Dietary butyric acid compounds for treatment or prevention of allergic diseases

Abstract

Compounds or combinations thereof having the formula: # imgabs0 # wherein R1, R2, R3, R4, R5 and R6 are independently long chain fatty acids having 16 to 20 carbons for use in the treatment or prevention of allergic diseases.

Description

[0001] This application is a divisional application. The application number of the original application is 201980079138.6, the application date is December 19, 2019, the priority date is December 21, 2018, and the name of the invention is “Dietary butyrate compounds for treating or preventing allergic diseases”. Technical Field

[0002] The present invention relates to a dietary source of butyrate having improved organoleptic properties for use in the treatment or prevention of allergic diseases. Background Art

[0003] Allergic diseases are now recognized as epidemics 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 incidence of food allergies and allergies seems to be steadily increasing, with the greatest increase observed in infants with food allergies or atopic eczema (Koplin, JJ et al., 2015, Current opinion in allergy and clinical immunology, 15 (5), pp. 409-416).

[0004] It has been proposed that changes in the composition of intestinal microflora are one of the explanations for the increased incidence of allergic diseases. Intestinal microbiota promotes the growth of regulatory T (Treg) cells that have previously been shown to play a key role in maintaining immune tolerance to allergens (Rivas, MN and Chatila, TA, 2016, Journal of Allergy and Clinical Immunology, 138 (3), pp. 639-652). Specifically, dietary fiber-derived metabolites are related to intestinal homeostasis and Treg cell biology (Tan, J. et al., 2016, Cell reports, 15 (12), pp. 2809-2824). Butyric acid is one of the most common short-chain fatty acids (SCFA) produced by human intestinal microbiota in response to indigestible dietary fiber in the diet. Salts and esters of butyric acid are referred to as butyrate compounds or butyrates / esters (butyrate or butanoate).

[0005] Preclinical data have demonstrated that direct oral delivery of butyrate is sufficient to prevent the development of food allergies (Tan, J. et al., 2016, Cell reports, 15 (12), pp. 2809-2824) and improves allergic lung inflammation (Thio, CLP et al., 2018, Journal of Allergy and Clinical Immunology, 142 (6), pp. 1867-1883, e12). In addition, elevated butyrate levels in feces are associated with accelerated spontaneous development of infant milk allergy (Canani, RB et al., 2016, The ISME journal, 10 (3), p. 742), and intestinal microbiota that produces more abundant butyrate is associated with milder symptoms in infants with atopic eczema (Nylund, L. et al., 2015, Allergy, 70 (2), pp. 241-244). Therefore, butyrate is a strong candidate for regulating food allergic responses by promoting Treg cell growth.

[0006] In addition to the determined impact on Treg responses, butyrate has also been confirmed to affect mast cell activity. Mast cells are considered to play important proinflammatory functions and potential immunomodulatory effects in various immune diseases by releasing mediators such as histamine, leukotrienes, cytokine chemokines and neutral proteases (Amin, K. et al., 2012, Respiratory medicine, 106 (1), pp. 9-14). When exposed to butyrate, mouse mast cell line MC / 9 shows reduced proliferation (Galli, SJ et al., 1982, The Journal of cell biology, 95 (2), pp. 435-444), and further studies show that butyrate interferes with mast cell activation, thereby inhibiting the release of mediators and the production of proinflammatory cytokines TNFα in mast cells (Diakos, C. et al., 2006, Biochemical and biophysical research communications, 349 (2), pp. 863-868). Butyrate is 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).

[0007] In the presence of butyrate, antigen-specific stimulation of B cells transforms plasma cell differentiation into regulatory B cell (Breg) development and IL-10 production, and Breg in vivo induction is associated with a concomitant reduction in the number of intestinal mast cells after experimental food allergy (Shi, Y. et al., 2015, Scientific reports, 5, p. 17651). Butyrate can also affect mast cell responses by affecting type 2 innate lymphocyte (ILC2) activation and / or cytokine responses. Butyrate, rather than acetate or propionate, is sufficient to improve ILC2-driven allergic inflammation (including eosinophilic inflammation) and reduce the production of cytokines in human ILC2 cells (Thio, CLP et al., 2018, Journal of Allergy and Clinical Immunology, 142 (6), p. 1867-1883, e12). ILC2 responses have been implicated in promoting IgE mast cell-mediated experimental food allergy (Chen, CY et al., 2015, Immunity, 43(4), pp. 788-802).

[0008] Common sources of butyrate are butyric acid and tributyrin, the latter being a triglyceride consisting of three ester functional groups with three butyrate moieties and a glycerol backbone. Butyric acid and tributyrin are generally regarded as safe (GRAS) (21 CFR582.60 and 21 CFR184.1903, respectively) food additives and are natural components of many dairy products. However, butyric acid is associated with negative organoleptic qualities, such as vomit-like, fecal-like and cheese-like aroma attributes. Tributyrin also has negative organoleptic qualities, particularly high bitterness. These unpleasant taste and odor attributes can make oral administration of compositions containing these compounds particularly difficult, especially in pediatric populations. The butyrate component from dairy products cannot be enriched, and therefore would require the consumption of large amounts of dairy fat, but this is not feasible for practical and nutritional reasons, especially because this would result in a large amount of undesirable calories derived from animal fat.

[0009] It would therefore be beneficial to provide a food grade source of butyrate for the treatment or prevention of allergic diseases having improved organoleptic properties compared to available solutions. Summary of the invention

[0010] The present invention provides compounds as a source of butyrate with improved organoleptic properties for use in treating or preventing allergic diseases. Specifically, the compounds have an improved smell and / or taste relative to butyric acid, butyrate and / or tributyrin. The compounds can be used as a dietary source of butyric acid. The compounds can be used, for example, in nutritional compositions, dietary supplements, infant formula and follow-on formula, beverages, pet care products.

[0011] According to a first aspect of the present invention, there is provided a compound having the following formula or a combination thereof for use in treating or preventing an allergic disease:

[0012]

[0013] Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Independently a long chain fatty acid having 16 to 20 carbons.

[0014] According to another aspect of the present invention, a composition comprising a compound of formula (1), formula (2), formula (3) or formula (4) or a combination thereof for treating or preventing an allergic disease is provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Independently a long chain fatty acid having 16 to 20 carbons.

[0015] 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).

[0016] The composition may comprise a compound having formula (1) and a compound having formula (2).

[0017] The composition may comprise a compound having formula (1) and a compound having formula (3).

[0018] The composition may comprise a compound having formula (1) and a compound having formula (4).

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

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

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

[0022] The composition may comprise a compound having formula (1), a compound having formula (2), and a compound having formula (3).

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

[0024] The composition may comprise a compound having formula (1), a compound having formula (3), and a compound having formula (4).

[0025] The composition may comprise a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0026] The composition may include a compound having formula (1), a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0027] In one embodiment, the compound of formula (1), the compound of formula (2), the compound of formula (3), and the compound of formula (4) comprise at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total triglycerides in the composition.

[0028] In one embodiment, the compound of formula (1), the compound of formula (2), the compound of formula (3), and the compound of formula (4) comprise at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0029] In one embodiment, the compound of formula (4) is the major triglyceride containing butyric acid moieties in the composition.

[0030] In one embodiment, the compound of formula (4) comprises at least 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, or at least 60 wt %, at least 70 wt %, at least 80 wt %, or at least 90 wt % of the total triglycerides containing butyric acid moieties in the composition.

[0031] In one embodiment, the composition comprises a compound having formula (1) and a compound having formula (4), and the combination of the compound having formula (1) and the compound having formula (4) is present in an amount of at least 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0032] In one embodiment, tributyrin comprises less than 10 wt %, preferably less than 8 wt %, more preferably less than 5 wt % of the total triglycerides in the composition.

