Dietary butyrate and its uses

Abstract

To provide a novel method for using butyrate as a food ingredient having improved organoleptic properties.SOLUTION: There are provided a compound having the formula (1), (2), (3) or (4), or combinations thereof, for use in the maintenance of bone health and / or the prevention and / or treatment of bone disorder associated with unbalanced bone catabolism, where R1, R2, R3, R4, R5 and R6 are independently a long chain fatty acid having 16 to 20 carbons.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel uses of the food ingredient butyrate with improved organoleptic properties. In particular, the present invention provides a food ingredient butyrate with improved organoleptic properties and its use in maintaining bone health and / or preventing, alleviating, and / or treating bone disorders associated with unbalanced bone catabolism. [Background technology]

[0002] Salts and esters of butyric acid are called butyrates or butanoates. Butyric acid in ester form is found in many foods, such as milk, especially goat, sheep, cow, camel, and buffalo milk, and milk-derived products, such as butter, and cheese, such as Parmesan cheese. Butyric acid is also a product of anaerobic fermentation, such as the fermentation product produced by the intestinal flora. Tributyrin is a triglyceride consisting of three ester functional groups with three butyrate moieties and a glycerol backbone. Under hydrolysis conditions, such as those occurring during digestion, tributyrin can be 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.

[0003] The multiple beneficial effects of butyrate are well documented in mammals and livestock: at the intestinal level, butyrate plays a regulatory role on transepithelial fluid transport, mucosal inflammation and oxidative status, strengthens the intestinal barrier function, and influences visceral hypersensitivity 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 production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer (Lupton, The Journal of Nutrition. 134(2):479-82). Bacteria in the large intestine that feed on or ferment non-digestible fibers 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, activate regulatory T cells in the colon through the suppression of histone deacetylase at the Foxp3 locus (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. Additionally, 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 neonatal piglets (Kotunia et al., J Physiol Pharmacol. 2004;55(2):59-68).

[0005] The gut microbiota may be involved in bone physiology, regulating bone mass via the immune system and promoting bone resorption and formation by production of SFCAs, including butyrate (Ohlsson and Sjogren, 2012).Furthermore, increased production of short-chain fatty acids induced by fiber fermentation positively correlates with increased calcium absorption in the lower intestine in both animals and humans, as well as increased bone mineral density and strength in animal models (Wallace at al., 2017).

[0006] Data from growing children and postmenopausal women suggest that prebiotics have both short-term and long-term beneficial effects on bone turnover and bone mineral accretion in the skeleton. The best accepted mechanism is through microbial fermentation of prebiotics resulting in the production of short-chain fatty acids (butyrate being one of them) and a concomitant decrease in pH, increasing calcium bioavailability in the colon. As a result, more calcium is available for absorption and bone mineralization (Whisner CM, Weaver CM, 2017).

[0007] Further evidence exists that short-chain fatty acids regulate whole-body bone mass and protect against pathological bone loss. Short-chain fatty acids (SCFAs), the main metabolic products derived from microbial fermentation of dietary fiber in the gut, affect local and systemic immune function. SCFAs (including butyrate) have been shown to be regulators of osteoclast metabolism and bone mass in vivo. Treating mice with SCFAs, as well as feeding them a high-fiber diet, significantly increases bone mass and prevents postmenopausal and inflammatory bone loss. In summary, SCFAs and butyrate have been identified as potent regulators of osteoclast metabolism and bone homeostasis (Lucas, Nat Comm, 2018).

[0008] Both butyric acid and tributyrin are generally regarded as safe (GRAS) food additives (21CFR582.60 and 21CFR184.1903, respectively) and are natural components of many dairy products. However, butyric acid is associated with negative sensory qualities, such as vomit, feces, and cheese-like odor characteristics. Tributyrin also has negative sensory qualities, especially a high degree of bitterness. These unpleasant taste and odor characteristics can make oral administration of compositions containing these compounds particularly difficult, especially in the pediatric population.

[0009] It would therefore be advantageous to provide a food grade source of butyrate for use in maintaining bone health and / or preventing, alleviating, and / or treating bone disorders associated with imbalanced bone catabolism, having improved organoleptic properties compared to available solutions. Summary of the Invention

[0010] The present invention provides a compound that is a butyrate source for use in improving or maintaining bone health, with improved sensory properties.In particular, the compound has improved odor and / or taste compared to butyric acid, butyrate salts, and tributyrin.The compound can be used as butyric acid in food ingredients.The compound can be used in, for example, nutritional compositions, dietary supplements, infant formulas, and follow-on formulas.

[0011] Advantageously, compounds for use according to the present invention have been shown to have a low degree of lipolysis in the stomach and may efficiently deliver butyric acid to the intestinal compartment.

[0012] According to one aspect of the present invention there is provided a compound having the formula:

[0013] [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently long-chain fatty acids having 16 to 20 carbons.

[0014] According to another aspect of the present invention, there is provided a method for maintaining bone health and / or preventing, alleviating, and / or treating bone disorders associated with imbalanced bone catabolism in a patient, comprising administering an effective amount of a compound having the formula:

[0015] [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently long-chain fatty acids having 16 to 20 carbons.

[0016] In one embodiment, a combination of a compound having formula (1) and a compound having formula (2) is used as defined herein or is 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 an amount of at least 10% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 10% by weight of the total amount of triglycerides in the composition.

[0017] In one embodiment, a combination of a compound having formula (1) and a compound having formula (2) is used as defined herein or is present in a composition as defined herein (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on milk), wherein the compound having formula (1) is present in an amount of at least 10% by weight of the total amount of butyric acid-containing triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 10% by weight of the total amount of butyric acid-containing triglycerides in the composition.

