Food-grade butyrates for the treatment or prevention of allergic diseases

Abstract

To provide a composition for use in the treatment or prevention of an allergic disorder.SOLUTION: The present invention provides compounds having the formulae or combinations thereof, where R1, R2, R3, R4, R5, and R6 independently represent a long chain fatty acid with between 16 and 20 carbons.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] This invention relates to a dietary source of butyrate having improved functional properties for use in the treatment or prevention of allergic diseases. [Background technology]

[0002] Allergic diseases are currently recognized as epidemic by the World Health Organization (WHO). In Europe and North America, food allergies are estimated to affect nearly 5% of adults and 8% of children (Sicherer, SH and Sampson, HA, 2014. Journal of Allergy and Clinical Immunology, 133(2), pp.291-307). The prevalence of food allergies and anaphylaxis is steadily increasing, with the greatest increase observed in infants with food allergies or atopic dermatitis (Koplin, JJ, et al., 2015. Current opinion in allergy and clinical immunology, 15(5), pp.409-416).

[0003] Changes in the composition of the gut microbiota have been identified as one of the causes of increased incidence of allergic diseases. The gut microbiota has been shown to play an important role in maintaining immune tolerance to allergens, promoting regulatory T (Treg) cells (Rivas, M. and Chatila, TA, 2016. Journal of Allergy and Clinical Immunology, 138(3), pp.639-652). In particular, dietary fiber-derived metabolites are involved in gut homeostasis and Treg cell dynamics (Tan, J., et al., 2016. Cell reports, 15(12), pp.2809-2824). Butyrate is one of the most common short-chain fatty acids (SCFAs) produced by the human gut microbiota in response to indigestible dietary fiber in food. Salts and esters of butyrate are called butyrates or butanoates.

[0004] Preclinical data have shown that direct oral administration of butyrate can effectively prevent the development of food allergies (Tan, J., et al., 2016. Cell reports, 15(12), pp. 2809-2824) and improve allergic pneumonia (Thio, CLP, et al., 2018. Journal of Allergy and Clinical Immunology, 142(6), pp. 1867-1883. e12). Furthermore, increased fecal butyrate concentrations were associated with accelerated progression of milk allergy in infants (Canani, RB, et al., 2016. The ISME journal, 10(3), p. 742), and a richer gut microbiota producing butyrate was associated with milder symptoms in infants with atopic eczema (Nylund, L., et al., 2015. Allergy, 70(2), pp. 241-244). Therefore, butyrates are a strong candidate for modulating food allergy responses by promoting Treg cell activity.

[0005] Butyrates have not only demonstrated efficacy against the Treg response, but have also been shown to act on mast cell activity. Mast cells are thought to exert important inflammatory and potential immunomodulatory functions in various immune diseases through the release of mediators such as histamine, leukotrienes, cytokines, chemokines, and neutral proteases (Amin, K., 2012. Respiratory medicine, 106(1), pp.9-14). The mouse mast cell line MC / 9 showed reduced proliferation when exposed to butyrate (Galli, SJ, et al., 1982. The Journal of Cell Biology, 95(2), pp.435-444). Further studies have shown that butyrate suppresses mast cell activation, inhibits mediator release, and suppresses the production of the inflammatory cytokine TNFα in mast cells (Diakos, C., et al., 2006. Biochemical and Biophysical Research Communications, 349(2), pp.863-868). Butyrate was also effective in inhibiting mast cell activation and the production of inflammatory mediators in vivo (Wang, CC, et al., 2018. Innate Immunity, 24(1), pp.40-46).

[0006] Antigen-specific stimulation of B cells in the presence of butyrate switched the differentiation of plasma cells to regulatory B cells (Bregs) and IL-10 production. Simultaneously, in vivo Breg induction was associated with a decrease in the number of intestinal mast cells after experimental induction of food allergy (Shi, Y., et al., 2015. Scientific Reports, 5, p. 17651). Butyrate can also influence mast cell responses by acting on the activation and / or cytokine response of type 2 innate lymphocytes (ILC2s). Butyrate, rather than acetate or propionate, significantly improved allergic inflammation (including eosinophilic inflammation) induced by ILC2s and reduced cytokine production in human ILC2 cells (Thio, CLP, et al. 2018. Journal of Allergy and Clinical Immunology, 142(6), pp. 1867-1883. e12). The ILC2 response is involved in the promotion of experimental food allergies mediated by IgE-mast cells (Chen, CY, et al., 2015. Immunity, 43(4), pp.788-802).

[0007] Common sources of butyrates are butyric acid and triptyline, a triglyceride consisting of three ester functional groups with three butyrate moieties and a glycerol backbone. Both butyric acid and triptyline are 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. Since the butyrate components of dairy products cannot be enriched, a considerable amount of milk fat must be consumed, which is impractical and nutritional for reasons such as the intake of large amounts of unnecessary calories, especially from animal fats.

[0008] Therefore, it is beneficial to provide a food-grade butyrate source having improved sensory properties compared to solutions available for the treatment or prevention of allergic diseases.

[0009] [Summary of the Invention] The present invention provides a compound that is a source of butyrate having improved sensory properties for use in the treatment or prevention of allergic diseases. In particular, the compound has an improved odor and / or taste compared to butyric acid, butyrate salts, and / or tributyrin. The compound can be used as a food ingredient of butyric acid. The compound can be used, for example, in nutritional compositions, dietary supplements, infant formulas, follow-on formulas, beverages, and pet care products.

[0010] According to a first aspect of the present invention, for use in the treatment or prevention of allergic diseases, the following formula [Chemical formula] [wherein, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently a long-chain fatty acid having 16 to 20 carbons.]. A compound having the formula, or a combination thereof, is provided.

[0011] According to another aspect of the present invention, there is provided a composition for use in the treatment or prevention of allergic diseases, comprising a compound having formula (1), a compound having formula (2), a compound having formula (3), or a compound having formula (4) or a combination thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently a long-chain fatty acid having 16 to 20 carbons.

[0012] In one embodiment, the composition comprises a compound having formula (1), a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0013] The composition may comprise a compound having formula (1) and a compound having formula (2).

[0014] The composition may comprise a compound having formula (1) and a compound having formula (3).

[0015] The composition may comprise a compound having formula (1) and a compound having formula (4).

[0016] The composition may comprise a compound having formula (2) and a compound having formula (3).

[0017] The composition may comprise a compound having formula (2) and a compound having formula (4).

[0018] The composition may comprise a compound having formula (3) and a compound having formula (4).

[0019] The composition may comprise a compound having formula (1), a compound having formula (2), and a compound having formula (3).

[0020] The composition may comprise a compound having formula (1), a compound having formula (2), and a compound having formula (4).

[0021] The composition may comprise a compound having formula (1), a compound having formula (3), and a compound having formula (4).

[0022] The composition may comprise a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0023] The composition may comprise a compound having formula (1), a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0024] In one embodiment, the compound having formula (1), the compound having (2), the compound having (3), and the compound having (4) constitute at least 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight of the total triglycerides in the composition.

[0025] In one embodiment, the compound having formula (1), the compound having formula (2), the compound having formula (3), and the compound having formula (4) constitute at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total butyrate-containing triglycerides in the composition.

