invention may also contain all vitamins and minerals that are understood to be essential in daily diets and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins, and other nutrients optionally present in the composition 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 will vary depending on the target population. If necessary, the nutritional composition of the present invention may also contain emulsifiers and stabilizers, such as soy, lecithin, and citrate esters of mono and diglycerides. The nutritional composition of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGFβ, slgA, glutamine, nucleotides, and nucleosides.

[0119] The composition of the present invention may further contain at least one indigestible oligosaccharide (e.g., prebiotic). These components are typically present 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. Therefore, prebiotics remain intact when they enter the large intestine, where they are selectively fermented by beneficial bacteria. Examples of prebiotics include certain oligosaccharides such as fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, or any mixture thereof. In certain embodiments, the prebiotics may be fructooligosaccharides and / or inulin. In certain embodiments, the prebiotics may be a combination of FOS and inulin, for example, the combination in a product marketed by BENEO-Orafti under the trademark name Orafti® Oligofructose (formerly Raftilose®), or the combination in a product marketed by BENEO-Orafti under the trademark 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 trademark name "Prebio1". The nutritional compositions of the present invention may also contain at least one milk oligosaccharide, which may be BMO (milk oligosaccharide) and / or HMO (human milk oligosaccharide). The compositions of the present invention may further contain at least one probiotic (i.e., a probiotic strain), such as a probiotic strain.

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

[0122] In some specific embodiments, the probiotic is a probiotic strain. In some specific embodiments, the probiotic strain is Bifidobacteria and / or Lactobacillus.

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

[0124] In one embodiment, the probiotics are live bacteria. In another embodiment, the probiotics are non-replicating or inactivated. The probiotics may also be a portion of the probiotic, such as a cell wall component, or a metabolite of the probiotic. In some other embodiments, both viable and inactivated probiotics may be present. The nutritional composition of the present invention may further include 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 that contains a milk-based product. Dairy products are generally made from a suitable mixture of concentrated milk protein and a fat source. Dairy products can be acidified. Examples of dairy products include ready-to-drink dairy beverages, concentrated milk, evaporated milk, sweetened concentrated milk, powdered milk, yogurt, fresh cheese, cheese, ice cream, and dairy spreads, such as spreadable fresh cheese, cottage cheese, quark, crème fraîche, clotted cream, and cream cheese. Powdered milk can be produced, for example, by spray drying or freeze-drying.

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

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

[0128] Acidified dairy products can be obtained by fermentation using suitable microorganisms. Fermentation imparts flavor and acidity to the dairy product. Fermentation may also affect the texture of the dairy product. In addition, the microorganisms used for fermentation are selected based on their ability to ferment milk into edible fermented dairy products. Typically, these microorganisms are known for their beneficial properties. Examples of such microorganisms include lactic acid bacteria and yeast. Some of these microorganisms can be considered probiotics. Examples of lactic acid bacteria include Lactobacillus delbrueckii subspecies 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 fermented dairy products, also called cultured dairy products or cultured dairy foods, or cultured milk, is fermented buttermilk fermented with Lactococcus lactis (Lactococcus lactis subgenus Lactococcus lactis, Lactococcus lactis subgenus Cremoris, Lactococcus lactis subgenus Lactococcus viover diacetylactis) and / or Leuconostoc mesenteroides subgenus Cremoris.

[0130] The microorganisms can be alive or inactive.

[0131] Dairy-like products are products manufactured in the same manner as the dairy products described above, but using (all or part) sources of protein other than milk, and / or (all or part) sources of edible fat other than milk. Suitable protein sources include plant proteins, such as soybeans, potatoes, and peas. Suitable fat sources include oils and fats of plant or marine origin. Fats and oils are used as interchangeable terms. Since the separation step can be omitted depending on the formulation of the dairy-like product, preparation in the same manner as described above means product processing in which the conventional whey separation step is omitted.

[0132] The nutritional composition according to the present invention can be prepared by any suitable method.