[0018] In another embodiment, a combination of a compound having formula (1) and a compound having formula (2) is used as defined herein or is present in a composition as defined herein (e.g., a nutritional composition, a dietary supplement, an infant formula, or a follow-on formula), wherein the compound having formula (1) is present in an amount of at least 15% by weight of the total amount of butyric acid-containing triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 15% by weight of the total amount of butyric acid-containing triglycerides in the composition.

[0019] In one embodiment, a combination of a compound having formula (1), a compound having formula (2), a compound having formula (3) and a compound having formula (4) is used as defined herein or is present in a composition as defined herein, i.e., in a nutritional composition, a dietary supplement, an infant formula or a follow-on milk.

[0020] In one embodiment, R as defined herein 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 is an unsaturated fatty acid, preferably a monounsaturated fatty acid.

[0021] In one embodiment, R as defined herein 1 , R 2 , R 3 , R 4 , R5 , and / or R 6 is selected from the group consisting of oleic acid, palmitic acid, stearic acid, or linoleic acid.

[0022] In one embodiment, R as defined herein 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 is oleic acid.

[0023] In one embodiment, R as defined herein 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 is palmitic acid.

[0024] In one embodiment, compound (1) is 1,3-dibutyryl-2-palmitoylglycerol.

[0025] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each of these is oleic acid.

[0026] In one embodiment, the compound having formula (1) is:

[0027] [ka]

[0028] In one embodiment, the compound having formula (2) is:

[0029] [ka]

[0030] In one embodiment, the compound having formula (3) is:

[0031] [ka]

[0032] In one embodiment, the compound having formula (4) is:

[0033] [ka]

[0034] According to another aspect of the present invention there is provided a composition for use in maintaining bone health and / or preventing, alleviating and / or treating bone disorders associated with imbalanced bone catabolism, the composition comprising a compound having the formula: [ka] The compound having formula (5) constitutes at least 10% by weight of the total triglycerides in the composition, and the compound having formula (6) constitutes at least 10% by weight of the total triglycerides in the composition.

[0035] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total triglycerides in the composition, and the compound having formula (6) comprises at least 15% by weight of the total triglycerides in the composition.

[0036] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total triglycerides in the composition, and the compound having formula (6) comprises at least 20% by weight of the total triglycerides in the composition.

[0037] In one embodiment, the compound having formula (5) comprises at least 20% by weight of the total triglycerides in the composition, and the compound having formula (6) comprises at least 20% by weight of the total triglycerides in the composition.

[0038] In one embodiment, the compound having formula (5) constitutes about 15% to about 30% by weight of the total amount of triglycerides in the composition, and the compound having formula (6) constitutes about 20% to about 30% by weight of the total amount of triglycerides in the composition.

[0039] In one embodiment, the composition for use in maintaining bone health and / or preventing, alleviating, and / or treating bone disorders associated with imbalanced bone catabolism further comprises a compound having the formula: [ka] Preferably, the compound having formula (7) constitutes at least 2% or 3% by weight of the total amount of triglycerides in the composition, and / or further comprises a compound having the formula: [ka] Preferably, the compound having formula (8) constitutes at least 2% or 3% by weight of the total triglycerides in the composition.

[0040] According to another embodiment of the present invention there is provided a composition for use in maintaining bone health and / or preventing, alleviating and / or treating bone disorders associated with imbalanced bone catabolism, the composition comprising a compound having the formula: [ka] The compound having formula (5) constitutes at least 10% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 10% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0041] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 15% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0042] In one embodiment, the compound having formula (5) comprises at least 15% by weight, preferably at least 20% by weight, of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 20% by weight, preferably at least 25% by weight, of the total amount of butyrate-containing triglycerides in the composition.

[0043] In one embodiment, the composition for use in maintaining bone health and / or preventing, alleviating, and / or treating bone disorders associated with imbalanced bone catabolism further comprises a compound having formula (7), preferably wherein the compound having formula (7) constitutes at least 2% or 3% by weight of the total amount of butyrate moiety-containing triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably wherein the compound having formula (8) constitutes at least 2% or 3% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

[0044] The composition of the present invention for use in maintaining bone health and / or preventing, alleviating and / or treating bone disorders associated with imbalanced bone catabolism comprises 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-butyric acid, 1-glyceryl-2-oleoyl-3-glycerol ... In some embodiments, the glycerol may further comprise 1-oleoyl-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.

[0045] The composition for use according to the invention may be in the form of a nutritional composition.

[0046] The composition for use according to the invention may be in the form of an infant formula or follow-on milk.

[0047] Compositions for use according to the invention may be in the form of a dietary supplement.

[0048] 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 administering to said subject an effective amount of a composition as defined herein.

[0049] According to another aspect of the present invention, there is provided a method for maintaining bone health and / or preventing, alleviating and / or treating bone disorders associated with imbalanced bone catabolism in a subject, comprising administering to the subject an effective amount of a composition as defined herein. [Brief description of the drawings]

[0050] [Figure 1] Figure 1 shows the release of fatty acids from emulsions containing 200 mg of (A) tributyrin, (B) high oleic sunflower oil, and (C) a mixture of butyrate moieties-containing triacylglycerols (TAGs) according to the present invention, which have been digested either i) in simulated intestinal fluid (SIF) or (ii) sequentially in gastric fluid (SGF) followed by simulated intestinal fluid (SIF). [Diagram 2] FIG. 1 shows the overall extent of lipid digestion for a mixture of tributyrin, high oleic sunflower oil, and butyrate moiety-containing TAG according to the present invention, after both SIF and SGF-SIF. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] Triglycerides Triglycerides (also called triacylglycerols) are triesters derived from glycerol and three fatty acids.

[0052] Fatty acids are carboxylic acids with 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).