[0026] In one embodiment, the compound having formula (4) is the main butyrate-containing triglyceride in the composition.

[0027] In one embodiment, the compound of formula (4) constitutes at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, or 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.

[0028] In one embodiment, the composition comprises a compound of formula (1) and a compound of formula (4), wherein the combination of the compound having formula (1) and the compound having formula (4) is present in an amount of at least 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, or 90% by weight of the total butyrate-containing triglycerides in the composition.

[0029] In one embodiment, triptyline constitutes less than 10% by weight of the total triglycerides in the composition, preferably less than 8% by weight of the total triglycerides in the composition, and more preferably less than 5% by weight of the triglycerides.

[0030] In one embodiment, the composition further comprises vitamin A and / or dietary fiber and / or probiotics.

[0031] In one embodiment, the composition is a nutritional composition, preferably a dietary supplement, an infant formula, a follow-on formula, a beverage, or a pet care product.

[0032] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 This is an unsaturated fatty acid, preferably a monounsaturated fatty acid.

[0033] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 It is selected from the group consisting of oleic acid, palmitic acid, or linoleic acid, and preferably R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each of these is oleic acid.

[0034] In one embodiment, the allergic disease is selected from one or more of the group consisting of food allergies, food intolerances, respiratory allergies, and skin allergies.

[0035] In one embodiment, the allergic disease is selected from one or more of the following groups: rhinitis, asthma, hives or hay fever, allergic conjunctivitis, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, psoriasis, eosinophilic esophagitis, and eosinophil-associated gastrointestinal disorders, allergic diarrhea, vomiting, abdominal pain, or bloating.

[0036] In one embodiment, the allergen in an allergic disease is selected from one or more of the following: food allergens, dust mites, pollen, mold or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet or animal hair, feathers, or pet dander.

[0037] In one embodiment, the allergen in an allergic disease is a food allergen, and preferably the food allergen is selected from nuts, tree nuts, peanuts, seafood, shellfish, mollusks, crustaceans, milk, eggs, soybeans, gluten, grains, wheat, oats, barley, rye, celery, corn, lupine, sulfites, sesame, mustard, rice, poultry, and meat.

[0038] In one embodiment, the compounds or combinations thereof have improved functional properties with respect to butyric acid, triptyline and / or butyrate salts.

[0039] In one embodiment, the compound is provided to young or adult mammals, preferably infants, toddlers, adolescents or adults, pets or livestock. [Brief explanation of the drawing]

[0040] [Figure 1] This graph shows the BLG-specific immunoglobulin E (IgE) response in mice sensitized with milk protein β-lactoglobulin (BLG) and in control mice. [Figure 2] This graph shows the BLG-specific immunoglobulin G1 (IgG1) response in mice sensitized with milk protein β-lactoglobulin (BLG) and control mice. [Figure 3] The graphs show the cumulative clinical scores after oral administration of OVA in mice from the following groups: "Control Group" (negative controls), "Allergy Group 1" (BLG-sensitized positive controls), "Allergy Group 2 treated with sodium butyrate," and "Allergy Group 3 treated with palatable butyrate." [Figure 4]The graphs show the OVA-specific IgE response when OVA was orally administered to allergic mice and control mice, namely the "control group" (negative control), "allergic group 1" (BLG-sensitized positive control), "allergic group 2 treated with sodium butyrate," and "allergic group 3 treated with palatable butyrate." [Figure 5] The graphs show the OVA-specific IgG1 response when OVA was orally administered to allergic mice and control mice, namely the "control group" (negative control), "allergic group 1" (BLG-sensitized positive control), "allergic group 2 treated with sodium butyrate," and "allergic group 3 treated with palatable butyrate." [Figure 6] This graph shows mast cell protease-1 (MCPT-1) levels in allergic mice and control mice, specifically the "control group" (negative control), "allergic group 1" (BLG-sensitized positive control), "allergic group 2 treated with sodium butyrate," and "allergic group 3 treated with palatable butyrate," after oral administration of OVA. [Modes for carrying out the invention]

[0041] As used herein, the terms “comprising,” “comprises,” and “comprised of” are synonymous with “including” or “including (animals, especially small animals such as pets, especially dogs)” or “containing” or “contains,” and are open-ended, and do not exclude additional, unlisted components, elements, or processes. The terms “comprising,” “comprises,” and “comprised of” also include the term “consisting of.”

[0042] Triglycerides Triglycerides (also called triacylglycerols) are triesters derived from glycerol and three fatty acids. Under hydrolysis conditions such as digestion, triglycerides can be a source of fatty acids. For example, triptyline can be a source of 3 moles of butyric acid per mole of triptyline.

[0043] 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).

[0044] The term "fatty acid portion" refers to the portion of the triglyceride derived from a fatty acid in the esterification reaction with glycerol. The triglycerides used in this invention include at least one butyric acid portion and at least one long-chain fatty acid portion.

[0045] The long-chain fatty acids preferred for use in the present invention are fatty acids having 16 to 20 carbon atoms. Examples of long-chain fatty acids include oleic acid, palmitic acid, stearic acid, and linoleic acid. Preferably, the long-chain fatty acid is oleic acid. For example, the present invention provides for use in the treatment or prevention of allergic diseases, using the following formula [ka] The present invention provides compounds having or combinations thereof.

[0046] Other examples of triglycerides that can be used in the present invention include 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- Examples include 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 1-linoleoyl-2,3-dioleoylglycerol.

[0047] The triglycerides of the present invention can be synthesized, for example, by the esterification reaction of long-chain fatty acids and butyric acid with glycerol.

[0048] The triglycerides of the present invention can be synthesized, for example, by transesterification between triptyline and another triglyceride containing long-chain fatty acids. In one embodiment, high-oleic sunflower oil is used as the raw material for the long-chain fatty acids. This produces a triglyceride mainly containing a butyrate moiety and an oleate moiety. This compound is free of dairy components, cholesterol, and animal-derived components. The fatty acids are detached from the 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.

[0049] Alternative methods for triglyceride synthesis can be determined by those skilled in the art as part of a standard procedure.

[0050] As an example, the method for obtaining 1,3-dibutyryl-2-palmitoylglycerol (BPB) is shown below.

[0051] [ka]

[0052] As another example, triglycerides can be synthesized by the esterification reaction of long-chain fatty acid monoacylglycerols (MAGs) with butyric acid (BA).

[0053] For example, it can be synthesized by the esterification reaction of long-chain fatty acid monoacylglycerol (MAG) and butyric acid (BA), with water being removed. As an example, a method for obtaining 1,2-dibutyryl-3-oleoylglycerol is shown below.

[0054] [ka]

[0055] The esterification reaction is preferably carried out under a molar ratio of butyric acid (BA) to monoacylglycerol (MAG) of 2 or more, i.e., under a molar excess of butyric acid. Water removal can be carried out by conventional methods routinely used in the art.

[0056] A single butyrate-partially-containing triglyceride may be used herein. Alternatively, a mixture of different butyrate-partially-containing triglycerides may be used.

[0057] The triglycerides may be further subjected to decolorization and / or deodorization processes that are conventional in the art and well known to those skilled in the art. Examples include processes conventionally used in the production of vegetable oils.