[0033] In one embodiment, the composition further comprises vitamin A and / or dietary fiber and / or probiotics.

[0034] In one embodiment the composition is a nutritional composition, preferably wherein the nutritional composition is a dietary supplement, an infant formula, a follow-on formula, a beverage or a pet care product.

[0035] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 It is an unsaturated fatty acid, preferably a monounsaturated one.

[0036] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 Selected from oleic acid, palmitic acid or linoleic acid, preferably R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each of which is oleic acid.

[0037] In one embodiment, the allergic disease is selected from one or more of the following: food allergy, food intolerance, respiratory allergy, and skin allergy.

[0038] In one embodiment, the allergic disease is selected from one or more of the following: rhinitis, asthma, urticaria or hay fever, allergic conjunctivitis, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, psoriasis, eosinophilic esophagitis and eosinophil-related gastrointestinal diseases, allergic diarrhea, vomiting, abdominal pain or bloating.

[0039] In one embodiment, the allergen in the 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.

[0040] In one embodiment, the allergen in the allergic disease is a food allergen, preferably wherein the food allergen is selected from the group consisting of nuts, tree nuts, peanuts, fish, shellfish, molluscs, crustaceans, milk, eggs, soy, gluten, cereals, wheat, oats, barley, rye, celery, corn, lupins, sulfites, sesame, mustard, rice, poultry and meat.

[0041] In one embodiment, the compound or combination thereof has improved organoleptic properties relative to butyric acid, tributyrin and / or butyrate.

[0042] In one embodiment, the compound is administered to a young or adult mammal, preferably an infant, toddler, young or adult human, pet, or farm animal. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a graphical representation of the BLG-specific immunoglobulin E (IgE) response in mice sensitized to the milk protein β-lactoglobulin (BLG) and in mice in the control group.

[0044] Figure 2 is a graphical representation of the BLG-specific immunoglobulin G1 (IgG1) response in mice sensitized with the milk protein β-lactoglobulin (BLG) and in mice in the control group.

[0045] Figure 3 is a graphical representation of the cumulative clinical scores after oral OVA challenge in mice "Control" (negative control), "Allergic Group 1" (BLG-sensitized positive control), "Sodium butyrate-treated Allergic Group 2" and "Oral butyrate-treated Allergic Group 3".

[0046] Figure 4 Figure 2 is a graphical representation of the OVA-specific IgE response to oral OVA challenge in allergic and control groups of mice, including 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".

[0047] Figure 5 Figure 2 is a graphical representation of the OVA-specific IgG1 response of mice in the allergic and control groups to oral OVA challenge, these groups include "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".

[0048] Figure 6It is a graphical representation of mast cell proteinase-1 (MCPT-1) in allergic group mice and control group mice to oral OVA challenge, these groups include "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". DETAILED DESCRIPTION

[0049] As used herein, the terms "comprising" and "consisting of" are synonymous with "including" or "containing" and are inclusive or open-ended and do not exclude additional unrecited members, elements or steps. The terms "comprising" and "consisting of" also include the term "consisting of".

[0050] Triglycerides

[0051] Triglycerides (also known as triacylglycerols) are triesters derived from glycerol and three fatty acids. Under hydrolysis conditions such as during digestion, triglycerides may be a source of fatty acids. For example, tributyrin may be a source of three moles of butyric acid per mole of tributyrin.

[0052] Fatty acids are carboxylic acids with a long tail (chain). Fatty acids can be unsaturated or saturated. Fatty acids that are not attached to other molecules are called free fatty acids (FFA).

[0053] The term "fatty acid moiety" refers to the portion of a triglyceride produced 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] Long chain fatty acids preferably used 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 a compound or a combination thereof having the following formula for treating or preventing allergic diseases:

[0055]

[0056] Other examples of triglycerides that can be used in the present invention include 1,3-dibutyryl-2-linoleoyl glycerol, 1,3-dibutyryl-2-stearoyl glycerol, 1-butyryl-2-oleoyl-3-palmitoyl glycerol, 1-palmitoyl-2-oleoyl-3-butyryl glycerol, 1-butyryl-2-oleoyl-3-linoleoyl glycerol, 1-linoleoyl-2-oleoyl-3-butyryl glycerol, 1-oleoyl-2-butyryl-3-linoleoyl glycerol, 1-linoleoyl-2-oleoyl-3-butyryl glycerol, 1-linoleoyl-2-butyryl-3-linoleoyl glycerol, 1-butyryl-2-oleoyl-3-oleoyl glycerol, 1-butyryl-2-oleoyl-3- Linoleoyl-3-oleoyl glycerol, 1-oleoyl-2-linoleoyl-3-butyryl glycerol, 1-butyryl-2-stearoyl-3-oleoyl glycerol, 1-oleoyl-2-stearoyl-3-butyryl glycerol, 1-butyryl-2-oleoyl-3-stearoyl glycerol, 1-stearoyl-2-oleoyl-3-butyryl glycerol, 1,2-dioleoyl-3-palmitoyl glycerol, 1-palmitoyl-2,3-dioleoyl glycerol, 1,2-dioleoyl-3-linoleoyl glycerol and 1-linoleoyl-2,3-dioleoyl glycerol.

[0057] The triglyceride of the present invention can be synthesized by, for example, esterification of long-chain fatty acids and butyric acid with glycerol.

[0058] The triglycerides of the present invention can be synthesized by, for example, 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 produces triglycerides containing primarily butyrate and oleate moieties. These compounds are dairy-free, cholesterol-free, and vegan. The fatty acids are released from the triglycerides by lipases naturally present in the gastrointestinal tract. Relative to butyrate, these compounds do not add additional mineral salts to the final formulation.

[0059] Alternative triglyceride synthesis methods can be routinely determined by one skilled in the art.

[0060] By way of example, a method for obtaining 1,3-dibutyryl-2-palmitoylglycerol (BPB) is as follows:

[0061]

[0062] As another example, triglycerides can be synthesized by esterification of the long-chain fatty acid monoacylglycerol (MAG) with butyric acid (BA).

[0063] For example, water is removed by esterification of long-chain fatty acid monoacylglycerol (MAG) with butyric acid (BA). By way of example, a method for obtaining 1,2-dibutyryl-3-oleoyl glycerol is as follows:

[0064]

[0065] The esterification reaction is preferably carried out with a butyric acid (BA):monoacylglycerol (MAG) molar ratio of ≥ 2; ie, in a molar excess of butyric acid.The removal of water may be carried out by conventional methods routinely used in the art.

[0066] Triglycerides containing a single butyric acid moiety may be used herein. Alternatively, mixtures of triglycerides containing different butyric acid moieties may be used.

[0067] The triglycerides may also be subjected to decolorization and / or deodorization steps conventional in the art and well known to those skilled in the art, for example as conventionally used in the manufacture of vegetable oils.

[0068] Composition

[0069] The compounds of the present invention may be administered in the form of a composition. Accordingly, the present invention provides a composition for treating or preventing an allergic disease, the composition comprising a triglyceride containing a butyric acid moiety as described herein.

[0070] In one embodiment, the combination of a compound of formula (1) and a compound of formula (2) is present in a composition as defined herein.

[0071] In one embodiment, the compound of formula (1) is present in an amount of at least 10% by weight of the total triglycerides in the composition, and the compound of formula (2) is present in an amount of at least 10% by weight of the total triglycerides in the composition.

[0072] In one embodiment, the compound of formula (1) is present in an amount of at least 15% by weight of the total triglycerides in the composition, and the compound of formula (2) is present in an amount of at least 15% by weight of the total triglycerides in the composition.

[0073] In one embodiment, the compound of formula (1) is present in an amount of at least 20% by weight of the total triglycerides in the composition, and the compound of formula (2) is present in an amount of at least 20% by weight of the total triglycerides in the composition.

