Composition for reducing advanced glycation end products

Abstract

The present invention aims to provide a novel probiotic that is less susceptible to the effects of stomach acid and bile acid and capable of reducing the amount of multiple types of advanced glycation end products (AGEs) and / or dimethylarginine metabolites, and provides a composition containing Heyndrickxia bacteria for use in reducing advanced glycation end products and / or dimethylarginine metabolites.

Description

[Technical Field]

[0001] The present invention relates to a composition for reducing advanced glycation end products and / or dimethylarginine metabolites. More specifically, the present invention relates to a composition for reducing advanced glycation end products and / or dimethylarginine metabolites, comprising a fungus of the genus Heyndrickxia, preferably Heyndrickxia coagulans (synonyms: Bacillus coagulans, Weizmannia coagulans). [Background technology]

[0002] Advanced glycation end products (AGEs) are substances formed as a result of the Maillard reaction (a non-enzymatic glycation reaction of proteins) in which amino acid groups such as lysine residues of proteins and reducing sugars occur without the action of enzymes. They are irreversible reaction products. In addition, some guanidino compounds are known to function as precursors of AGEs and are sometimes considered to be AGEs-related compounds in a broad sense. Once these advanced glycation end products (AGEs) (hereinafter including AGEs-related compounds in a broad sense) are produced in the body or taken up into the body, they accumulate in tissues and abnormally alter the structure and function of tissues. Therefore, they are thought to be one of the causes of diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic cataracts, and diabetic nephropathy, as well as diabetes, chronic kidney disease, heart disease, vascular disease, and glycation / aging. In recent years, it has been pointed out that Western-style diets and the consumption of processed foods increase the amount of advanced glycation end products (AGEs) in the body, thereby increasing the risk of various chronic diseases. Coupled with the growing health consciousness, AGEs have become one of the substances attracting attention today.

[0003] Dimethylarginine metabolites (asymmetric dimethylarginine: ADMA and symmetric dimethylarginine: SDMA) are metabolites released during protein degradation after arginine residues in proteins are enzymatically methylated. Both are constitutively produced in the body. ADMA is known to cause vascular endothelial dysfunction by inhibiting nitric oxide (NO) synthesis. SDMA is mainly excreted by the kidneys, and its blood concentration increases with declining renal function. Therefore, ADMA is considered to have high clinical significance as a risk indicator for cardiovascular disease, and SDMA as a renal function marker. In recent years, the accumulation of these dimethylarginine metabolites has been reported to be involved in pathological conditions such as chronic inflammation, oxidative stress, and endothelial damage, and they are attracting increasing attention, along with AGEs, from the perspective of preventing and suppressing the progression of chronic diseases.

[0004] Probiotics are live microorganisms that, when ingested in sufficient quantities, provide beneficial effects to the host, and their supplementation can promote the health of the gut microbiota. It has been reported that ingesting / administering lactic acid bacteria such as Lactococcus lactis KF140, Lactobacillus paracasei TCI708, Lactobacillus paracasei KF00816, and Lactobacillus pentosus KF8, as well as Bacillus subtilis KF11, can reduce Nε-(carboxymethyl)lysine (CML), one of the advanced glycation end products (Patent Documents 1-3).

[0005] However, some probiotics are easily destroyed by stomach acid and bile acid, making it difficult to continuously deliver a sufficient amount of live bacteria to the intestines through oral intake or administration. Furthermore, no probiotics were known that could reduce the levels of multiple advanced glycation end products and / or dimethylarginine metabolites.

[0006] Therefore, in this field, there was a strong demand for new probiotics that are less susceptible to the effects of stomach acid and bile acid, and that can reduce the amount of multiple advanced glycation end products and / or dimethylarginine metabolites.

[0007] Hindrixia coagulans SANK70258 (synonyms: Bacillus coagulans SANK70258, Weitzmania coagulans SANK70258) is a spore-forming lactic acid bacterium with high lactic acid production capacity, isolated from green malt in 1949. A food preparation containing Hindrixia coagulans SANK70258 (product name: Lacris) has been sold for over 50 years since 1966. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Special Publication No. 2020-515296 [Patent Document 2] Special Publication No. 2022-528040 [Patent Document 3] Publication number CN112239732 [Overview of the project] [Problems that the invention aims to solve]

[0009] The main objective of this invention is to provide a novel probiotic that is less susceptible to the effects of gastric acid and bile acid, and that can reduce the amount of multiple advanced glycation end products and / or dimethylarginine metabolites. [Means for solving the problem]

[0010] As a result of diligent research to solve the above problems, the inventors of the present invention have found that Hindrixia coagulans, a spore-forming probiotic, is less affected by stomach acid and bile acid, and can reduce the amount of multiple advanced glycation end products and / or dimethylarginine metabolites when taken orally.