[0058] composition The compounds of the present invention can be administered in the form of a composition. Accordingly, the present invention provides compositions comprising a butyrate-partially-containing triglyceride as referred herein for use in the treatment or prevention of allergic diseases.

[0059] In one embodiment, the compositions defined herein include a combination of a compound having formula (1) and a compound having formula (2).

[0060] In one embodiment, the compound having formula (1) is present in an amount of at least 10% by weight of the total triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 10% by weight of the total triglycerides in the composition.

[0061] In one embodiment, the compound having formula (1) is present in an amount of at least 15% by weight of the total triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 15% by weight of the total triglycerides in the composition.

[0062] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 20% by weight of the total triglycerides in the composition.

[0063] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 30% by weight of the total triglycerides in the composition.

[0064] In one embodiment, the compound having formula (1) constitutes about 20% to about 40% by weight of the total triglycerides in the composition, and / or the compound having formula (2) constitutes about 30% to about 40% by weight of the total triglycerides in the composition.

[0065] In one embodiment, the compound having formula (1) and the compound having formula (2) constitute at least 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, or 70% by weight of the total triglycerides in the composition, preferably about 40% by weight to about 80% by weight, or about 50% by weight to about 75% by weight of the total triglycerides in the composition.

[0066] In one embodiment, the composition further comprises a compound having formula (3), preferably the compound having formula (3) making up at least 2% by weight, 3% by weight, 4% by weight, or 5% by weight of the total triglycerides in the composition, and / or the composition further comprises a compound having formula (4), preferably the compound having formula (4) making up at least 1% by weight, 2% by weight, or 3% by weight of the total triglycerides in the composition.

[0067] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total butyric acid-containing triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 30% by weight of the total butyric acid-containing triglycerides in the composition.

[0068] In one embodiment, the compound having formula (1) constitutes about 30% to about 50% by weight of the total butyric acid-containing triglycerides in the composition, and / or the compound having formula (2) constitutes about 40% to about 60% by weight of the total butyric acid-containing triglycerides in the composition.

[0069] In one embodiment, the compound having formula (1) and the compound having formula (2) constitute at least 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, or 80% by weight of the total butyric acid-containing triglycerides in the composition, preferably about 60% to about 90% by weight of the total butyric acid-containing triglycerides in the composition.

[0070] In one embodiment, the compound having formula (4) is the main butyrate-containing triglyceride in the composition.

[0071] In one embodiment, the compound of formula (4) constitutes at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, or 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.

[0072] In one embodiment, the composition comprises a compound of formula (1) and a compound of formula (4), wherein the combination of the compound having formula (1) and the compound having formula (4) is present in an amount of at least 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, or 90% by weight of the total butyrate-containing triglycerides in the composition.

[0073] In one embodiment, the compound having formula (5) constitutes at least 10% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 10% by weight of the total triglycerides in the composition.

[0074] In one embodiment, the compound having formula (5) constitutes at least 15% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 15% by weight of the total triglycerides in the composition.

[0075] In one embodiment, the compound having formula (5) constitutes at least 15% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 20% by weight of the total triglycerides in the composition.

[0076] In one embodiment, the compound having formula (5) constitutes at least 20% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 20% by weight of the total triglycerides in the composition.

[0077] In one embodiment, the compound having formula (5) constitutes about 15% to about 30% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes about 20% to about 30% by weight of the total triglycerides in the composition.

[0078] In one embodiment, the compound having formula (5) and the compound having formula (6) constitute at least 20% by weight, 30% by weight, or 40% by weight of the total triglycerides in the composition, preferably about 30% to about 60% by weight, or about 40% to about 50% by weight of the total triglycerides in the composition.

[0079] In one embodiment, the composition further comprises a compound having formula (7), preferably the compound having formula (7) making up at least 2% or 3% by weight of the total triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably the compound having formula (8) making up at least 2% or 3% by weight of the total triglycerides in the composition.

[0080] In one embodiment, the compound having formula (5) constitutes at least 10% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 10% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

[0081] In one embodiment, the compound having formula (5) constitutes at least 15% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 15% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

[0082] In one embodiment, the compound having formula (5) constitutes at least 15% by weight of the total butyrate-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 20% by weight of the total butyrate-containing triglycerides in the composition.

[0083] In one embodiment, the compound having formula (5) constitutes at least 20% by weight of the total butyrate-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 20% by weight of the total butyrate-containing triglycerides in the composition.

[0084] In one embodiment, the compound having formula (5) constitutes about 15% to about 30% by weight of the total butyrate-containing triglycerides in the composition, and the compound having formula (6) constitutes about 20% to about 30% by weight of the total butyrate-containing triglycerides in the composition.

[0085] In one embodiment, the composition further comprises a compound having formula (7), preferably the compound having formula (7) comprising at least 2% or 3% by weight of the total butyrate-partially-containing triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably the compound having formula (8) comprising at least 2% or 3% by weight of the total butyrate-partially-containing triglycerides in the composition.

[0086] In another embodiment, the compound having formula (8) is the main butyrate-containing triglyceride in the composition.

[0087] In one embodiment, the compound of formula (8) constitutes at least 20% by weight, at least 30% by weight, at least 40% by weight, at least 50% by weight, or 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.

[0088] In one embodiment, the compound having formula (8) constitutes about 20% to about 95% by weight of the total butyrate-containing triglycerides in the composition, for example, about 30% to about 90% by weight of the total butyrate-containing triglycerides in the composition, or about 40% to about 80% by weight, for example, about 50% to about 70% by weight of the total butyrate-containing triglycerides in the composition.

[0089] In one embodiment, the compound having formula (8) 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.

[0090] In one embodiment, the composition comprises a compound of formula (8) and a compound of formula (5), wherein the combination of the compound having formula (8) and the compound having formula (5) is present in an amount of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight of the total butyrate-containing triglycerides in the composition.

[0091] In one embodiment, the composition of the present invention is 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 The following may further be included: glycerol, 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.

[0092] In one embodiment, triptylin constitutes less than 10% by weight of the total amount of butyrate-containing triglycerides in the composition, preferably less than 8% by weight of the total amount of butyrate-containing triglycerides in the composition, and more preferably less than 5% by weight.

[0093] 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.

[0094] 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.

[0095] The composition may be in the form of a pharmaceutical composition and may contain one or more suitable pharmaceutically acceptable carriers, diluents, and / or excipients. Examples of such excipients suitable for the compositions described herein can be found in "Handbook of Pharmaceutical Excipients," 2nd Edition, (1994), edited by A. Wade and P.J. Weller. Acceptable carriers or diluents for therapeutic use are also well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro edit. 1985).

[0096] The pharmaceutical composition may contain, or in addition to, any suitable binder, lubricant, suspending agent, coating agent, and / or solubilizer as a carrier, excipient, 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. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[0097] The composition may contain preservatives, stabilizers, dyes, and even flavorings. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0098] The composition may be a nutritional composition.

[0099] The term "nutritional composition" means a composition that provides nutrition to a subject. This nutritional composition is preferably taken orally and may contain lipids, or fat sources and protein sources. Such a composition may also contain carbohydrate sources. In one embodiment, the nutritional composition contains only lipids or fat sources. In other specific embodiments, the nutritional composition contains lipid (or fat) sources together with protein sources, carbohydrate sources, or all of these.