[0074] In one embodiment, the compound of formula (1) is present in an amount of at least 20% by weight of the total triglycerides in the composition, and the compound of formula (2) is present in an amount of at least 30% by weight of the total triglycerides in the composition.

[0075] In one embodiment, the compound of formula (1) comprises about 20% to about 40% by weight of the total triglycerides in the composition, and / or the compound of formula (2) comprises about 30% to about 40% by weight of the total triglycerides in the composition.

[0076] In one embodiment, the compound of formula (1) and the compound of formula (2) comprise at least 20%, 30%, 40%, 50%, 60% or 70% by weight of the total triglycerides in the composition, preferably from about 40% to about 80%, or from about 50% to about 75% by weight of the total triglycerides in the composition.

[0077] In one embodiment, the composition further comprises a compound of formula (3), preferably wherein the compound of formula (3) accounts for at least 2 weight %, 3 weight %, 4 weight % or 5 weight % of the total triglycerides in the composition, and / or the composition further comprises a compound of formula (4), preferably wherein the compound of formula (4) accounts for at least 1 weight %, 2 weight % or 3 weight % of the total triglycerides in the composition.

[0078] In one embodiment, the compound of formula (1) is present in an amount of at least 20 weight % of the total butyric acid-containing triglycerides in the composition, and the compound of formula (2) is present in an amount of at least 30 weight % of the total butyric acid-containing triglycerides in the composition.

[0079] In one embodiment, the compound of formula (1) comprises about 30% to about 50% by weight of the total butyric acid-containing triglycerides in the composition, and / or the compound of formula (2) comprises about 40% to about 60% by weight of the total butyric acid-containing triglycerides in the composition.

[0080] In one embodiment, the compound of formula (1) and the compound of formula (2) comprise at least 20%, 30%, 40%, 50%, 60%, 70% or 80% by weight of the total butyric acid-containing triglycerides in the composition, preferably from about 60% to about 90% by weight of the total butyric acid-containing triglycerides in the composition.

[0081] In one embodiment, the compound of formula (4) is the major triglyceride containing butyric acid moieties in the composition.

[0082] In one embodiment, the compound of formula (4) comprises at least 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, or at least 60 wt %, at least 70 wt %, at least 80 wt %, or at least 90 wt % of the total triglycerides containing butyric acid moieties in the composition.

[0083] In one embodiment, the composition comprises a compound having formula (1) and a compound having formula (4), and the combination of the compound having formula (1) and the compound having formula (4) is present in an amount of at least 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0084] In one embodiment, the compound of formula (5) comprises at least 10% by weight of the total triglycerides in the composition and / or the compound of formula (6) comprises at least 10% by weight of the total triglycerides in the composition.

[0085] In one embodiment, the compound of formula (5) comprises at least 15% by weight of the total triglycerides in the composition and / or the compound of formula (6) comprises at least 15% by weight of the total triglycerides in the composition.

[0086] In one embodiment, the compound of formula (5) comprises at least 15% by weight of the total triglycerides in the composition and / or the compound of formula (6) comprises at least 20% by weight of the total triglycerides in the composition.

[0087] In one embodiment, the compound of formula (5) comprises at least 20% by weight of the total triglycerides in the composition and / or the compound of formula (6) comprises at least 20% by weight of the total triglycerides in the composition.

[0088] In one embodiment, the compound of formula (5) comprises from about 15% to about 30% by weight of the total triglycerides in the composition, and / or the compound of formula (6) comprises from about 20% to about 30% by weight of the total triglycerides in the composition.

[0089] In one embodiment, the compound of formula (5) and the compound of formula (6) comprise at least 20%, 30% or 40% by weight of the total triglycerides in the composition, preferably from about 30% to about 60% or from about 40% to about 50% by weight of the total triglycerides in the composition.

[0090] In one embodiment, the composition further comprises a compound having formula (7), preferably wherein the compound having formula (7) accounts for at least 2 weight % or 3 weight % of the total triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably wherein the compound having formula (8) accounts for at least 2 weight % or 3 weight % of the total triglycerides in the composition.

[0091] In one embodiment, the compound having formula (5) comprises at least 10 weight percent of the total triglycerides containing butyric acid moieties in the composition, and the compound having formula (6) comprises at least 10 weight percent of the total triglycerides containing butyric acid moieties in the composition.

[0092] In one embodiment, the compound having formula (5) comprises at least 15 weight percent of the total triglycerides containing butyric acid moieties in the composition, and the compound having formula (6) comprises at least 15 weight percent of the total triglycerides containing butyric acid moieties in the composition.

[0093] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total triglycerides containing butyric acid moieties in the composition, and the compound having formula (6) comprises at least 20% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0094] In one embodiment, the compound having formula (5) comprises at least 20 weight percent of the total triglycerides containing butyric acid moieties in the composition, and the compound having formula (6) comprises at least 20 weight percent of the total triglycerides containing butyric acid moieties in the composition.

[0095] In one embodiment, the compound having formula (5) comprises from about 15% to about 30% by weight of the total triglycerides containing butyric acid moieties in the composition, and the compound having formula (6) comprises from about 20% to about 30% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0096] In one embodiment, the composition further comprises a compound of formula (7), preferably wherein the compound of formula (7) accounts for at least 2% or 3% by weight of the total triglycerides containing butyric acid moieties in the composition, and / or the composition further comprises a compound of formula (8), preferably wherein the compound of formula (8) accounts for at least 2% or 3% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0097] In another embodiment, the compound of formula (8) is the major triglyceride containing butyric acid moieties in the composition.

[0098] In one embodiment, the compound of formula (8) comprises at least 20 weight %, at least 30 weight %, at least 40 weight %, at least 50 weight %, or at least 60 weight %, at least 70 weight %, at least 80 weight % or at least 90 weight % of the total triglycerides containing butyric acid moieties in the composition.

[0099] In one embodiment, the compound having formula (8) comprises from about 20% to about 95% by weight of the total triglycerides containing butyric acid moieties in the composition, for example, from about 30% to about 90% or from about 40% to about 80% by weight of the total triglycerides containing butyric acid moieties in the composition, for example, from about 50% to about 70% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0100] In one embodiment, the compound having formula (8) comprises from about 50% to about 90% by weight of the total triglycerides containing butyric acid moieties in the composition, for example from about 60% to about 80% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0101] In one embodiment, the composition comprises a compound of formula (8) and a compound of formula (5), and the combination of the compound of formula (8) and the compound of formula (5) is present in an amount of at least 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the total triglycerides containing butyric acid moieties in the composition.

[0102] In one embodiment, the composition of the present invention may also include 1,3-dibutyryl-2-linoleoyl glycerol, 1,3-dibutyryl-2-stearoyl glycerol, 1-butyryl-2-oleoyl-3-palmitoyl glycerol, 1-palmitoyl-2-oleoyl-3-butyryl glycerol, 1-butyryl-2-oleoyl-3-linoleoyl glycerol, 1-linoleoyl-2-oleoyl-3-butyryl glycerol, 1-oleoyl-2-butyryl-3-linoleoyl glycerol, 1-linoleoyl-2-oleoyl-3-butyryl glycerol, 1-oleoyl-2-butyryl-3-linoleoyl glycerol, 1-linoleoyl-2-butyryl-3-oleoyl glycerol, 1-butyryl-2- Oleyl-3-oleoyl glycerol, 1-oleoyl-2-linoleoyl-3-butyryl glycerol, 1-butyryl-2-stearoyl-3-oleoyl glycerol, 1-oleoyl-2-stearoyl-3-butyryl glycerol, 1-butyryl-2-oleoyl-3-stearoyl glycerol, 1-stearoyl-2-oleoyl-3-butyryl glycerol, 1,2-dioleoyl-3-palmitoyl glycerol, 1-palmitoyl-2,3-dioleoyl glycerol, 1,2-dioleoyl-3-linoleoyl glycerol and / or 1-linoleoyl-2,3-dioleoyl glycerol.