[0053] The term "fatty acid moiety" refers to the portion of a triglyceride that is derived from a fatty acid in an esterification reaction with glycerol. The triglycerides used in the present invention contain at least one butyric acid moiety and at least one long chain fatty acid moiety.

[0054] Preferred long chain fatty acids for use in the present invention are those having from 16 to 20 carbon atoms.

[0055] Examples of long chain fatty acids include oleic acid, palmitic acid, stearic acid, and linoleic acid.

[0056] The triglyceride of the present invention can be synthesized, for example, by an esterification reaction between a long-chain fatty acid and butyric acid and glycerol.

[0057] The triglycerides of the present invention can be synthesized, for example, by transesterification between tributyrin and another triglyceride containing long chain fatty acids. In one embodiment, high oleic sunflower oil is the source of long chain fatty acids. This creates a triglyceride that contains mainly butyrate and oleate moieties. Oleic acid is the main fatty acid present in breast milk. This compound is dairy-free, cholesterol-free, and animal-derived-free. The fatty acids are released from the triglyceride by lipases naturally occurring in the gastrointestinal tract. Compared to butyrate salts, this compound does not add additional mineral salts to the final formulation.

[0058] Alternative methods for the synthesis of triglycerides can be determined by those skilled in the art as part of routine procedures. As an example, a method for obtaining 1,3-dibutyryl-2-palmitoylglycerol (BPB) is shown below.

[0059] [ka]

[0060] A single butyrate moiety-containing triglyceride can be used herein, or a mixture of different butyrate moiety-containing triglycerides can be used.

[0061] composition The present invention provides a composition comprising the butyrate moiety-containing triglycerides referred to herein. The composition may be, for example, a nutritional composition, a dietary supplement, an infant formula, or a follow-on milk.

[0062] 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.

[0063] In some particular embodiments, the nutritional composition according to the invention is an "enteral nutritional composition", i.e. a foodstuff in which administration of the composition involves the gastrointestinal tract. Introduction to the stomach may involve the use of a tube passing 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.

[0064] The compositions of the invention can be administered to individuals, such as humans, e.g., elderly people, infants, children, and / or adults, in a therapeutically effective dose. The therapeutically effective dose can be determined by one of skill in the art and can vary depending on a number of factors known to those of skill in the art, such as the severity of the condition and the weight and general condition of the individual.

[0065] 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.

[0066] As used herein, the expression "infant formula" refers to a food intended for the specific nutritional supplementation of infants during the first month of life and which, by its own milk, 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 for infant and follow-on formulas).

[0067] Starter formulas are generally 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 diverse 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.

[0068] 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.

[0069] The term "dietary supplement" can be used to supplement the nutrition of an individual (typically used for nutritional supplementation, but also can 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 further 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, gelling 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 sulfonates, talc, sugar, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, coloring agents, wetting agents, fillers, and the like.

[0070] 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, when the infant or toddler is a premature infant, the fortifier is a particularly advantageous embodiment.

[0071] When the composition is a nutritional supplement, it can be provided in a unit dosage form.

[0072] 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 lipid (or a lipid source) may be present.

[0073] The nutritional composition according to the present invention may contain a protein source. The protein may be in an amount of 1.6-3g / 100kcal. In some embodiments, especially when the composition is intended for premature infants / toddlers, the protein amount may be 2.4-4g / 100kcal, or more than 3.6g / 100kcal. In some other embodiments, the protein amount may be less than 2.0g / 100kcal, for example 1.8-2g / 100kcal, or less than 1.8g / 100kcal.

[0074] For example, protein sources based on whey, casein, and mixtures thereof can be used, as well as plant-based protein sources, for example based on soy. With regard to whey protein, the protein source may be based on acid whey or sweet whey or mixtures thereof and may contain alpha-lactalbumin and beta-lactoglobulin in any desired proportion. In some embodiments, the main protein source is whey (i.e., more than 50%, such as more than 60% or more than 70% of the protein originates from whey protein). The protein may be an intact protein or a hydrolyzed protein, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the major part of the protein is intact, i.e., the molecular structure is not altered, for example, at least 80% of the protein is not altered, for example, at least 85% of the protein is not altered, preferably at least 90% of the protein is not altered, even more preferably at least 95% of the protein is not altered, for example, at least 98% of the protein is not altered. In certain embodiments, the protein is not altered at all.

[0075] 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.

[0076] Proteins can be either fully hydrolyzed or partially hydrolyzed. If hydrolyzed protein is required, the hydrolysis process can be carried out as desired as known in the art. For example, whey protein hydrolysates can be prepared by enzymatically hydrolyzing whey fractions 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 total lysine to less than about 10% by weight of total lysine, for example about 7% by weight of lysine, which significantly improves the nutritional value of the protein source.

[0077] In a particular embodiment, the proteins of the composition are hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the proteins may be 2-20, or 8-40, or 20-60, or 20-80, or more than 10, or more than 20, or more than 40, or more than 60, or more than 80, or more 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®.

[0078] At least 70%, 80%, 85%, 90%, 95%, or 97% of the protein may be hydrolysed, hi certain embodiments, 100% of the protein is hydrolysed.

[0079] In one particular embodiment, the protein of the composition is a plant-based protein.

[0080] The nutritional composition according to 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 that is usually found in infant formula can be used, such as lactose, sucrose, saccharose, maltodextrin, starch, and mixtures thereof, but one of the preferred carbohydrate sources for infant formula is lactose. The nutritional composition of the present invention may also contain all the vitamins and minerals that are understood to be essential in daily diet and in significant amounts for nutrition. Minimum requirements for certain vitamins and minerals have been established. Examples of minerals, vitamins and other nutrients that may be 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 vary depending on the target population. If necessary, the nutritional composition of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, citrate esters of mono- and diglycerides, etc. 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, nucleosides, etc.