[0100] 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 that leads directly to the stomach through the oral / nasal passage or the abdominal cavity. Such a tube can be used particularly in hospitals or clinics.

[0101] The composition according to the present invention may be a dietary supplement.

[0102] 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, for example, in the form of tablets, capsules, lozenges, or liquids. Dietary supplements may further contain protective hydrophilic colloids (such as gums, proteins, and modified starches), binders, membrane-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, excipients, 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.

[0103] If the composition is a nutritional supplement, it can be provided in the form of a unit dose.

[0104] The compositions according to the present invention may be infant formulas (e.g., infant starter formulas), follow-up or follow-on formulas, growing-up milk, baby food, infant cereal compositions, or fortifiers such as breast milk fortifiers.

[0105] 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).

[0106] Generally, starter formulas are breast milk substitutes for infants from birth onward. 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.

[0107] 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.

[0108] The composition according to the present invention may be a dairy product, a liquid beverage, a beverage powder, a dried soup, a dietary supplement, a meal replacement, a nutrition bar, a cereal, a confectionery product, or a dried pet food.

[0109] The composition may further contain dietary fiber. Dietary fiber has been shown to enhance oral tolerance and protect against food allergies (Tan, J., et al., 2016. Cell reports, 15(12), pp. 2809-2824). "Dietary fiber" may contain at least one indigestible oligosaccharide (e.g., prebiotic). Prebiotics may be present in an amount of 0.3 to 10% by weight of the composition. Dietary fiber and / or prebiotics can promote the production of endogenous butyrates by the gut microbiota and thus can provide further beneficial effects.

[0110] 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 as the trademark "Prebio 1". The nutritional compositions of the present invention may also contain at least one milk oligosaccharide, which may be BMO (bovine milk oligosaccharide) and / or HMO (human milk oligosaccharide). In certain embodiments, the nutritional composition according to the present invention comprises an oligosaccharide mixture comprising 0.1 to 4.0% by weight of N-acetylated oligosaccharides, 92.0 to 98.5% by weight of galactooligosaccharides, and 0.3 to 4.0% by weight of sialylated oligosaccharides.

[0111] The composition of the present invention may further contain at least one probiotic (i.e., a probiotic strain), such as a probiotic strain. Ingestion of a probiotic strain can also promote the production of endogenous butyrates by the gut microbiota, and thus provide further beneficial effects.

[0112] 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.

[0113] In some specific embodiments, the probiotic is a probiotic strain. In some specific embodiments, the probiotic strain is Bifidobacterium and / or Lactobacillus.

[0114] 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.

[0115] 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 a mixture of phages, preferably against pathogenic streptococci, Haemophilus, Moraxella, and Staphylococcus.

[0116] 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.

[0117] 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.

[0118] For example, protein sources may be based not only on soybeans but also on whey, casein, and mixtures thereof. 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. In some embodiments, the protein source may also be partially or entirely provided by adding amino acids.

[0119] The term "intact" means that the main part of the protein is intact, that is, its molecular structure remains unchanged, for example, at least 80% of the protein remains unchanged, for example, at least 85% of the protein remains unchanged, preferably at least 90% of the protein remains unchanged, and more preferably at least 95% of the protein remains unchanged, for example, at least 98% of the protein remains unchanged. In certain embodiments, the protein is completely unchanged.

[0120] In relation to the present invention, the term "hydrolyzed" means that a protein has been hydrolyzed, or broken down to its constituent amino acids.

[0121] The protein may be completely hydrolyzed or partially hydrolyzed. If 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.

[0122] In a particular embodiment, the protein in the composition is hydrolyzed, extensively hydrolyzed, or partially hydrolyzed. The degree of hydrolysis (DH) of the protein may be 2 to 20, or 8 to 40, or 20 to 60, or 20 to 80, or greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, or greater than 90. For example, nutritional compositions containing hydrolysates with a degree of hydrolysis of less than about 15% are commercially available from Nestle under the trademark name Peptamen®.

[0123] In some embodiments, the protein is extensively hydrolyzed. For example, infant formulas containing extensively hydrolyzed proteins are commercially available from Nestle under the trademarks Althera® and Alfare®.

[0124] At least 70%, 80%, 85%, 90%, 95%, or 97% of the protein may be hydrolyzed. In certain embodiments, 100% of the protein is hydrolyzed.

[0125] In a particular embodiment, the protein is provided as amino acids. For example, an infant formula based on amino acids as a protein source is commercially available from Nestle under the trademark Alfamino®.

[0126] In one particular embodiment, the protein of the composition is a plant-derived protein.

[0127] The nutritional composition according to the present invention may contain a carbohydrate source. The inclusion of a carbohydrate source is particularly preferable 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, maltodextrin, starch, and mixtures thereof, can be used, but one preferred carbohydrate source for infant formulas is lactose.

[0128] The nutritional compositions 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 for specific vitamins and minerals have been established. Examples of minerals, vitamins, and other nutrients optionally present in the compositions of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amount of specific minerals and other vitamins will vary depending on the target population.

[0129] In a particular embodiment, the composition may further contain vitamin A and / or retinol. Butyrate can promote the conversion of vitamin A to retinoic acid by CD103-expressing dendritic cells (CD103+DCs), which in turn promotes the differentiation of naive T cells into Treg cells (Tan, J., et al., 2016. Cell reports, 15(12), pp.2809-2824). Specifically, Tan et al. have shown that dietary fiber containing vitamin A enhances the tolerogenicity of CD103+DCs.

[0130] If necessary, the nutritional composition of the present invention may 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.

[0131] The nutritional composition according to the present invention can be prepared by any preferred method. For example, the composition can be prepared by combining and mixing appropriately separated components, or optionally by mixing with one or more carriers, and then mixing the dried mixture with a liquid component (liquefier) ​​to form a liquid mixture. If the final product is a powder, the liquid mixture can then be homogenized, pasteurized, and optionally spray-dried. The composition may be homogenized before or after pasteurization.

[0132] For example, formulas such as infant formulas 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 in to form a liquid mixture. The water temperature should be in the range of about 50°C to about 80°C, as appropriate, to aid in the dispersion of the components. A commercially available liquefaction device can be used to form the liquid mixture. In particular, if the final product is in liquid form, any oligosaccharides can be added at this stage. If the final product is a powder, any oligosaccharides can also be added at this stage as desired. The liquid mixture can then be homogenized, for example, in two stages.

[0133] Allergic diseases The compounds defined herein are sources of butyrate / butyric acid and may therefore be used to prevent or treat allergic diseases. The compounds may be used in infants, children, or adults.

[0134] The development of an "allergic phenotype" or "atopy" has been shown to promote sensitization to other allergens later in life. Therefore, allergic sensitization in childhood, especially in early childhood and particularly to food allergens, is of great importance and attracts the most attention. Eczema in infancy also predisposes individuals to the development of food allergies or other types of allergies later in life. Consequently, allergies in childhood can be the first step in an allergy cascade in which multiple types of allergies develop later in life, a process commonly known as the "allergic march." For example, children who exhibit chronic food hypersensitivity in early childhood have a dramatically increased risk of developing allergic rhinitis (hay fever) or asthma in late childhood (Ostblom, E. et al. (2008); Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life, Clinical and Experimental Allergy, 38(8):1325-1332). Children with less severe food sensitivities also have an increased risk of developing respiratory allergies, though less severely than children with chronic food sensitivities. Therefore, reducing the severity of food sensitivities may be important in preventing the progression of the "allergic march." In this regard, managing the onset of allergic symptoms and preventing allergies are of paramount importance during childhood and infancy.