[0103] In one embodiment, tributyrin comprises less than 10 wt %, preferably less than 8 wt %, more preferably less than 5 wt % of the total triglycerides containing butyric acid moieties in the composition.

[0104] The composition of the invention may be in the form of, for example, a solid (eg, powder), a liquid or a gel.

[0105] The composition of the present invention may be in the form of, for example, tablets, dragees, capsules, pellets, powders, granules, solutions, emulsions, suspensions, coated granules, spray-dried granules or pills.

[0106] The composition can be in the form of a pharmaceutical composition and can include one or more suitable pharmaceutically acceptable carriers, diluents and / or excipients. 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, edited by A Wade and PJ Weller. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., edited by A R Gennaro, 1985.

[0107] The pharmaceutical composition may include the following materials as carriers, excipients or diluents or in addition to carriers, excipients or diluents: 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, free-flowing lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.

[0108] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0109] The composition may be a nutritional composition.

[0110] The expression "nutritional composition" refers to a composition that supplies nutrients to an individual. Such a nutritional composition is preferably orally administered and may comprise a lipid or fat source and a protein source. It 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 may comprise a lipid (or fat) source and a protein source, a carbohydrate source, or both.

[0111] In some embodiments, the nutritional composition according to the invention is an "enteral nutritional composition", i.e., it involves a food material to be administered in the gastrointestinal tract. Gastric introduction may involve the use of a tube passed through the oral / nasal passages or a tube in the abdomen directly to the stomach. This may be used in particular in a hospital or clinic.

[0112] The composition according to the invention may be a dietary supplement.

[0113] The term "dietary supplement" can be used to supplement an individual's nutrition (it is usually used as such, but it can also be added to any kind of composition intended for ingestion). The supplement can be in tablet, capsule, lozenge or liquid form, for example. The supplement can also contain protective hydrophilic colloids (such as gums, proteins, modified starches), binders, film formers, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, weighting 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 from any source, vegetable gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavors, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, etc.

[0114] When the composition is a supplement, it may be provided in unit dosage form.

[0115] The composition according to the invention may be an infant formula (eg a first stage infant formula), a second stage or follow-on formula, a growing-up milk, a baby food, an infant cereal composition or a fortifier such as a human milk fortifier.

[0116] The expression "infant formula" as used herein means a food intended for the nutrition of infants in the first few months of life and which meets the multiple nutritional requirements of such persons (e.g. in accordance with Article 2(c) of Council Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 on infant formula and follow-on formula).

[0117] Generally speaking, stage 1 infant formula is used as a breast milk substitute for infants from birth. Stage 2 or follow-on infant formula is provided from the 6th month onwards. Infant formula constitutes the main liquid element in the gradually diversified diet of such people. "Growing-up milk" (or GUM) is provided from the age of one year. It is usually a milk-containing beverage adapted to the specific nutritional needs of young children.

[0118] The term "fortifier" relates 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 breast milk or mother's colostrum, or donor's breast milk or donor's colostrum.

[0119] The composition according to the present invention may be a dairy product, a liquid beverage, a beverage powder, a dehydrated soup powder, a dietary supplement, a meal replacement, a nutritional bar, a cereal, a confectionery product or a dry pet food.

[0120] The composition may also include dietary fiber. Dietary fiber has been shown to enhance oral tolerance and prevent food allergies (Tan, J. et al., 2016, Cell reports, 15 (12), pp. 2809-2824). "Dietary fiber" may include at least one non-digestible oligosaccharide (e.g., prebiotic). Prebiotics may be present in an amount between 0.3% and 10% by weight of the composition. Dietary fiber and / or prebiotics may promote the production of endogenous butyrate by intestinal microflora, thereby providing additional beneficial effects.

[0121] Prebiotics are generally non-digestible in the sense that they are not broken down and absorbed in the stomach or small intestine, and thus they can remain intact as they pass through the stomach and small intestine to the colon, 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 a specific embodiment, the prebiotic may be fructooligosaccharides and / or inulin. In a specific embodiment, the prebiotic is a combination of FOS and inulin, such as in the product sold by BENEO-Orafti under the trademark Fructo-oligosaccharides (formerly ) or sold by BENEO-Orafti under the trademark Inulin (formerly ). Another example is a combination of 70% short-chain fructo-oligosaccharides and 30% inulin, which is registered by Nestle under the trademark "Prebio 1". The nutritional composition of the present invention may also contain at least one milk oligosaccharide, which may be a BMO (bovine milk oligosaccharide) and / or an HMO (human milk oligosaccharide). In a specific embodiment, the nutritional composition according to the present invention comprises an oligosaccharide mixture, which comprises 0.1% to 4.0% by weight of N-acetylated oligosaccharides, 92.0% to 98.5% by weight of galacto-oligosaccharides and 0.3% to 4.0% by weight of sialylated oligosaccharides.

[0122] The composition of the present invention may also comprise at least one probiotic (or probiotic strain), such as a probiotic bacterial strain. Consumption of the probiotic strain may also promote the production of endogenous butyrate by the intestinal microflora, thereby providing additional beneficial effects.

[0123] The most commonly used probiotic microorganisms are mainly most bacteria and yeasts of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0124] In some embodiments, the probiotic is a probiotic bacterial strain. In some embodiments, it is a bifidobacterium and / or a lactobacillus.

[0125] Based on dry weight, the nutritional composition according to the invention may comprise 10e3 to 10e12 cfu of the probiotic strain per g of composition, more preferably between 10e7 and 10e12 cfu, such as between 10e8 and 10e10 cfu.

[0126] In one embodiment, the probiotic is live. In another embodiment, the probiotic is non-replicating or inactivated. It can also be a probiotic part, such as a cell wall component or a product of probiotic metabolism. In some other embodiments, live probiotics and inactivated probiotics can be present simultaneously. The nutritional composition of the present invention may also include at least one bacteriophage (bacteriophage) or a mixture of bacteriophages, which are preferably directed against pathogenic Streptococci, Haemophilus, Moraxella and Staphylococcus.

[0127] The nutritional composition of the present invention, especially infant formula, typically comprises a protein source, a carbohydrate source and a lipid source. However, in some embodiments, particularly if the nutritional composition of the present invention is a supplement or fortifier, only lipid (or lipid source) may be present.

[0128] The nutritional composition according to the present invention may contain a protein source. The amount of protein may be 1.6 g / 100 kcal to 3 g / 100 kcal. In some embodiments, particularly when the composition is used for premature infants / young children, the amount of protein may be between 2.4 g / 100 kcal and 4 g / 100 kcal or higher than 3.6 g / 100 kcal. In some other embodiments, the amount of protein may be lower than 2.0 g / 100 kcal, for example, between 1.8 g / 100 kcal and 2 g / 100 kcal, or the amount may be lower than 1.8 g / 100 kcal.

[0129] Protein sources based on, for example, whey, casein and mixtures thereof may be used, as may soy-based protein sources. Insofar as whey protein is concerned, 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 protein source is whey-based (i.e., more than 50% of the protein is from whey protein, such as 60%> or 70%>). The protein may be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. In some embodiments, the protein source may also be provided partially or completely in the form of added amino acids.

[0130] The term "intact" means that the main part of the protein is intact, i.e. the molecular structure has not changed, for example at least 80% of the protein has not changed, such as at least 85% of the protein has not changed, preferably at least 90% of the protein has not changed, even more preferably at least 95% of the protein has not changed, such as at least 98% of the protein has not changed. In a specific embodiment, 100% of the protein has not changed.

[0131] In the context of the present invention, the term "hydrolyzed" refers to a protein that has been hydrolyzed or broken down into its constituent amino acids.