[0133] For example, formulas such as infant formula can be prepared by blending protein sources, carbohydrate sources, and fat sources together in appropriate proportions. If used, emulsifiers can be added at this stage. Vitamins and minerals may be added at this stage, but are usually added later to avoid thermal decomposition. Any lipophilic vitamins and emulsifiers can be dissolved in the fat source before blending. Then, preferably, reverse osmosis treated water can be mixed to form a liquid mixture. The water temperature should be appropriately in the range of about 50°C to about 80°C to aid in the dispersion of the components. A commercially available liquefaction device can be used to form the liquid mixture.

[0134] In particular, if the final product is in liquid form, any oligosaccharide may be added at this stage. If the final product is in powder form, any oligosaccharide may also be added at this stage if desired.

[0135] Next, the liquid mixture is homogenized, for example, in two steps.

[0136] In one embodiment, the nutritional composition of the present invention is given to an infant or toddler as a composition that complements breast milk.

[0137] The composition of the present invention may be in the form of, for example, a solid (e.g., powder), a liquid, or a gelatinous substance.

[0138] The compositions of the present invention may be, for example, tablets, sugar-coated tablets, capsules, gel caps, 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 contain one or more suitable carriers, diluents, and / or additives that are pharmaceutically acceptable.

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

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

[0142] The pharmaceutical composition may contain, or in addition to, any suitable binder, lubricant, suspending agent, coating agent, and / or solubilizer as a carrier, additive, or diluent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, fluid lactose, and β-lactose, 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, and sodium chloride.

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

[0145] Gastrointestinal health The compounds defined herein are sources of butyrate / butyric acid and can therefore 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 diseases, such as Crohn's disease or ulcerative colitis.

[0147] Butyrate has been well documented to have multiple beneficial effects on GI health. At intestinal concentrations, butyrate acts to regulate transepithelial fluid transport, mucosal inflammation, and oxidation, 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), and are most important for colonic cells in the distal colon. The strong nutritional effect of butyrate on the small intestinal mucosa has 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 the usefulness of the matrix to colonic cells. On the other hand, administration of butyrate into the colonic lumen induces weight gain, increased DNA synthesis, and increased depth of intestinal crypts (Kripke et al., J Parenter Enter Nutr. 1989;13:109-116).

[0149] High concentrations of butyrate, obtained by the fermentation of insoluble dietary fiber or after rectal administration of butyrate, may inhibit early and late-stage tumorigenesis in the colon by regulating the transcription, expression, and activation of key proteins in the apoptosis 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 captures far greater amounts of butyrate compared to glutamine or glucose. Experiments have shown that butyrate injection results in a significant reduction in inflammation and a decrease in the degree of colonic wall ulceration in rats (Andoh et al., J Parenter Enter Nutr. 1999;23(5):70-73).

[0151] The effectiveness of butyrate enemas has been demonstrated through 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 butyrates may be related to the inhibition of nuclear factor κB (NFκB) translocation and binding to DNA, as well as the inhibition of transcription and production of inflammatory cytokines (Segain et al., Gut. 2000; 47: 397-403).

[0153] Therefore, the triglyceride compounds used in this invention are sources of butyrate and can play a significant 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] Generally speaking, the administration of the combinations or compositions described herein may be, for example, administered orally or via another route into the gastrointestinal tract, and may also be administered by enteral nutrition.

[0157] The subject may be mammals such as humans, dogs, cats, horses, goats, cattle, sheep, pigs, deer, and primates. Preferably, the subject is humans. [Examples]

[0158] Example 1 - Preparation of a butyrate-containing triglyceride A composition containing a butyrate-containing triglyceride was produced by the esterification reaction of monoolein (derived from sunflower oil) with butyric acid added in molar excess (total 5 equivalents). These two reagents were mixed together in a flask and heated under 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] Table 1 below shows the components (mainly triglycerides) of the obtained oil composition. These triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by the number of lipids: 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. For example, 16:0-4:0-18:1 represents two different triglycerides, both of which have 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, the 4:0-4:0-18:1 triglyceride was identified as the most abundant.