[0135] An infant's immune system develops actively during the first few years of life. In such young patients, addressing, preventing, avoiding, managing, reducing, or regulating allergic reactions can have short-term effects, as well as long-term effects on the subsequent allergy profile. In one embodiment, the prevention or treatment of an allergic disease is through primary prevention. "Primary prevention" is the effect of preventing or reducing a patient's risk of sensitization to an allergen, characterized by the absence or reduction of allergen-specific IgE antibodies. By preventing or reducing sensitization, allergic symptoms upon exposure to the same allergen become absent or reduced. By adjusting the way a patient becomes sensitized to one allergen or a group of allergens (primary prevention), subsequent allergic reactions can be regulated. Therefore, in one embodiment, the prevention or treatment of an allergic disease includes reducing or preventing allergic reactions to further allergens or multiple allergens in allergic patients (patients with a history of allergies).

[0136] Food allergens are the first allergens an infant encounters early after birth, and typically, infants not exclusively breastfed may encounter milk protein. Milk protein is, in fact, one of the most frequently observed causes of food allergies in infants, followed by egg, soy, and wheat proteins. Generally, food allergies can manifest in infants and children as skin symptoms (rashes, eczema, etc.) and gastrointestinal symptoms (abdominal cramps; pain, especially abdominal pain; vomiting). Food allergies are the most common trigger for severe allergic reactions that can lead to life-threatening anaphylaxis.

[0137] Furthermore, allergic sensitization and onset can also occur when infants / children are exposed to foods they encounter for the first time, such as grains, vegetables, fruits, nuts, or fish, as well as when exposed to airborne allergens such as pollen, dust mites, and animal dander. In adults, contact allergies and respiratory allergies have a greater impact. Recent WHO data (Clark, M.Jand. Million, RP (2009) Allergic rhinitis: market evolution, Nature Reviews, Drug Discovery, 8, pp. 271-272) indicates that up to 30-40% of the world's population suffers from some form of respiratory allergy.

[0138] Animals, especially small animals like pets, particularly companion animals such as dogs and cats, can also suffer from food allergies and intolerances, as well as environmental allergens. These typically manifest as symptoms similar to those in humans, such as gastrointestinal disorders including diarrhea, vomiting, and abdominal discomfort, as well as dermatitis or itching. In small animals, especially dogs, the main cause of chronic diarrhea is food-responsive enteropathy (food-responsive enteropathy or food-responsive diarrhea).

[0139] The compounds and compositions of the present invention may be used to prevent or treat food allergies, food intolerances, respiratory allergies, and skin allergies by preventing or reducing the risk of sensitization of subjects to allergens.

[0140] In some embodiments, the allergic reaction is a specific IgE-related immune response and / or a T cell-dependent hypersensitivity response. Therefore, in some embodiments, reducing or preventing allergies involves reducing or preventing the specific IgE-related immune response and / or the T cell-dependent hypersensitivity response. In some embodiments, allergic inflammation is reduced and / or oral tolerance is enhanced.

[0141] As used herein, “food allergy” refers to an abnormal immune response to one or more food allergens, typically an IgE response resulting from the release of histamine, but also includes non-IgE immune responses. Symptoms of food allergies may include itching, eczema, hives, tongue swelling, vomiting, diarrhea, skin rash, difficulty breathing, or hypotension. When symptoms are severe and involve two or more systems in the body, it is known as anaphylaxis.

[0142] As used herein, the term “food allergen” refers to a protein or derivative thereof that elicits an abnormal immune response. Purified food allergens may be named using the systematic nomenclature of the World Health Organization and the International Federation of Immunology Societies' Allergen Nomenclature Sub-Committee. Allergen names consist of an abbreviated form of the scientific name of its source (genus: 3-4 letters; species: 1-2 letters) and Arabic numerals. For example, Der p 1 is the allergen first reported from the house dust mite Dermatophagoides pteronyssinus. Food allergens are derived from proteins with a variety of biological functions, including proteases, ligand-binding proteins, structural proteins, pathogenicity-associated proteins, lipid delivery proteins, profilins, and calcium-binding proteins. A list of food allergens is available on the official website of the WHO / IUIS Allergen Nomenclature Database, http: / / www.allergen.org / index.php (Radauer, C., et al., 2014. Allergy, 69(4), pp.413-419 and Pomes, A., et al., 2018. Molecular Immunology).

[0143] In one embodiment, the food allergen is selected from one or more lists consisting of nuts, seeds, peanuts, seafood, shellfish, mollusks, crustaceans, milk, eggs, soy, gluten, grains, wheat, oats, barley, rye, celery, corn, lupine, sulfites, sesame, mustard, rice, poultry, and meat.

[0144] As used herein, “food intolerance” refers to an adverse (often delayed) reaction to a food, beverage, food additive, or compound contained in food that causes various symptoms in one or more bodily organs and systems, and generally refers to reactions other than food allergies. “Food hypersensitivity” can broadly refer to both food intolerance and food allergies.

[0145] As used herein, “respiratory allergy” refers to an abnormal immune response to one or more airborne allergens. Airborne allergens include pollen, mold or mold spores, weed pollen, tree pollen, grass pollen, and dandruff. Examples of respiratory allergies include allergic rhinitis and allergic asthma. Symptoms of allergic rhinitis (hay fever) include rhinitis or nasal congestion, sneezing, conjunctivitis, itchiness, and watery eyes, as well as swelling around the eyes. Symptoms of allergic asthma include wheezing, coughing, chest tightness, and shortness of breath.

[0146] As used herein, “skin allergy” refers to an abnormal immune response caused by contact with one or more environmental allergens or ingestion of allergenic foods. Environmental allergens include food allergens, dust mites, pollen, mold or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, or pet dander. Examples of skin allergies include dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, and psoriasis. These are typically a group of diseases that cause inflammation of the skin, and symptoms include itching, redness of the skin, and rashes.

[0147] Allergic diseases may also include other allergic inflammatory conditions, such as eosinophilic esophagitis and other eosinophilic gastrointestinal disorders. Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus involving eosinophils, a type of white blood cell. Symptoms include difficulty swallowing, food ingestion, vomiting, and heartburn.

[0148] Butyrate, and therefore the compounds and compositions of the present invention, can prevent or reduce allergic reactions through one or more mechanisms.