[0132] The protein may be fully hydrolyzed or partially hydrolyzed. If hydrolyzed protein is desired, a hydrolysis process may be performed as desired and as known in the art. For example, a whey protein hydrolyzate may be prepared by enzymatic hydrolysis of the whey fraction in one or more steps. If the whey fraction used as a raw material is substantially lactose-free, it is found that the protein undergoes much less lysine blockage during the hydrolysis process. This makes it possible to reduce the degree of lysine blockage from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example, about 7% by weight of lysine, which greatly improves the nutritional quality of the protein source.

[0133] In a specific embodiment, the protein of the composition is hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein may be between 2 and 20, between 8 and 40, between 20 and 60, between 20 and 80, or greater than 10, 20, 40, 60, 80 or 90. For example, a nutritional composition containing a hydrolyzate having a degree of hydrolysis of less than about 15% is available from Nestle Company under the trademark Commercially available.

[0134] In some embodiments, the protein is fully hydrolyzed. For example, infant formula products containing fully hydrolyzed protein are available from Nestle under the trademark Commercially available.

[0135] At least 70%, 80%, 85%, 90%, 95% or 97% of the protein may be hydrolyzed. In a particular embodiment, 100% of the protein is hydrolyzed.

[0136] In a specific embodiment, the protein is provided as amino acids. For example, amino acid-based infant formula products as a protein source are available from Nestle under the trademark Commercially available.

[0137] In a specific embodiment, the protein of the composition is a plant-based protein.

[0138] The nutritional composition according to the invention may comprise a carbohydrate source. This is particularly preferred in case the nutritional composition according to the invention is an infant formula. In this case, any carbohydrate source commonly present in infant formulas may be used, such as lactose, sucrose, sucrose, maltodextrin, starch and mixtures thereof, but one of the preferred carbohydrate sources for infant formulas is lactose.

[0139] The nutritional composition of the present invention may also contain all vitamins and minerals that are considered to be necessary for daily diet and in a significant amount of nutrition. The minimum requirements of some vitamins and minerals have been determined. The examples of minerals, vitamins and other nutrients optionally present in the composition of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine. Minerals are usually added in salt form. The presence and amount of specific minerals and other vitamins will vary according to the target population.

[0140] In a specific embodiment, the composition may also contain vitamin A and / or retinol. Butyrate can promote dendritic cells expressing CD103 (CD103+DC) to convert vitamin A into retinoic acid, which promotes the differentiation of natural T cells into Treg cells (Tan, J. et al., 2016, Cell reports, 15 (12), pp. 2809-2824). Specifically, Tan et al. have confirmed that dietary fiber containing vitamin A increases the effectiveness of tolerogenic CD103+DC.

[0141] If necessary, the nutritional composition of the present invention may contain emulsifiers and stabilizers, such as soy, lecithin, citric acid monoglyceride and citric acid diglyceride, etc. The nutritional composition of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGFbeta, slgA, glutamine, nucleotides, nucleosides, etc.

[0142] The nutritional composition according to the present invention can be prepared in any suitable manner. For example, the composition can be prepared by blending the components together in appropriate portions, optionally with one or more carriers, and then mixing the dry blended mixture using a liquefier to form a liquid mixture. If the final product is to be a powder, the liquid mixture can then be homogenized, pasteurized, and optionally spray-dried. The composition can be homogenized before or after pasteurization.

[0143] For example, formula foods such as infant formula foods can be prepared by blending protein sources, carbohydrate sources and fat sources in appropriate proportions. If used, emulsifiers can be added at this time. Vitamins and minerals can be added at this time, but they are usually added later to avoid thermal degradation. Before blending, any lipophilic vitamins, emulsifiers, etc. can be dissolved in the fat source. Then water (preferably water subjected to reverse osmosis) can be mixed to form a liquid mixture. The water temperature is suitably in the range of about 50°C to about 80°C to help disperse the ingredients. Commercially available liquefiers can be used to form a liquid mixture. Especially if the final product is in liquid form, any oligosaccharides can be added at this stage. If the final product is a powder, these ingredients can also be added at this stage as needed. Then, for example, the liquid mixture is homogenized in two stages.

[0144] Allergic diseases

[0145] The compounds defined herein are sources of butyrate / butyric acid and are therefore useful for preventing or treating allergic diseases. The compounds may be used in infants, children or adults.

[0146] Allergic sensitization (especially sensitization to food allergens) that occurs during childhood, especially in early childhood, is dangerous and of great concern because it has been shown that the development of an "allergic phenotype" or "atopic reactivity" promotes subsequent sensitization to other allergens. Infant eczema is also a susceptibility factor for the subsequent development of food allergies or other types of allergies. Therefore, the occurrence of allergies in childhood may be the first step in an allergic cascade that triggers multiple allergic reactions in later life, a process often referred to as the "atopic march". For example, children who suffer from persistent food hypersensitivity early in life have a significantly 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), pp. 1325-1332). Children with mild food hypersensitivity also have an increased risk of upper respiratory allergy, but the increase is less than that of children with persistent food hypersensitivity. Therefore, reducing the severity of food hypersensitivity may be crucial to slowing the "atopic progression." In this setting, managing allergic episodes and preventing allergic reactions during childhood and infancy are extremely important.

[0147] In the first few years after birth, the immune system of an infant is in an active state of development. Intervention of allergies, prevention, avoidance, management, alleviation or regulation of allergies in such young patients can affect not only their short-term allergic conditions, but also their long-term allergic conditions in later life. In one embodiment, allergic diseases are prevented or treated by primary prevention. "Primary prevention" refers to the effect of preventing or reducing the risk of sensitization of a patient to an allergen, characterized by the absence of allergen-specific IgE antibodies or a reduction in the level of allergen-specific IgE antibodies. The result of preventing or reducing sensitization is that when contacted with the same allergen, allergic symptoms do not occur or allergic symptoms are alleviated. By regulating the way in which a patient is sensitized to an allergen or a group of allergens (primary prevention), subsequent allergic responses can also be regulated. Therefore, in one embodiment, preventing or treating allergic diseases includes reducing or preventing allergic responses to one or more additional allergens in allergic individuals (individuals with pre-existing allergies).

[0148] Food allergens are some of the first allergens that infants encounter early in life, and infants who are not only breastfed are likely to encounter cow's milk proteins in general. Milk proteins are indeed the most common cause of food allergies in infants, followed by egg, soy, and wheat proteins. Generally speaking, food allergies in infants and young children can present with 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, which can lead to life-threatening anaphylaxis.

[0149] Other sensitization and allergic reactions may also occur when infants / young children are exposed to new foods (such as grains, vegetables, fruits, nuts or fish) and airborne allergens (such as pollen, household dust mites and animal dander). Adults are greatly affected by contact allergies and respiratory allergies. Recent data from WHO (Clark, MJ and Million, RP, 2009, Allergic rhinitis: market evolution, Nature Reviews, Drug Discovery, 8, pp. 271-272) indicate that up to 30% to 40% of the world's population suffers from some form of respiratory allergy.

[0150] Animals, in particular small animals such as pets, and especially companion animals such as dogs and cats, may also suffer from food allergies and food intolerances as well as environmental allergens. These often manifest themselves as symptoms similar to those of humans, such as gastrointestinal disturbances such as diarrhea, vomiting and abdominal discomfort, and dermatitis or pruritus. For small animals, in particular dogs, the most common cause of chronic diarrhea is food-responsive enteropathy (diet-responsive enteropathy or food-responsive diarrhea).

[0151] The compounds and compositions of the invention are useful for preventing or treating food allergies, food intolerance, respiratory allergies, and skin allergies by preventing or reducing the risk of an individual becoming sensitized to an allergen.