[0081] The compositions of the present invention may further comprise at least one non-digestible oligosaccharide (eg, a prebiotic). These ingredients will typically be present in an amount of 0.3-10% by weight of the composition.

[0082] Prebiotics are usually indigestible in the sense that they are not broken down or absorbed in the stomach or small intestine. Thus, they 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 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 (previously Raftilose®) or in the product sold by BENEO-Orafti under the trade name Orafti® Inulin (previously 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 composition of the present invention may also comprise at least one milk oligosaccharide, which may be BMO (bovine milk oligosaccharide) and / or HMO (human milk oligosaccharide). The composition of the present invention may further comprise at least one probiotic (i.e. probiotic strain), such as a probiotic strain.

[0083] 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.

[0084] In some particular embodiments, the probiotic is a probiotic strain, hi some particular embodiments, the probiotic strain is Bifidobacteria and / or Lactobacilli.

[0085] The nutritional composition according to the invention may contain, on a dry weight basis, from 10e3 to 10e12 cfu of the probiotic strain per gram of composition, more preferably from 10e7 to 10e12 cfu, for example from 10e8 to 10e10 cfu of the probiotic strain.

[0086] In one embodiment, the probiotics are live bacteria. In another embodiment, the probiotics do not replicate or are inactivated. The probiotics may also be parts of the probiotics, such as cell wall components, or metabolic products of the probiotics. 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.

[0087] The nutritional compositions according to the present invention may be prepared in any suitable manner.

[0088] For example, a formula, such as an infant formula, can be prepared by blending together a protein source, a carbohydrate source, and a fat source 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 prior to blending. Water, preferably treated with reverse osmosis, can then be mixed 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 liquefying device can be used to form the liquid mixture.

[0089] 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 be added at this stage as well, if desired.

[0090] The liquid mixture is then homogenized, for example in two stages.

[0091] In one embodiment, the nutritional composition of the present invention is given to an infant or young child as a composition to complement breast milk.

[0092] Compositions of the present invention may be, for example, in solid (eg, powder), liquid, or gelatinous form.

[0093] 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.

[0094] The composition may be in the form of a pharmaceutical composition and may comprise one or more suitable pharma- ceutically acceptable carriers, diluents and / or excipients.

[0095] Examples of such suitable excipients for the compositions described herein can be found in the Handbook of Pharmaceutical Excipients, 2nd Edition (1994), edited by A Wade and PJ Weller.

[0096] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0097] 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.

[0098] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0099] 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 can also be used.

[0100] The nutritional composition according to the invention may be a dairy product in one embodiment. A dairy product is a product that includes a milk-based product. Dairy products are generally made from a suitable mixture of concentrated milk protein sources 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 by freeze drying.

[0101] 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 that contains less than 0.1% milk fat. Semi-skimmed milk is milk that contains 1.5% to 2.5% milk fat. Full-fat milk is usually milk that contains 3% to 4% fat. The exact fat content of skimmed, semi-skimmed, and full-fat milk depends mainly on local food regulations.

[0102] Dairy products are generally produced from cow's milk. Dairy products can also be produced from buffalo milk, yak milk, goat milk, sheep milk, horse milk, donkey milk, camel milk, reindeer milk, moose milk, or combinations thereof.

[0103] Acidified dairy products can be obtained by fermentation with suitable microorganisms. Fermentation provides flavor and sourness to the dairy product. Fermentation may also affect the texture of the dairy product. In addition, the microorganisms used for fermentation are selected for their ability to ferment milk into a fermented dairy product that can be consumed. Usually, the microorganisms are known for their beneficial properties. The microorganisms include lactic acid bacteria and yeasts. Some of these microorganisms can be considered as 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.

[0104] Another example of a fermented dairy product, also known as cultured dairy products or cultured dairy foods, or cultured milks, is cultured buttermilk fermented with Lactococcus lactis (Lactococcus lactis subsp. lactis, Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. lactis biovar. diacetylactis) and / or Leuconostoc mesenteroides subsp. cremoris.

[0105] The microorganisms may be live or inactivated.

[0106] Dairy analogues are products made in a similar manner to the dairy products described above, but using (all or part) a non-dairy protein source and / or using (all or part) a non-dairy edible fat source. Suitable protein sources include vegetable proteins, such as soybean, potato, and pea. Suitable fat sources include oils and fats of plant or marine origin. Fats and oils are used as interchangeable terms. Preparations similar to those described above are meant to include product processing in which the traditional whey separation step is omitted, since the dairy analogue formulation of the product allows the elimination of the separation step.

[0107] The nutritional composition according to the present invention may in one embodiment be a food product.

[0108] treatment All references made herein to "treatment" are understood to include curative, palliative and prophylactic treatment. Treatment may also include arresting the progression of the severity of the disease.

[0109] Both human and veterinary treatments are within the scope of the present invention.

[0110] Bone Health The multiple beneficial effects of butyrate on bone health have been documented in the scientific literature, as reported in the Background of the Invention.

[0111] The compounds defined herein are sources of butyrate / butyric acid and may therefore be used for maintaining bone health and / or for the prevention, mitigation, and / or treatment of bone disorders associated with unbalanced bone catabolism.

[0112] According to the present invention, "maintaining bone health" relates to and also means preventing, inhibiting and / or limiting bone loss.

[0113] In the context of the present invention, the term "maintaining bone health" means one or more of the following: preventing, inhibiting and / or limiting bone loss (especially bone loss associated with aging or with long-term hospitalization), preventing, inhibiting and / or limiting bone loss, regulating and / or inhibiting bone catabolism, modulating the rate of bone formation and / or the rate of bone resorption, inhibiting and / or limiting bone resorption, improving bone density, assisting in bone regeneration during fracture healing.