[0149] The compounds and compositions of the present invention can modulate and / or promote the differentiation of Treg cells. Regulatory T (Treg) cells are crucial for inducing tolerance, and by modulating and / or promoting the induction of oral tolerance, they can control type 2 allergic reactions and prevent food allergies by reducing IgE production, or may accelerate the development of food allergies. Many chronic inflammatory diseases, such as psoriasis, allergies, and inflammatory bowel disease, are thought to develop due to a breakdown of immune tolerance. Preclinical data have demonstrated that direct oral delivery of butyrate increased Treg cell differentiation (Tan, J., et al., 2016. Cell reports, 15(12), pp.2809-2824). Failure to induce Treg activity has been shown to lead to abnormal Th2 responses and the development of allergic diseases. Abnormal responses of type 2 helper T (Th2) cells can result in allergic inflammation. Type 2 innate lymphoid cells (ILC2s) are important sources of Th2 cytokines IL-5 and IL-13, which trigger acute exacerbations of asthma. Butyrates are important regulators of ILC2 proliferation and have been shown to function through histone deacetylase (HDAC) inhibitory activity (Thio, CLP, et al. 2018. Journal of Allergy and Clinical Immunology, 142(6), pp. 1867-1883. e12). Furthermore, antigen-specific stimulation of B cells in the presence of butyrates switches the differentiation of plasma cells to the development of regulatory B cells (Bregs) and the resulting production of IL-10 (Shi, Y., et al., 2015. Scientific Reports, 5, p. 17651).

[0150] The compounds and compositions of the present invention can increase the production and / or expression of one or more anti-inflammatory cytokines and / or decrease the production and / or expression of one or more inflammatory cytokines, and thus reduce tissue inflammation. Butyrates have also been shown to alter the production of anti-inflammatory cytokines, such as IL-10 (Shi, Y., et al., 2015. Scientific Reports, 5, p. 17651). Butyrates have also been shown to alter the production of many anti-inflammatory cytokines, such as TNFα, IL-5, IL-13, and IL-17 (Diakos, C., et al., 2006. Biochemical and biophysical research communications, 349(2), pp.863-868; Thio, CLP, et al., 2018. Journal of Allergy and Clinical Immunology, 142(6), pp.1867-1883.e12; and Singh, N., et al., 2014. Immunity, 40(1), pp.128-139).

[0151] The compounds and compositions of the present invention can modulate and / or reduce mast cell activity and all mast cell-mediated allergic symptoms, such as diarrhea or rash. Butyrate has been demonstrated to be effective in inhibiting mast cell activation and the production of inflammatory mediators in vivo (Wang, CC, et al., 2018. Innate Immunity, 24(1), pp.40-46).

[0152] The compounds and compositions of the present invention can improve GATA-3 expression. GATA-3 is a transcription factor that is specifically expressed in type 2 helper T cells (Th2 cells) and plays an important role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes. Therefore, the compounds can suppress the development of allergic reactions. In addition, GATA-3 is essential for the gene expression of cytokines IL-4, IL-5, and IL-13, which mediate allergic inflammation (Barnes, PJ, 2008. Current molecular medicine, 8(5), pp.330-334). High doses of sodium butyrate (1 mM) in vitro were sufficient to improve Gata3 expression in Th2-biased CD4+ T cells, along with conversion to IFNγ (Kespohl, M., et al., 2017. Frontiers in immunology, 8, p.1036). Other studies have shown that 0.1 mM sodium butyrate was insufficient to affect GATA-3 or FoxP3 expression in Th2-biased CD4+ T cells (Furusawa, Y., et al., 2013. Nature, 504(7480), p.446).

[0153] Administration Preferably, the compounds and compositions described herein are administered enterally.

[0154] Enteral administration may be oral, gastric, and / or rectal.

[0155] In one embodiment, administration is by oral or gastric. In a preferred embodiment, administration is by oral.

[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.

[0158] Sensory characteristics The present invention provides a compound that has improved sensory properties and is a source of butyric acid. In particular, the compound has improved odor and / or taste compared to butyric acid, butyrate salts, and / or triptyline. In one embodiment, the compound has an improved taste compared to triptyline. In one embodiment, the compound has an improved odor compared to butyrate salts (e.g., sodium butyrate).

[0159] 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. [Examples]

[0160] Example 1 - Preparation of butyrated triglycerides (TAGs) A composition containing butyrate-containing TAG was prepared by chemical transesterification between tributylin and high-oleic sunflower oil in the presence of a catalyst such as sodium methoxide. Tributylin was used in a molar excess relative to the high-oleic sunflower oil.

[0161] Three reagents, namely triptyline, high-oleic sunflower oil, and a catalyst, were mixed in a reactor under a nitrogen atmosphere and then heated at 80°C for 3 hours with stirring. After the reaction was complete, the product was washed several times with water and then dried under vacuum (25 mBar, 60°C for 2 hours). The resulting oil product was then subjected to a decolorization step using bleaching earth and purified by either short-pass distillation (130°C, 0.001-0.003 mbar) or deodorization by injection of steam water (160°C, 2 mbar, 2 hours).

[0162] Table 1 below shows the components of the obtained oil composition (mostly triglycerides). These triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by their lipid number: 4:0 for butyrate, 16:0 for palmitate, 18:0 for stearate, 18:1 for oleate, and 18:2 for linoleate. The central fatty acid is located at the sn-2 position of the triglyceride. For example, 16:0-4:0-18:1 represents two different triglycerides, each containing either a molecule with butyrate at the sn-2 position and palmitate at the sn-1 position and oleate at the sn-3 position, or oleate at the sn-1 position and palmitate at the sn-3 position.

[0163] TAG profiles and positional isomers were analyzed by liquid chromatography connected to a high-resolution mass spectrometer. The proportion of each lipid was evaluated by liquid chromatography connected to an evaporative light scattering detector (ELSD).

[0164] [Table 1]

[0165] In the compositional samples, the two most abundant TAGs were 4:0-18:1-4:0 and 18:1-18:1-4:0, totaling approximately 40-50g / 100g.

[0166] Example 2 - Odor characteristics of a butyrate-containing triglyceride The odor of a solution containing butyrate-containing TAG (mainly composed of oleic acid and butyric acid fatty acids) was compared with that of a solution containing sodium butyrate.

[0167] Sample preparation Solutions containing a butyrate-containing TAG (see Example 1) or sodium butyrate were prepared and stored at 4°C until passed to a functional panel. Each 250 mL solution contained 600 mg of butyrate (equivalent to one commercially available sodium butyrate capsule as a nutritional supplement: concentration 2.4 mg / mL) and 1 wt / vol% of BEBA Optipro 1 infant formula in acidic deionized water.

[0168] The samples were prepared the day before the test by placing 4 mL of each solution (TAG butyrate solution; sodium butyrate solution) into Agilent vials.

[0169] method A "2-to-5 test" was conducted. In this test, five samples were presented to a panelist. The panelist was instructed to identify two samples that were different from the other three. To avoid bias due to the order of presentation, the order in which the samples were presented was randomized.

[0170] In addition to the 2-to-5 scoring test, panelists were shown a comment section and asked to comment on the nature of the perceived differences (e.g., odor intensity, odor quality).

[0171] result Five samples were presented to the panelists simultaneously. The panelists were asked to remove the caps in a predetermined order, smell the samples, and then recap each vial. The results are shown in Table 2.

[0172] [Table 2]

[0173] The p-value was calculated using a binomial test performed with Fizz software (Biosystems, France).

[0174] According to a panelist who was able to distinguish between the correct response (a butyrate-containing TAG sample that differs from sodium butyrate), sodium butyrate had a "cheese" smell, while the butyrate-containing TAG sample had a significantly reduced "cheese" smell and was described as having almost no distinctive odor.