[0161] Next, the obtained oil product was subjected to a decolorization step using bleached clay, and purified by short-pass 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 triptylin).

[0162] When the obtained oil product was evaluated using a descriptive sensory evaluation method, it was found that the oil product had a better odor and taste than triptyline and butyric acid.

Claims

1. A nutritional composition for providing a source of butyrate or butyric acid, comprising the formula 【Chemistry 1】 [In the formula, R ６ A nutritional composition comprising a compound having a long-chain fatty acid having 16 to 20 carbon atoms as the main butyrate-containing triglyceride in the nutritional composition.

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

3. The nutritional composition according to claim 1 or 2, wherein the compound of formula (1) provides at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially all of the butyrate-containing triglyceride provided by the nutritional composition.

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

5. A dietary supplement according to claim 4, in the form of a capsule, liquid, tablet, sachet, or powder.

6. The nutritional composition according to any one of claims 1 to 3, wherein the nutritional composition is in the form of an infant formula or a follow-on formula.

7. A nutritional composition according to any one of claims 1 to 5, for use in improving or maintaining gastrointestinal (GI) health.

8. A nutritional composition for providing a source of butyrate or butyric acid with improved functional properties, formula 【Chemistry 2】 [In the formula, R ６ The use of a compound having [a long-chain fatty acid having 16 to 20 carbon atoms], wherein the compound of formula (1) is the major butyrate-containing triglyceride in the nutritional composition.

9. The use according to claim 8, wherein the nutritional composition is selected from fortified foods, medical foods or foods for special medical purposes, foods for special dietary uses, dietary supplements, infant formulas or follow-on formulas.

10. The nutritional composition according to any one of claims 1 to 6, the compound for use according to claim 7, or the use according to claim 8 or 9, 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.

11. The nutritional composition according to any one of claims 1 to 6, the compound for use according to claim 7, or the use according to claim 8 or 9, wherein the compound having formula (1) is present in the composition containing the compound having formula (1) in an amount of at least 30% by weight of the total amount of the butyrate-partially-containing triglycerides in the composition, preferably at least 50% by weight of the total amount of the butyrate-partially-containing triglycerides in the composition.

12. The nutritional composition according to any one of claims 1 to 5, the compound for use according to claim 7, or the use according to claim 8 or 9, wherein the compound having formula (1) is present in the composition containing the compound having formula (1) in an amount of at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of the total amount of the butyrate-partially-containing triglycerides in the composition.

13. R ６ The nutritional composition according to any one of claims 1 to 6 or 10 to 12, selected from the group consisting of oleic acid, palmitic acid, or linoleic acid; the compound for use according to any one of claims 7 or 10 to 12; or the use according to any one of claims 8 to 9 or 10 to 12.

14. formula 【Transformation 3】 A nutritional composition comprising a compound having formula (5), wherein the compound having formula (5) constitutes at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition.

15. The nutritional composition according to claim 14, wherein the compound having formula (5) constitutes at least 3% by weight of the total triglycerides in the nutritional composition.

16. The nutritional composition according to claim 14 or 15, wherein the compound having formula (5) constitutes at least 30% by weight, at least 40% by weight, preferably at least 50% by weight of the total amount of the butyrate-containing triglycerides in the composition.

17. The nutritional composition according to claim 16, wherein the compound having formula (5) constitutes at least 60% by weight, at least 70% by weight, preferably at least 80% by weight of the total amount of the butyrate-containing triglycerides in the composition.

18. The composition according to any one of claims 14 to 17, wherein the composition is an infant formula, a follow-on formula, or a dietary supplement.

19. Use of the composition according to any one of claims 14 to 18 to provide a source of butyrate with improved functional properties.

20. A composition according to any one of claims 14 to 19, for use in improving or maintaining gastrointestinal health.

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