[0152] In some embodiments, the allergic response is a specific IgE-related immune response and / or a T cell-dependent hypersensitivity reaction. Therefore, in some embodiments, reducing or preventing allergic reactions includes reducing or preventing specific IgE-related immune responses and / or T cell-dependent hypersensitivity reactions. In some embodiments, allergic inflammation is alleviated and / or oral tolerance is enhanced.

[0153] As used herein, "food allergy" refers to an abnormal immune response to one or more food allergens, usually an IgE response caused by the release of histamine, but non-IgE immune responses are also encompassed. Symptoms of food allergy may include itching, eczema, hives, swollen tongue, vomiting, diarrhea, urticaria, difficulty breathing, or low blood pressure. When symptoms are severe and involve more than one system of the body, it is called an allergy.

[0154] As used herein, the term "food allergen" refers to a protein or derivative thereof that causes an abnormal immune response. The purified food allergens can be named using the systematic nomenclature of the Allergen Nomenclature Sub-Committee of the World Health Organization and the International Union of Immunology. The allergen name consists of the abbreviation of the scientific name of its source (genus: 3 to 4 letters; species: 1 to 2 letters) and Arabic numerals, for example, Der p 1 refers to the first allergen to be described from the household dust mite Dermatophagoides pteronyssinus. Food allergens are derived from proteins with a variety of biological functions, including proteases, ligand binding proteins, structural proteins, pathogen-related proteins, lipid transfer proteins, exoproteins, and calcium-binding proteins. A list of food allergens is provided on the official website of the WHO / IUIS Allergen Nomenclature Database at http: / / www.allergen.org / index.php. (Radauer, C. et al., 2014, Allergy, 69(4), pp. 413-419, and Pomés, A. et al., 2018, Molecular immunology).

[0155] In one embodiment, the food allergens are selected from one or more of the list consisting of nuts, tree nuts, peanuts, fish, shellfish, molluscs, crustaceans, milk, eggs, soy, gluten, cereals, wheat, oats, barley, rye, celery, corn, lupins, sulfites, sesame, mustard, rice, poultry and meat.

[0156] As used herein, "food intolerance" refers to an often delayed adverse reaction to a food, beverage, food additive, or compound present in food that produces symptoms in one or more body organs and systems, but generally refers to reactions other than food allergies. "Food hypersensitivity" can broadly refer to both food intolerance and food allergies.

[0157] As used herein, "respiratory allergy" refers to an abnormal immune response to one or more airborne allergens. Airborne allergens can include pollen, mold or mold spores, weed pollen, tree pollen, grass pollen, and dander. Respiratory allergy can include, for example, allergic rhinitis and allergic asthma. Symptoms of allergic rhinitis (hay fever) include runny or stuffy nose, sneezing, red, itchy and tearing eyes, and swelling around the eyes. Symptoms of allergic asthma include wheezing attacks, coughing, chest tightness, and shortness of breath.

[0158] 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 may include food allergens, dust mites, pollen, mold or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, or pet dander. Skin allergies may include, for example, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, and psoriasis. These are typically a group of diseases that cause skin inflammation, and symptoms include itching, redness of the skin, and rash.

[0159] Allergic diseases may also include other allergic inflammatory conditions, such as eosinophilic esophagitis and other eosinophil-related gastrointestinal diseases. Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus involving eosinophils (a type of white blood cell). Symptoms are difficulty swallowing, food impaction, vomiting, and heartburn.

[0160] Butyrate, and therefore the compounds and compositions of the present invention, may prevent or reduce allergic responses by one or more mechanisms.

[0161] The compounds and compositions of the present invention can regulate and / or promote Treg cell differentiation. T regulatory (Treg) cells are essential for tolerance induction, and therefore can regulate and / or promote oral tolerance induction, thereby preventing food allergies or causing faster natural development of food allergies by regulating type 2 allergic responses and reducing IgE production. Many chronic inflammatory diseases such as psoriasis, allergies and inflammatory bowel disease are considered to develop via tolerance destruction. Preclinical data have confirmed that direct oral delivery of butyrate increases Treg cell differentiation (Tan, J. et al., 2016, Cellreports, 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 type 2 helper T cells (Th2) responses can cause allergic inflammation. Type 2 innate lymphoid cells (ILC2) are key sources of Th2 cytokines IL-5 and IL-13 that promote acute asthma exacerbation. It has been confirmed that butyrate is a key regulator of ILC2 proliferation, and it works through its histone deacetylase (HDAC) inhibitory activity (Thio, CLP et al., 2018, Journal of Allergy and Clinical Immunology, 142 (6), pp. 1867-1883, e12). In addition, in the presence of butyrate, antigen-specific stimulation of B cells transforms plasma cell differentiation into regulatory B cell (Breg) development and IL-10 production (Shi, Y. et al., 2015, Scientific reports, 5, p. 17651).

[0162] The compounds and compositions of the present invention can increase the production and / or expression of one or more anti-inflammatory cytokines, and / or reduce the production and / or expression of one or more pro-inflammatory cytokines, thereby reducing tissue inflammation. It has been shown that butyrate changes the production of anti-inflammatory cytokines such as IL-10 (Shi, Y. et al., 2015, Scientific reports, 5, p. 17651). Butyrate has also been shown to change the production of many pro-inflammatory cytokines such as TNFα, IL-5, IL-13, 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).

[0163] The compounds and compositions of the present invention can regulate and / or reduce mast cell activity and all mast cell-mediated allergic symptoms, such as diarrhea or urticaria. Butyrate has been shown 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).

[0164] 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 (Th2) cells and plays a key role in differentiating Th2 cells from uncharacterized CD4+ lymphocytes. Therefore, the compound can reduce the establishment of allergic responses. In addition, GATA-3 is essential for the gene expression of cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation (Barnes, PJ et al., 2008, Currentmolecular medicine, 8 (5), pp. 330-334). High doses of in vitro sodium butyrate (1mM) are sufficient to improve Gata3 expression in Th2 polarized CD4+T cells, accompanied by the reversal of IFNγ (Kespohl, M. et al., 2017, Frontiers inimmunology, 8, p. 1036). In other studies, 0.1 mM sodium butyrate was not sufficient to affect GATA-3 or FoxP3 expression in CD4+ T cells under Th2 polarizing conditions (Furusawa, Y. et al., 2013, Nature, 504(7480), p. 446).

[0165] Application

[0166] Preferably, the compounds and compositions described herein are administered enterally.

[0167] Enteral administration may be oral, gastric and / or rectal administration.

[0168] In one embodiment, administration is oral or gastric administration. In a preferred embodiment, administration is oral administration.

[0169] Generally, administration of the combinations or compositions described herein may be, for example, by the oral route or another route into the gastrointestinal tract, such as by tube feeding.

[0170] The subject may be a mammal, such as a human, canine, feline, equine, caprine, bovine, ovine, porcine, cervidae, and primate. Preferably, the subject is a human.

[0171] Sensory properties

[0172] The present invention provides compounds as a source of butyrate, the compounds having improved organoleptic properties. Specifically, the compounds have improved odor and / or taste relative to butyric acid, butyrate and / or tributyrin. In one embodiment, the compounds have improved taste relative to tributyrin. In one embodiment, the compounds have improved odor relative to butyrate (e.g., sodium butyrate).

[0173] In one embodiment, the improved organoleptic property is improved smell. In one embodiment, the improved organoleptic property is improved taste. In one embodiment, the improved organoleptic property is improved smell and improved taste. In one embodiment, the improved taste is reduced bitterness.

[0174] Example

[0175] Example 1 - Preparation of butylated triglyceride (TAG)

[0176] The composition comprising butylated TAG is produced by chemical transesterification between tributyrin and high oleic sunflower oil in the presence of a catalyst such as sodium methoxyde. A molar excess of tributyrin is used compared to high oleic sunflower oil.