[0175] Example 3. Taste characteristics of butyrate-containing triglycerides Functional benchmarking of a solution containing a butyrate-containing TAG (see Example 1), mainly composed of oleic acid and butyric acid fatty acids, was performed in comparison with a solution containing triptyline.

[0176] Sample preparation One tablespoon (4.6g) of BEBA Optipro 1 infant formula was added to warm water (boiled water cooled as per instructions) to a final volume of 150mL (approximately 3 wt / vol% solution). 600mg of butyrate was prepared by weighing each TAG form separately, and the infant formula was added to each solution to a final volume of 50mL.

[0177] Solution A contained a butyrate-containing TAG (see Example 1). Solution B contained triplyline.

[0178] method The panel group repeatedly conducted tastings without knowing the contents.

[0179] The samples were prepared immediately before the preliminary bitterness evaluation, and each solution was vigorously shaken. Small amounts of each solution were simultaneously filled into tasting cups labeled A and B.

[0180] The two samples were presented to the panelists simultaneously. The panelists were asked to taste the solutions by taking a sip and spitting them out, and to rate the perceived bitterness on a scale of 0 to 10 [0 being no bitterness perceived, and 10 being the strongest bitterness imaginable].

[0181] result Regarding the bitterness of solution A, the panelists rated it as 4.33 ± 1.52, on a mean ± standard deviation.

[0182] Regarding the bitterness of solution B, the panelists rated it as 8.33 ± 1.52, on a mean ± standard deviation.

[0183] These data indicate that the butyrate-containing TAG composition in the infant formula had significantly lower bitterness compared to triptyline in the infant formula.

[0184] 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 method.

[0185] [ka]

[0186] When BPB was evaluated using a descriptive sensory panel evaluation, it was found to have no unpleasant taste or odor.

[0187] Example 5 - Preparation of butyrate-modified triglycerides (TAGs) 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.

[0188] The components (mainly triglycerides) of the obtained oil composition are shown in Table 3 below. Similar to Example 1, the 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.

[0189] [Table 3]

[0190] In this composition, the 4:0-4:0-18:1 triglyceride was identified as the most abundant.

[0191] Next, the obtained oil product was subjected to a decolorization process 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).

[0192] 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.

[0193] Example 6 - Administration of butyrate-modified triglycerides (TAGs) as an infant formula and reduction of allergic reactions in mammals with a history of allergies. Eight-week-old female BALB / c mice were sensitized to milk protein β-lactoglobulin (BLG) by applying it to the skin, inducing allergy to milk ("allergy group"). At this stage, all three "allergy groups" (allergy group 2, allergy group 3, and allergy group 3) received the same sensitization by applying milk protein β-lactoglobulin (BLG) to the skin. The non-allergic negative control group was treated only with phosphate-buffered saline (PBS) ("control group"). A total of three patches were applied, with a one-week patch-free period between each application. Six days after the last skin patch, the mice were orally administered BLG according to a conventional procedure known to those skilled in the art. Serum was processed for ELISA, and BLG-specific immunoglobulin E (IgE) and BLG-specific immunoglobulin G1 (IgG1) were measured (Figures 1 and 2, respectively). As can be seen from Figures 1 and 2, all three groups of mice—allergy group 1, allergy group 2, and allergy group 3—showed an allergic reaction to oral administration of BLG, demonstrating that the mice were sensitized to the milk protein β-lactoglobulin (BLG).

[0194] After inducing milk allergy, the "control group" and "allergy group 1" were administered for 3 weeks a reconstitution of an infant formula for nutritional management of milk allergy (in this example, a widely hydrolyzed infant formula commercially available under the trademark Althera® was used) with drinking water. "Allergy group 2" and "allergy group 3" were given ad libitum access to butyrate for 3 weeks in the presence of the infant formula for nutritional management of milk allergy reconstituted with drinking water. Butyrate was administered to allergy group 2 in the form of sodium butyrate, and to allergy group 3 in the form of a butyrate-containing TAG composition (referred to herein as "palatable butyrate") prepared according to Example 1. The sodium butyrate or palatable butyrate was prepared so that the final concentration of butyrate was 600 μg per 1 mL of infant formula. Subsequently, egg allergy was induced in "allergy group 1". In "Allergy Group 2 treated with sodium butyrate" and "Allergy Group 3 treated with palatability butyrate," egg protein ovalbumin (OVA) was administered intraperitoneally with aluminum hydroxide as an adjuvant. The "control group" received only the adjuvant intraperitoneally. Two weeks after the last intraperitoneal administration, mice were orally administered OVA three times a week for a total of 12 doses. All groups continued to receive infant formula + / - butyrate throughout their exposure to egg allergy. Mice were observed after each oral OVA dose to determine their clinical score. Allergic symptoms were defined as follows: 0 = normal stool; 1 = loose / sticky stools; 2 = loose stools; 3 = liquid stools / diarrhea; 4 = at least two episodes of liquid diarrhea; 5 = score of 4 at the end of the study. These data were combined to calculate the cumulative clinical score for each mouse during the study (Figure 3). Figure 3 shows that "Allergy Group 2 treated with sodium butyrate" and "Allergy Group 3 treated with palatability butyrate" showed a reduction in allergic symptoms compared to "Allergy Group 1" which did not receive butyrate treatment. Serum was processed for ELISA, and OVA-specific IgE, OVA-specific IgG1, and mast cell protease-1 (MCPT-1) were measured (Figures 4, 5, and 6, respectively).The similar levels of OVA-specific IgE and OVA-specific IgG1 observed in the three allergy groups indicate that the reduction in allergic reactions after oral administration of OVA is not due to a decrease in allergic sensitization to the allergen. Figure 6 shows that mast cell protease-1 was reduced in "Allergy Group 2 treated with sodium butyrate" and "Allergy Group 3 treated with palatability butyrate," indicating that the mast cell response was regulated in the butyrate-treated groups.

[0195] This example demonstrates that oral administration of butyrate to mammals with a history of milk protein allergy reduces allergic reactions to egg allergens.

[0196] All publications referenced in the above specification are incorporated herein by reference. Various modifications and changes to the methods, cells, compositions, and uses of the disclosed invention will be apparent to those skilled in the art, without departing from the scope and spirit of the invention. While the invention is disclosed in relation to certain preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the form disclosed for carrying out the invention are intended to be obvious to those skilled in the art and fall within the scope of the following claims.

Claims

1. Compounds having formula (1) and compounds having formula (2) for use in the treatment or prevention of allergic diseases 【Chemistry 1】 [In the formula, R １ , R ２ A composition comprising: , and R3, which are independently long-chain fatty acids having 16 to 20 carbon atoms.

2. The composition for use according to claim 1, wherein the compound having formula (1) constitutes at least 10% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) constitutes at least 10% by weight of the total amount of triglycerides in the composition.

3. The composition for use according to claim 1 or 2, wherein the compound having formula (1) constitutes at least 15% by weight of the total triglycerides in the composition, and the compound having formula (2) constitutes at least 15% by weight of the total triglycerides in the composition.