[0114] The term "prevention and / or treatment of bone disorders associated with unbalanced bone catabolism" refers to the prevention of bone diseases and the reduction in frequency and / or incidence and / or severity and / or duration. Incidence relates to the number of occurrences of any bone disease. Frequency relates to the number of occurrences of the same bone disease. This prevention encompasses the reduction in frequency and / or severity of said bone diseases in later life.

[0115] In the context of the present invention, the term "prevention and / or treatment of bone disorders associated with unbalanced bone catabolism" means the prevention and / or treatment of osteoporosis, osteoarthritis and / or osteopenia.

[0116] In one embodiment, osteoporosis may be associated with one or more of the following conditions: inflammation, metabolic imbalance, the aging process, nutrient deficiency, and / or metabolic disease.

[0117] Administration Preferably, the compounds and compositions described herein are administered enterally.

[0118] Enteral administration may be, for example, oral or gastric.

[0119] 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.

[0120] The subject may be a mammal, such as a human, dog, cat, horse, goat, cow, sheep, pig, deer, and a primate. Preferably, the subject is a human.

[0121] Although the present invention may be useful in many different mammalian age groups, in preferred embodiments, compositions for use according to the present invention are targeted to adult and / or geriatric populations, particularly elderly patients.

[0122] In one embodiment, the subject is an infant and / or child, or a young canine and / or feline.

[0123] In one embodiment, the subject is an infant and / or a young child.

[0124] The term "child" refers to a human at a stage between birth and adolescence. An adult is an older human than a child. The term "infant" refers to a child under 12 months of age, including premature and low birth weight infants. The term "premature infant" refers to an infant born at a gestational age of less than 37 weeks. The term "low birth weight infant" refers to an infant whose birth weight is less than 2,500 g. The term "toddler" refers to a child between 1 and 3 years of age.

[0125] Sensory characteristics The present invention provides compounds that have improved organoleptic properties and are sources of butyric acid. In particular, the compounds have improved odor and / or taste compared to butyric acid, butyrate salts, and / or tributyrin. In one embodiment, the compounds have improved taste compared to tributyrin. In one embodiment, the compounds have improved odor compared to butyrate salts (e.g., sodium butyrate).

[0126] 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.

[0127] Working Example Example 1 - Preparation of triglycerides containing butyrate moieties A composition comprising butyrate-containing triglycerides was made by chemical transesterification between tributyrin and high oleic sunflower oil in the presence of a catalyst such as sodium methanoate. A molar excess of tributyrin was used compared to the high oleic sunflower oil.

[0128] The three reagents, namely tributyrin, high oleic sunflower oil and catalyst, were mixed in a reactor under nitrogen atmosphere and then heated with stirring at 80° C. for 3 hours. After the reaction was completed, the product was washed with water and dried under vacuum (25 mBar, 60° C. for 2 hours). The oil product obtained was then subjected to a decolorization step by the action of bleaching earth and purified either by short path distillation (130° C., 0.001-0.003 mBar) and / or deodorization by injection of air and water (160° C., 2 mBar, 2 hours).

[0129] The components of the oil composition obtained (mainly triglycerides) are shown in Table 1 below. The triglycerides are represented by the three fatty acids they contain, which 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 in the sn-2 position of the triglyceride. As an example, 16:0-4:0-18:1 represents two different triglycerides, which include both molecules with butyrate in the sn-2 position and palmitate in the sn-1 position and oleate in the sn-3 position or oleate in the sn-1 position and palmitate in the sn-3 position.

[0130] The triglyceride profile and positional isomers were analyzed by liquid chromatography coupled to a high-resolution mass spectrometer. The proportion of each lipid was assessed by liquid chromatography coupled to an evaporative light scattering detector (ELSD).

[0131] [Table 1]

[0132] In the composition sample, the two most abundant triglycerides were 4:0-18:1-4:0 and 18:1-18:1-4:0, which together amounted to approximately 40-50 g / 100 g.

[0133] Example 2 - Odor characteristics of triglycerides containing butyrate moieties An odor comparison of a solution containing a butyrate moiety-containing triglyceride (composed primarily of oleic and butyric fatty acids) was compared to a solution containing sodium butyrate.

[0134] Sample preparation Solutions containing butyrate-containing triglycerides (see Example 1) or sodium butyrate were prepared and stored at 4° C. until presented to the sensory panel. Each 250 mL solution contained 600 mg of butyric acid (equivalent to one capsule of commercially available sodium butyrate as a nutritional supplement, concentration 2.4 mg / mL) and 1% w / v BEBA Optipro 1 infant formula in acidified deionized water.

[0135] The samples were prepared the day before the test by placing 4 mL of each solution (triglyceride butyrate solution, sodium butyrate solution) in an Agilent vial.

[0136] method A "2 vs 5 test" was conducted. In this test, five samples are presented to panelists. Panelists are asked to identify two samples that are different from the other three. The order of presentation of the samples is randomized to avoid presentation order bias.

[0137] In addition to the 2-to-5 test, a comment box was presented to the panelists allowing them to comment on the nature of the difference they perceived (e.g., odor intensity, odor quality).

[0138] result The five samples were presented simultaneously to the panelists, who were asked to remove the caps of each vial, smell it, and then recap it in a given order. The results are shown in Table 2.

[0139] [Table 2]

[0140] P values ​​were calculated using a binomial test implemented in the Fizz software (Biosystemes, France).

[0141] Panelists who were able to distinguish the correct answer (TAG containing butyrate moieties different from sodium butyrate) explained that while sodium butyrate had a "cheese" smell, this "cheese" smell was greatly reduced in the TAG containing butyrate moieties samples, making the odor almost neutral.

[0142] Example 3 - Taste characteristics of triglycerides containing butyrate moieties Sensory benchmarking of solutions containing butyrate moiety-containing triglycerides (see Example 1), composed primarily of oleic and butyric fatty acids, was performed against solutions containing tributyrin.