[0177] The three reagents, tributyrin, high oleic sunflower oil and catalyst, are mixed together in a reactor under a nitrogen atmosphere and then heated at 80°C for 3 hours under stirring. Once the reaction is complete, the product is washed several times with water and then dried under vacuum (25 mbar, 60°C, 2 hours). The resulting oil product is then subjected to a decolorization step under the action of bleaching earth and purified by short-path distillation (130°C, 0.001 to 0.003 mbar) or by deodorization by injection of steam water (160°C, 2 mbar, 2 hours).

[0178] The components of the resulting oil composition (mainly triglycerides) are shown in Table 1 below. These triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by their lipid numbers: butyrate is 4:0, palmitate is 16:0, stearate is 18:0, oleate is 18:1, and linoleate is 18:2. The middle fatty acid is located at the sn-2 position in the triglyceride. For example, 16:0-4:0-18:1 represents two different triglycerides that have both sn-2 butyrate and sn-1 palmitate and sn-3 oleate or sn-1 oleate and sn-3 palmitate.

[0179] TAG distribution and regioisomers were analyzed by liquid chromatography coupled to a high-resolution mass spectrometer. The proportions of lipid classes were assessed by liquid chromatography coupled to an evaporative light scattering detector (ELSD).

[0180] Table 1: TAG regioisomer distribution [g / 100g]

[0181]

[0182] In the composite samples, the two most abundant TAGs were 4:0-18:1-4:0 and 18:1-18:1-4:0, which together were approximately 40 g / 100 g to 50 g / 100 g.

[0183] Example 2 - Odor properties of triglycerides containing butyric acid moieties

[0184] The odor of a solution containing TAGs with a butyric acid moiety (composed mainly of oleic and butyric fatty acids) was compared to a solution containing sodium butyrate.

[0185] Sample preparation

[0186] Solutions containing TAGs with butyric acid moieties (see Example 1) or containing sodium butyrate were prepared and stored at 4° C. before delivery to the sensory panel. Each 250 mL solution contained 600 mg butyric acid (equivalent to one commercially available sodium butyrate capsule as a supplement; concentration 2.4 mg / mL) and 1% w / v BEBA Optipro 1 infant formula in acidified deionized water.

[0187] The day before the assay, samples were prepared by placing 4 mL of each solution (TAG butyrate solution; sodium butyrate solution) into Agilent vials.

[0188] method

[0189] A "two out of five test" was performed. In this test, five samples were presented to the panelists. The panelists were instructed to identify the two samples that were different from the other three samples. The order of presentation of the samples was randomized to avoid presentation order bias.

[0190] In addition to the 2 out of 5 test, panelists were provided with a comment box to allow them to comment on the nature of the perceived difference (eg, odor intensity, odor quality).

[0191] result

[0192] The five samples were presented to the panelists simultaneously. They were asked to uncap, sniff, and then cap each vial in the given order. The results are shown in Table 2.

[0193] Table 2

[0194] Number of responses Number of correct responses Significance 11 9 p<0.0001***

[0195] P values ​​were calculated using the binomial test performed by Fizz software (Biosystemes, France).

[0196] It was found that panelists who responded correctly (TAG containing butyric acid moiety is different from sodium butyrate) mentioned that sodium butyrate smelled like "cheese", while for TAG samples containing butyric acid moiety, this "cheese" smell was significantly reduced and the smell was quite neutral.

[0197] Example 3 - Taste properties of triglycerides containing butyric acid moieties

[0198] A sensory benchmark test of a solution comprising TAGs with a butyric acid moiety (see Example 1) consisting mainly of oleic and butyric fatty acids versus a solution comprising tributyrin was performed.

[0199] Sample preparation :

[0200] One scoop (4.6 g) of BEBA Optipro 1 infant formula was added to warm water (cooled, boiled tap water as directed) to a final volume of 150 mL (approximately 3% w / v solution). Each TAG form of butyrate was weighed separately to deliver 600 mg butyrate, and infant formula was added to bring the final volume of each solution to 50 mL.

[0201] Solution A contained TAG having a butyric acid moiety (see Example 1); and solution B contained tributyrin.

[0202] method

[0203] A group of panelists performed repeated blind tastings.

[0204] The samples were prepared immediately prior to the initial bitterness assessment and each solution was shaken vigorously. Tasting cups labeled A and B were simultaneously filled with a small amount of the respective solution.

[0205] The two samples were presented to the panelists simultaneously. They were asked to taste the solutions in small sips and rate the perceived bitterness on a scale of 0-10; where 0 is no perceived bitterness and 10 is similar to the maximum imaginable bitterness.

[0206] result

[0207] The panelists rated the bitterness of Solution A as 4.33 + / - 1.52, mean + / - SD.

[0208] The panelists rated the bitterness of Solution B as 8.33 + / - 1.52, mean + / - SD.

[0209] These data indicate that TAG compositions containing butyric acid moieties in infant formula are significantly less bitter than tributyrin in infant formula.

[0210] Example 4 - Taste Properties of 1,3-Dibutyryl-2-Palmitoyl Glycerol

[0211] 1,3-Dibutyryl-2-palmitoylglycerol (BPB) was synthesized as a single compound using the following synthesis:

[0212]

[0213] BPB was evaluated in a descriptive sensory panel evaluation and found to have a neutral taste and odor.

[0214] Example 5 - Preparation of butylated triglyceride (TAG)

[0215] A composition comprising triglycerides having a butyric acid moiety is obtained by an esterification reaction between monoolein (derived from sunflower oil) and butyric acid added in a molar excess (5 equivalents in total). The two reagents are mixed together in a flask and heated to reflux (butyric acid boiling point is 163.5° C.). Water is removed using a condenser (“colonne de Vigreux”). The reaction is monitored by TLC and stopped when all monoacylglycerols are converted into triacylglycerols.

[0216] The components of the obtained oil composition (mainly triglycerides) are shown in Table 3 below. As in Example 1, the triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by their lipid numbers: butyrate is 4:0, palmitate is 16:0, stearate is 18:0, oleate is 18:1, and linoleate is 18:2. The middle fatty acid is located at the sn-2 position in the triglyceride.

[0217] Table 3: Triglyceride distribution [wt %]

[0218]

[0219] In the composition, 4:0-4:0-18:1 was identified as the most abundant triglyceride.

[0220] The resulting oil product is then subjected to a decolorization step under the action of bleaching earth and purified by short-path distillation (130° C., 0.001 to 0.003 mbar) or by deodorization by injection of steam water (160° C., 2 mbar, 2 hours) to remove residual reagents and intermediates such as butyric acid and MAG, and by-products such as DAG and tributyrin.

[0221] The resulting oil product was evaluated in a descriptive sensory evaluation and was found to have a better smell and taste than tributyrin and butyric acid.

[0222] Example 6 - Administration of butylated triglycerides (TAG) in infant formula and in infants with pre-existing Reducing allergic responses in mammals with allergic reactions

[0223] Allergy to milk was induced in eight-week-old female BALB / c mice by sensitization via transdermal administration of the milk protein β-lactoglobulin (BLG) ("allergic group"). At this stage, all three "allergic groups" (allergic group 2, allergic group 2 and allergic group 3) were subjected to the same sensitization via transdermal administration of the milk protein β-lactoglobulin (BLG). The non-allergic negative control group received only phosphate-buffered saline (PBS) ("control group"). A total of three patches were applied, each one week apart, with no patches applied during the period. Six days after the final skin patch, the mice were subjected to oral BLG stimulation according to routine procedures known to those skilled in the art. The serum was processed by ELISA, and BLG-specific immunoglobulin E (IgE) and BLG-specific immunoglobulin G1 (IgG1) (respectively) were determined. Figure 1 and Figure 2 ).from Figure 1 and Figure 2 As can be seen in the Figures, mice in all three allergy groups 1, 2 and 3 showed allergic responses to oral BLG challenge, indicating that the mice were sensitive to the milk protein β-lactoglobulin (BLG).