4. The composition for use according to any one of claims 1 to 3, wherein the compound having formula (1) constitutes at least 20% by weight of the total triglycerides in the composition, and the compound having formula (2) constitutes at least 20% by weight of the total triglycerides in the composition.

5. The composition for use according to any one of claims 1 to 4, wherein the compound having formula (1) constitutes at least 20% by weight of the total triglycerides in the composition, and the compound having formula (2) constitutes at least 30% by weight of the total triglycerides in the composition.

6. The composition for use according to any one of claims 1 to 5, wherein the compound having formula (1) constitutes 20% to 40% by weight of the total triglycerides of the composition, and / or the compound having formula (2) constitutes 30% to 40% by weight of the total triglycerides of the composition.

7. The composition for use according to any one of claims 1 to 6, wherein the compound having formula (1) and the compound having formula (2) constitute at least 50% by weight of the total amount of triglycerides in the composition.

8. The composition for use according to claim 7, wherein the compound having formula (1) and the compound having formula (2) constitute 50% to 75% by weight of the total amount of triglycerides in the composition.

9. A composition for use according to any one of claims 1 to 8, further comprising a compound having formula (3) and / or a compound having formula (4). 【Chemistry 2】 [In the formula, R4, R5, and R6 are independently long-chain fatty acids having 16 to 20 carbon atoms.]

10. The composition for use according to claim 9, wherein the compound having formula (3) constitutes at least 2% by weight of the total triglycerides of the composition, and / or the compound having formula (4) constitutes at least 1% by weight of the total triglycerides of the composition.

11. The composition for use according to claim 1, wherein the compound having formula (1) constitutes at least 20% by weight of the total butyric acid-containing triglycerides in the composition, and the compound having formula (2) constitutes at least 30% by weight of the total butyric acid-containing triglycerides in the composition.

12. The composition for use according to claim 11, wherein the compound having formula (1) constitutes 30% to 50% by weight of the total butyric acid-containing triglycerides in the composition, and / or the compound having formula (2) constitutes 40% to 60% by weight of the total butyric acid-containing triglycerides in the composition.

13. The composition for use according to claim 11 or 12, wherein the compound having formula (1) and the compound having formula (2) constitute at least 70% by weight of the total butyric acid-containing triglycerides in the composition.

14. formula 【Transformation 3】 A composition for use according to claim 1, comprising a compound having formula (5) and a compound having formula (6).

15. The composition for use according to claim 14, wherein the compound having formula (5) constitutes at least 10% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 10% by weight of the total triglycerides in the composition.

16. The composition for use according to claim 14 or 15, wherein the compound having formula (5) constitutes at least 15% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes at least 15% by weight of the total triglycerides in the composition.

17. The composition for use according to any one of claims 14 to 16, wherein the compound having formula (5) constitutes at least 15% by weight of the total triglycerides of the composition, and / or the compound having formula (6) constitutes at least 20% by weight of the total triglycerides of the composition.

18. The composition for use according to any one of claims 14 to 17, wherein the compound having formula (5) constitutes at least 20% by weight of the total triglycerides of the composition, and / or the compound having formula (6) constitutes at least 20% by weight of the total triglycerides of the composition.

19. The composition for use according to any one of claims 14 to 18, wherein the compound having formula (5) constitutes 15% to 30% by weight of the total triglycerides in the composition, and / or the compound having formula (6) constitutes 20% to 30% by weight of the total triglycerides in the composition.

20. The composition for use according to any one of claims 14 to 19, wherein the compound having formula (5) and the compound having formula (6) constitute at least 40% by weight of the total amount of triglycerides in the composition.

21. A composition for use according to any one of claims 14 to 20, further comprising the compound having formula (7) and / or the compound having formula (8).

22. The composition for use according to claim 21, wherein the compound having formula (7) constitutes at least 2% by weight of the total triglycerides of the composition, and / or the compound having formula (8) constitutes at least 2% by weight of the total triglycerides of the composition.

23. The composition for use according to any one of claims 14 to 22, wherein the compound having formula (5) constitutes at least 10% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 10% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

24. The composition for use according to any one of claims 14 to 23, wherein the compound having formula (5) constitutes at least 15% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 15% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

25. The composition for use according to any one of claims 14 to 24, wherein the compound having formula (5) constitutes at least 15% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 20% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

26. The composition for use according to any one of claims 14 to 25, wherein the compound having formula (5) constitutes at least 20% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes at least 20% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

27. The composition for use according to any one of claims 14 to 26, wherein the compound having formula (5) constitutes 15% to 30% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and the compound having formula (6) constitutes 20% to 30% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

28. The composition for use according to any one of claims 21 to 27, wherein the compound having formula (7) constitutes at least 2% by weight of the total amount of butyrate-partially-containing triglycerides in the composition, and / or the compound having formula (8) constitutes at least 2% by weight of the total amount of butyrate-partially-containing triglycerides in the composition.

29. The composition for use according to any one of claims 14 to 28, wherein the compound having formula (8) is a butyrate-partially-containing triglyceride.

30. The composition for use according to any one of claims 14 to 29, wherein the compound having formula (8) constitutes at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition.

31. The composition for use according to any one of claims 14 to 30, wherein the compound having formula (8) constitutes 20% to 95% by weight of the total amount of butyrate-containing triglycerides in the composition.

32. The composition for use according to any one of claims 14 to 31, wherein the compound having formula (8) constitutes 50% to 90% by weight of the total amount of butyrate-containing triglycerides in the composition.

33. A composition for use according to any one of claims 14 to 32, comprising the compound having formula (8), wherein the compound having formula (8) and the compound having formula (5) constitute at least 50% by weight of the total amount of butyrate-containing triglycerides in the composition.

34. 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-Butyryl-2-Linoleoyl-3-Oleoylglycerol, 1-Oleoyl-2-Linoleoyl-3-Butyryl A composition for use according to any one of claims 1 to 33, comprising at least one selected from the group consisting of glycerol, 1-butyryl-2-stearoyl-3-oleoylglycerol, 1-oleoyl-2-stearoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-stearoylglycerol, 1,2-dioleoyl-3-palmitoylglycerol, 1-palmitoyl-2,3-dioleoylglycerol, 1,2-dioleoyl-3-linoleoylglycerol, and 1-linoleoyl-2,3-dioleoylglycerol.

35. A composition for use according to any one of claims 1 to 34, which is in the form of a solid, liquid, or gelatinous substance.

36. A composition for use according to any one of claims 1 to 35, further comprising 0.3% to 10% by weight of a prebiotic.

37. A nutritional composition containing a protein source, a carbohydrate source, and a lipid source, wherein the protein is present in an amount of 2.4 g / 100 kcal to 4 g / 100 kcal, according to any one of claims 1 to 36.

38. A nutritional composition containing a protein source, a carbohydrate source, and a lipid source, wherein the protein is present in an amount of less than 2.0 g / 100 kcal, according to any one of claims 1 to 36.

39. The composition for use according to any one of claims 1 to 38, wherein the allergic disease is selected from one or more of the group consisting of food allergies, food intolerances, respiratory allergies, and skin allergies.

40. A composition for use according to any one of claims 1 to 39, for enteral administration.

41. A composition for use according to any one of claims 1 to 40, for oral, gastric, and / or rectal administration.

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