[0143] Sample preparation: A scoop (4.6 g) of BEBA Optipro1 infant formula was added to warm water (cooled boiled tap water as per instructions) to a final volume of 150 mL (approximately a 3% w / v solution). Each triglyceride form of butyrate was weighed separately to provide 600 mg of butyrate, and infant formula was added to bring each solution to a final volume of 50 mL.

[0144] Solution A contained a butyrate moiety-containing triglyceride (see Example 1) and solution B contained tributyrin.

[0145] method Groups of panelists conducted repeated blind tastings.

[0146] The samples were prepared immediately prior to the preliminary bitterness evaluation, and each solution was vigorously shaken. Tasting cups, labeled A and B, were filled simultaneously with small amounts of each solution.

[0147] The two samples were presented simultaneously to panelists who were asked to taste the solutions by holding them in their mouths and spitting them out, and to rate their perceived bitterness on a scale of 0 to 10 (0 being no perception of bitterness, 10 being the most bitter taste imaginable).

[0148] result The bitterness of Solution A was rated by panelists as 4.33±1.52, mean±SD.

[0149] The bitterness of solution B was rated by panelists as 8.33±1.52, mean±SD.

[0150] These data indicate that the butyrate moiety-containing TAG composition was significantly less bitter in taste compared to tributyrin in infant formula.

[0151] Example 4 - Taste characteristics of 1,3-dibutyryl-2-palmitoylglycerol 1,3-Dibutyryl-2-palmitoylglycerol (BPB) was synthesized as a single compound using the following synthesis.

[0152] [ka]

[0153] When BPB was evaluated by a sensory panel, it was found to have no unpleasant taste or odor.

[0154] Example 5 - Digestion of triglycerides containing butyrate moieties 5.1.Materials Sodium taurocholate, sodium chloride, hydrochloric acid, sodium hydroxide, potassium hydroxide, maleic acid, tris(hydroxymethyl)aminomethane, pepsin (porcine, 800-111 2500 U / mg, P7000, actual activity used 674 U / mg and 561 U / mg), pancreatin (porcine, USPx8, P7585), and porcine bile extract (total bile salt content = 49% by weight; contains 10-15% glycodeoxycholic acid, 3-9% taurodeoxycholic acid, 0.5-7% deoxycholic acid; phospholipids 5%, B8631) were used as received and purchased from Sigma-Aldrich (St. Louis, MO, USA). Rabbit stomach extract (RGE70 ≥ 70 U / mL RGL, and pepsin ≥ 280 U / mL) was purchased from Lipolytech (Marseille, France). All water used in this study was purified Milli-Q grade. Tributyrin was from Sigma (food grade) and high oleic sunflower oil was from Florin. Transesterified triglycerides were obtained by chemical transesterification using sodium methanoate (Evonik) as catalyst.

[0155] 5.2. Emulsion Preparation Polyoxyethylene sorbitan monooleate (Tween® 80) was mixed into the oil phase at 40° C. and then mixed with the water phase using a magnetic stirrer to prepare a 10 wt % oil-in-water emulsion stabilized by 0.3 wt % Tween 80. The emulsion was then created using a Hielscher UP400S ultrasonic probe homogenizer equipped with a 5 mm diameter rod probe, applying 100% amplitude at 100% cycle for 2 minutes, during which the sample was cooled using ice water.

[0156] 5.3. Particle size measurement The droplet size of each lipid emulsion was measured by laser light scattering using a Mastersizer 3000 equipped with a Hydro SM from Malvern Instruments (Malvern, Worcestershire, United Kingdom). The laser specs for the two lasers are 4 mW, 632.8 nm and 10 mW, 470 nm. To avoid multiple scattering effects, the samples were diluted to about 0.002 wt%. Information on the emulsion particle size was then obtained by the best agreement between the theory of light scattering (Mie) and the measured particle size distribution. A refractive index of 1.456 and an absorption of 0.01 were used for the oil phase. The particle size of the emulsion is estimated as two values: the volume surface average diameter D3,2 (D3,2 1 / 4 Pnidi 3 / nidi 2) or the volume length average diameter D4,3 (D4,3 1 / 4 Pnidi 4 / nidi 3). The average of three measurements of two freshly prepared emulsions is taken as the emulsion particle size result.

[0157] 5.4.Statistical analysis Statistical analysis was performed using two-tailed t-tests with unequal variances using the software Igor Pro.

[0158] 5.5. In vitro digestion Lipid emulsions (2 mL) containing 200 mg of fat were subjected to in vitro gastrointestinal lipolysis. Digestion was carried out in a thermostated glass vessel (37° C.) in a pH-STAT assembly controlled by a TIM 856 bi-burette pH-STAT (Radiometer Analytical (France)). For gastric digestion, samples were incubated for 90 min at 37° C. and pH 5.5 with 8.5 mL of simulated gastric fluid (SGF) containing 150 mM NaCl, 450 U / mL pepsin, 18 U / mL rabbit gastric lipase. Digestion was started by adding 18 U / mL rabbit gastric lipase (TBU, activity against tributyrin assessed at pH 5.4).