[0224] After induction of milk allergy, the "control group" and "allergic group 1" received infant formula for nutritional management of cow's milk allergy reconstituted in drinking water (in this example, the trademark FDA-approved formula was used). "Allergic Group 2" and "Allergic Group 3" received butyrate ad libitum for three weeks in the presence of an infant formula for nutritional management of bovine milk allergy reconstituted in drinking water. Allergic Group 2 received butyrate in the form of sodium butyrate, and Allergic Group 3 received butyrate in the form of a butylated TAG composition prepared according to Example 1 (referred to herein as "palatable butyrate"). Sodium butyrate or palatable butyrate was prepared to a final concentration of 600 μg butyrate / ml infant formula. Subsequently, allergy to eggs was induced in "Allergic Group 1"; for "Allergic Group 2 treated with sodium butyrate" and "Allergic Group 3 treated with palatable butyrate", egg protein ovalbumin (OVA) and aluminum hydroxide adjuvant were administered via intraperitoneal injection. The "Control Group" received intraperitoneal injection of adjuvant alone. Two weeks after the final intraperitoneal injection, mice were challenged with oral OVA three times a week for a total of 12 challenges. During exposure to egg allergy, all groups continued to receive infant formula + / - butyrate. Mice were monitored after each oral OVA challenge to define clinical scores. Symptoms of allergy were defined as follows: 0 = normal stool; 1 = soft / sticky stool; 2 = loose stool; 3 = liquid stool / diarrhea; 4 = at least 2 episodes of liquid diarrhea; 5 = 4 points at the end of the study. These data were combined to generate a cumulative clinical score for each mouse in the study ( Figure 3 ).from Figure 3 It can be seen that the "allergic group 2 treated with sodium butyrate" and the "allergic group 3 treated with palatable butyrate" showed a reduction in allergic symptoms compared to the "allergic group 1" which did not receive any butyrate treatment. The serum was processed by ELISA, and OVA-specific IgE, OVA-specific IgG1, and mast cell protease-1 (MCPT-1) (respectively Figure 4 , Figure 5 and Figure 6 ). Similar OVA-specific IgE and OVA-specific IgG1 levels were observed in the three allergic groups, indicating that the reduction in allergic response after oral OVA challenge could not be attributed to a reduction in allergic sensitization to the allergen. Figure 6 Mast cell protease-1 was shown to be reduced in "Sodium butyrate treated allergic group 2" and "Oral butyrate treated allergic group 3", indicating modulation of mast cell response in the butyrate treated groups.

[0225] This example demonstrates that oral administration of butyrate reduces the allergic response to egg allergen in mammals with pre-existing milk protein allergy.

[0226] All publications mentioned in the above description are incorporated herein by reference. Various modifications and variations of the methods, cells, compositions and uses disclosed in the present invention will be apparent to the skilled person without departing from the scope and spirit of the present invention. Although the present invention has been disclosed in conjunction with specific preferred embodiments, it should be understood that the present invention protected by the claims should not be unduly limited to such specific embodiments. In fact, various modifications to the mode disclosed for practicing the present invention that are apparent to the skilled person are intended to fall within the scope of the following claims.

Claims

1. A compound or a combination thereof having the following formula for treating or preventing allergic diseases: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Independently a long chain fatty acid having 16 to 20 carbons.

2. A composition for treating or preventing allergic diseases comprising a compound of the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Independently a long chain fatty acid having 16 to 20 carbons.

3. The composition for use according to claim 2, wherein the composition comprises a compound of formula (1), a compound of formula (2), a compound of formula (3) and a compound of formula (4).

4. A composition for use according to claim 2 or claim 3, wherein the compound of formula (1), the compound of formula (2), the compound of formula (3) and the compound of formula (4) account for at least 50%, 60%, 70%, 80%, 90%, 95% or 99% by weight of the total triglycerides in the composition.

5. The composition for use according to claim 1, wherein the composition comprises the compound of formula (4) as the main triglyceride containing butyric acid moiety in the composition, wherein the compound of formula (4) accounts for 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 triglyceride containing butyric acid moiety in the composition.

6. A composition for use according to any one of claims 2 to 5, wherein the compound of formula (1), the compound of formula (2), the compound of formula (3) and the compound of formula (4) account for at least 50%, 60%, 70%, 80%, 90%, 95% or 99% by weight of the total triglycerides containing butyric acid moieties in the composition.

7. The composition for use according to any one of claims 2 to 6, wherein tributyrin accounts for less than 10% by weight of the total triglycerides in the composition, preferably less than 8% by weight, more preferably less than 5% by weight of the total triglycerides in the composition.

8. The composition for use according to any one of claims 2 to 7, wherein the composition further comprises vitamin A and / or dietary fiber.

9. The composition for use according to any one of claims 2 to 8, wherein the composition is a nutritional composition, preferably wherein the nutritional composition is a dietary supplement, an infant formula, a follow-on formula, a beverage or a pet care product.

10. The compound or combination thereof for use according to claim 1, or the composition for use according to any one of claims 2 to 9, wherein R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 It is an unsaturated fatty acid, preferably a monounsaturated one.

11. The compound or combination thereof for use according to claim 1 or claim 10, or the composition for use according to any one of claims 2 to 10, wherein R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 is selected from oleic acid, palmitic acid or linoleic acid, preferably wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each of which is oleic acid.

12. The compound for use according to any one of claims 1, 10 or 11 or a combination thereof, or the composition for use according to any one of claims 2 to 11, wherein the allergic disease is selected from one or more of the following: food allergy, food intolerance, respiratory allergy and skin allergy.

13. The compound for use according to any one of claims 1 or 10 to 12 or a combination thereof, or the composition for use according to any one of claims 2 to 12, wherein the allergic disease is selected from one or more of the following: rhinitis, asthma, urticaria, hay fever, allergic conjunctivitis, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, psoriasis, eosinophilic esophagitis and other eosinophilic-related gastrointestinal diseases, allergic diarrhea, vomiting, abdominal pain or bloating.

14. The compound or combination thereof for use according to any one of claims 1 or 10 to 13, or the composition for use according to any one of claims 2 to 13, wherein the allergen in the 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 hair, feathers or pet dander.

15. A compound for use according to any one of claims 1 or 10 to 14 or a combination thereof, or a composition for use according to any one of claims 2 to 14, wherein the allergen in the allergic disease is a food allergen, preferably wherein the food allergen is selected from the group consisting of nuts, tree nuts, peanuts, fish, shellfish, molluscs, crustaceans, milk, eggs, soy, gluten, cereals, wheat, oats, barley, rye, celery, corn, lupins, sulfites, sesame, mustard, rice, poultry and meat.

16. The compound for use according to any one of claims 1 or 10 to 15 or a combination thereof, or the composition for use according to any one of claims 2 to 15, wherein the treatment or prevention of allergic diseases comprises reducing or preventing allergic symptoms in response to allergens.

17. A compound for use according to any one of claims 1 or 10 to 16 or a combination thereof, or a composition for use according to any one of claims 2 to 16, wherein the treatment or prevention of an allergic disease comprises enhancing oral tolerance.

18. A compound for use according to any one of claims 1 or 10 to 16 or a combination thereof, or a composition for use according to any one of claims 2 to 16, wherein the treatment or prevention of allergic diseases comprises reducing or preventing allergic responses to other allergens in allergic individuals.

19. A compound or combination thereof for use according to any one of claims 1 or 9 to 18, or a composition for use according to any one of claims 2 to 18, wherein the compound or combination thereof has improved organoleptic properties relative to butyric acid, tributyrin and / or butyrate.

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