[0159] The intestinal digestion step was performed in a pH-STAT, and the pH was kept constant at 6.8 by the addition of NaOH (0.05M). Bile salts mixture (bile salts prepared in Tris buffer, 5 mM Tris, 150 mM NaCl) and calcium solution (20 mM Ca, 176 5 mM Tris, 150 mM NaCl) were added to the SGF sample mixture. The mixture was transferred to the pH-STAT, and the pH was adjusted to approximately 6.78. The intestinal digestion step was started when the temperature reached 37±0.5°C. The pH was adjusted to 6.8 and incubated at this pH and temperature for 2 minutes, after which a pancreatin solution (5 mM Tris, 150 mM NaCl, pH 6.8) was added. The final composition of the intestinal fluid was 10 mM CaCl2, 12 mM mixed bile salts, 0.75 mM phospholipids, 150 mM NaCl, and 4 mM tris(hydroxymethyl)aminomethane buffer. The intestinal digestion step was carried out for 3 hours in a Radiometer titration manager. During the intestinal digestion phase, the digestion rate was followed using the pH-STAT (TIM856, Radiometer) method and expressed as titratable acids (not fatty acids) calculated by the following formula:

[0160] TA=V NaOH x0:05x1000 TA: total amount of titratable acid released, mmol, V NaOH : Volume of NaOH used to titrate the acid released in 3 hours, mL.

[0161] 5.6.Results Since dietary lipid digestion involves both gastric and intestinal lipases, lipid digestibility was evaluated using two digestion models: i) simulated intestinal fluid (SIF) with porcine pancreatic lipase (PPL), and ii) sequential digestion in simulated gastric fluid (SGF) with rabbit gastric lipase (RGL) followed by porcine pancreatic lipase (PPL) in simulated intestinal fluid (SIF). All lipids were emulsified with polyoxyethylene sorbitan monooleate (Tween® 80) and had similar particle size distribution and specific surface area (Figure 2). This means that the difference in digestion mainly arises from the molecular structure of triglycerides.

[0162] Figure 1A-C i) shows the digestion by porcine pancreatic lipase (from spleen) in the presence of mixed bile and calcium of tributyrin (C4), high oleic sunflower oil (HOSFO, mostly C18:1) and the butyrate moiety-containing triglyceride "C4-C18:1" according to the invention, produced by chemical transesterification between tributyrin and high oleic sunflower oil (see Example 1) (SIF model). The lipids generally showed the same lipolysis behavior, with an initial rapid lipolysis period in the first 15 minutes, which gradually slowed down during the last 2.5 hours of simulated intestinal digestion. C4 triglycerides showed an initial maximum rate of lipolysis of 223 ± 59 μmol / min. The initial degradation rate in high oleic sunflower oil, 34.5 ± 2.3 μmol / min, was significantly lower than that of the short-chain triglycerides (p < 0.0001). C4-C18:1 showed an initial hydrolysis rate of 153±47 μmol / min between C4 and C18:1. Taken together, it can be seen that all triglycerides are rapidly and fully digested in the presence of porcine pancreatic lipase.

[0163] These triglycerides were then digested in a sequential SGF(RGL)SIF(PPL) model. Digestion in the SIF section is shown in Fig. 1A-C ii). Measurements in the stomach section were not performed due to limited ionization of the fatty acids of interest. Compared to digestion in SIF alone, C4 and C18:1 triglycerides generally released less titratable acid during the 3-h digestion. The effect was greatest with tributyrin, which has a significantly (p<0.0001) lower initial lipolysis rate of 44.1±8.8 μmol / min during SGF-SIF digestion compared to 223±59 μmol / min for SIF alone. The total amount of acid released after SGF-SIF digestion of tributyrin, 381±20 μmol, is almost one-third of the amount released after digestion in SIF alone, 958±12.5 μmol. These results clearly demonstrate that digestion of tributyrin in the gastric model is substantial.

[0164] After sequential exposure to SGF and SIF, the rate of SIF lipolysis of butyrate-containing triglyceride C4-C18:1 was 124 ± 20 μmol / min, showing a slight, but not significant, decrease compared to SIF alone (124 ± 20 μmol / min). The most interesting observation is that the decrease in SIF lipolysis caused by pre-exposure to RGL is influenced by the secondary fatty acid chain length. Originally, tributyrin reduced total fatty acid release during SIF lipolysis by 60.2% (147 ± 7.6 μmol) after pre-exposure to RGL in SGF. In comparison, C4-C18:1 transesterified triglyceride showed a decrease of 6.1% (45 ± 7.6 μmol).

[0165] The overall extent of lipid digestion after both SIF and SGF-SIF for the three triglycerides using direct and back titration is presented in Figure 2. Because many fatty acids are only partially ionized at pH 6.8, direct titration only partially captures the extent of lipid digestion, and back titration to pH 11.5 or GC-FAME analysis is required instead to fully estimate the extent of digestion. Back titration results for the three triglycerides show that tributyrin and butyrate moiety-containing triglycerides C4-C18:1 were digested at 101.5 ± 0.9% and 101 ± 1.6%, respectively, implying that complete digestion releases three fatty acids per molecule. Meanwhile, back titration results show that high oleic sunflower oil was digested at 72.3 ± 2%, implying that complete digestion releases two fatty acids per molecule.

[0166] Overall, we found that tributyrin was fully hydrolyzed in the stomach, whereas high oleic sunflower triglycerides were only very limitedly hydrolyzed in the stomach. Surprisingly, butyrate moiety-containing triglycerides (C4-C18:1), prepared by transesterification of C4 with long chain fatty acids, were found to reduce the extent of C4 fatty acid lipolysis in the stomach. Tributyrin was lipolyzed by gastric lipase to approximately 60%, as shown by the reduction in total fatty acid release during SIF lipolysis after pre-exposure to RGL in SGF. In comparison, C4-C18:1 butyrate moiety-containing triglycerides reduced total fatty acid release in SGF-SIF by only 6.1%. These results suggest that transesterification of C4 with long-chain fatty acids (C4-C18:1) tailors the release of butyrate in the stomach to the later post-digestive intestine, and that design of structured lipids alters the timing (but not the extent) of short-chain fatty acid delivery in the gastrointestinal tract.

Claims

1. 13. A compound having the formula: or a combination thereof for use in maintaining bone health and / or preventing and / or treating bone disorders associated with imbalanced bone catabolism: 【Chemistry 1】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ are independently long-chain fatty acids having 16 to 20 carbons.

2. 2. The compound for use according to claim 1, wherein a combination of a compound having the formula (1) and a compound having the formula (2) is used, preferably said combination being present in a composition comprising a compound having the formula (1) in an amount of at least 10% by weight of the total amount of triglycerides and a compound having the formula (2) in an amount of at least 10% by weight of the total amount of triglycerides.

3. 2. The compound for use according to claim 1, wherein a combination of a compound having the formula (1) and a compound having the formula (2) is used, said combination being present in a composition comprising a compound having the formula (1) in an amount of at least 10% by weight of the total amount of triglycerides containing butyrate moieties and a compound having the formula (2) in an amount of at least 10% by weight of the total amount of triglycerides containing butyrate moieties.

4. 4. The compound for use according to claim 1, 2 or 3, wherein a combination of a compound having formula (1), a compound having formula (2), a compound having formula (3) and a compound having formula (4) is used.

5. R １ , R ２ , R ３ , R ４ , R ５ , and / or R ６ A compound for use according to any one of claims 1 or 2 to 4, wherein is an unsaturated fatty acid, preferably a monounsaturated fatty acid.

6. R １ , R ２ , R ３ , R ４ , R ５ , and / or R ６ A compound for use according to any one of claims 1 or 2 to 4, wherein is selected from the group consisting of oleic acid, palmitic acid or linoleic acid.

7. R １ , R ２ , R ３ , R ４ , R ５ , and R ６ A compound for use according to any one of claims 1 or 2 to 4, wherein each of is oleic acid.

8. 8. A compound according to any one of claims 1 to 7 for use in maintaining bone health, for preventing, inhibiting and / or limiting bone loss, for preventing, inhibiting and / or limiting bone loss, for regulating and / or inhibiting bone catabolism, for modulating the rate of bone formation and / or the rate of bone resorption, for inhibiting and / or limiting bone resorption, for improving bone density and / or for assisting bone regeneration during fracture healing.

9. A compound according to any one of claims 1 to 7 for use in the prevention and / or treatment of bone disorders associated with bone imbalance, said disorders being selected in the group consisting of osteoporosis, osteoarthritis and osteopenia.

10. 1. A composition for use in maintaining bone health and / or preventing and / or treating bone disorders associated with imbalanced bone catabolism, comprising a compound having the formula: 【Chemistry 2】 A composition, wherein the compound having the formula (5) constitutes at least 10% by weight of the total amount of triglycerides in the composition, and the compound having the formula (6) constitutes at least 10% by weight of the total amount of triglycerides in the composition.

11. The composition for use according to claim 10, wherein the compound having the formula (5) constitutes at least 15% by weight of the total amount of triglycerides in the composition, and the compound having the formula (6) constitutes at least 20% by weight of the total amount of triglycerides in the composition.

12. Further included are compounds having the formula: 【Chemistry 3】 Preferably, the compound having formula (7) constitutes at least 2% by weight of the total amount of triglycerides in the composition, and / or further comprises a compound having the formula: 【Chemistry 4】 12. A composition for use according to claim 10 or 11, wherein the compound having formula (8) preferably constitutes at least 2% by weight of the total amount of triglycerides in the composition.

13. 13. A composition according to any one of claims 10 to 12 for use in maintaining bone health, for preventing, inhibiting and / or limiting bone loss, for preventing, inhibiting and / or limiting bone loss, for regulating and / or inhibiting bone catabolism, for modulating the rate of bone formation and / or the rate of bone resorption, for inhibiting and / or limiting bone resorption, for improving bone density and / or for assisting bone regeneration during fracture healing.

14. The composition according to any one of claims 10 to 12, for use in the prevention and / or treatment of bone disorders associated with bone imbalance, said disorders being selected in the group consisting of osteoporosis, osteoarthritis, and osteopenia.

15. 1. A composition for use in maintaining bone health and / or preventing and / or treating bone disorders associated with imbalanced bone catabolism, comprising a compound having the formula: 【Chemistry 5】 A composition, wherein the compound having the formula (5) constitutes at least 10% by weight of the total amount of butyrate moiety-containing triglycerides in the composition, and the compound having the formula (6) constitutes at least 10% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

16. 12. The composition for use according to claim 11, wherein the compound having formula (5) constitutes at least 15% by weight, preferably at least 20% by weight, of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 20% by weight, preferably at least 25% by weight, of the total amount of butyrate-containing triglycerides in the composition.

17. 13. A composition for use according to claim 11 or 12, further comprising a compound having the formula (7), preferably wherein the compound having the formula (7) constitutes at least 2% by weight of the total amount of butyrate-containing triglycerides in the composition, and / or further comprising a compound having the formula (8), preferably wherein the compound having the formula (8) constitutes at least 2% by weight of the total amount of butyrate-containing triglycerides in the composition.

18. 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 14. The composition for use according to any one of claims 8 to 13, further comprising 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.

19. 19. A composition according to any one of claims 15 to 18 for use in maintaining bone health, for preventing, inhibiting and / or limiting bone loss, for preventing, inhibiting and / or limiting bone loss, for regulating and / or inhibiting bone catabolism, for modulating the rate of bone formation and / or the rate of bone resorption, for inhibiting and / or limiting bone resorption, for improving bone density and / or for assisting bone regeneration during fracture healing.

20. The composition according to any one of claims 15 to 18, for use in the prevention and / or treatment of bone disorders associated with bone imbalance, said disorders being selected in the group consisting of osteoporosis, osteoarthritis, and osteopenia.

21. The composition for use according to any one of claims 15 to 18, wherein the composition is a nutritional composition.

22. The composition for use according to any one of claims 10 to 18, wherein the composition is an infant formula, a follow-on milk, or a dietary supplement.

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