[0011] This invention is based on these novel findings and encompasses the following inventions. [1] A composition containing the genus Heyndrickxia for use in reducing advanced glycation end products. [2] The composition of [1], wherein the fungus of the genus Hendrickxia is Hendrickxia coagulans. [3] The composition of [1] or [2], wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline. [4] Any of the compositions [1] to [3] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu (colony formation units) in terms of viable cells. [5] Any composition of [1] to [4] wherein the Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant strain derived from these strains.

[0012] [6] A composition containing the genus Heyndrickxia for use in reducing advanced glycation end products and dimethylarginine metabolites. [7] The composition of [6], wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline. [8] The composition of [6] or [7], wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of symmetric dimethylarginine (hereafter SDMA) and asymmetric dimethylarginine (hereafter ADMA). [9] The Hindrixia species is Hindrixia coagulans, one of the compositions of [6] to [8].

[10] Any composition of [6] to [9] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

[0013]

[11] A composition for use in reducing dimethylarginine metabolites, including those of the genus Hindrixia.

[12] The composition of

[11] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[13] The composition of

[11] or

[12] , wherein the fungus of the genus Hindrixia is Hindrixia coagulans.

[14] Any of the compositions

[11] to

[13] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0014]

[15] Any of the compositions [1] to

[14] , which are administered orally.

[16] A food composition of any of [1] to

[15] .

[17] A beverage, comprising any of the compositions of [1] to

[15] .

[18] A supplement comprising any of the compositions of [1] to

[15] .

[19] A composition of any of [1] to

[15] which is a feed, feed additive, or pet food composition.

[0015]

[20] An agent for reducing advanced glycation end products, comprising a bacterium belonging to the genus Hindrixia.

[21] The agent for reducing

[20] , wherein the bacterium belonging to the genus Hindrixia is Hindrixia coagulans.

[22] The agent for reducing

[20] or

[21] , wherein the advanced glycation end product contains one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyrraline.

[23] The agent for reducing any one of

[20] to

[22] , wherein the daily dosage of the Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cell count.

[24] The agent for reducing any one of

[20] to

[23] , wherein the Hindrixia coagulans is the SANK70258 strain, P-22 strain, lilac-01 strain, SIM-7 DSM14043 strain, C101 strain, NBRC12583 strain, GBI-1 strain, GBI-20 strain, GBI-30 strain, GBI-40 strain, or a mutant derived from these strains.

[0016]

[25] An agent for reducing advanced glycation end products and dimethylarginine metabolites, comprising a bacterium belonging to the genus Hindrixia.

[26] The agent for reducing

[25] , wherein the advanced glycation end product contains one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyrraline.

[27] The agent for reducing

[25] or

[26] , wherein the dimethylarginine metabolite contains one or more selected from the group consisting of SDMA and ADMA.

[28] The agent for reducing any one of

[25] to

[27] , wherein the bacterium belonging to the genus Hindrixia is Hindrixia coagulans.

[29] The agent for reducing any one of

[25] to

[28] , wherein the daily dosage of the Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cell count.

[0017]

[30] An agent for reducing dimethylarginine metabolites, comprising a bacterium belonging to the genus Hindrixia.

[31] The reducing agent of

[30] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[32] The Hindrixia species is Hindrixia coagulans, a reducing agent of

[30] or

[31] .

[33] A reducing agent of any of

[30] to

[32] , wherein the daily application dose of Hindrixia coagulance is 1 to 2 billion cfu in terms of viable cells.

[0018]

[34] Any of the

[20] -

[33] reduction agents administered orally. Foods containing any of the reducing agents listed in

[35]

[20] to

[34] . A beverage containing any of the reducing agents listed in

[36]

[20] to

[34] . A supplement containing one of the following reducing agents:

[37]

[20] ~

[34] . A feed, feed additive, or pet food composition containing any of the reducing agents listed in

[38]

[20] to

[34] .

[0019]

[39] A method for reducing advanced glycation end products, comprising a step of orally administering a composition containing the genus Hindrixia.

[40] The Hindrixia fungus is Hindrixia coagulans, by the method of

[39] .

[41] The method of

[39] or

[40] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[42] Any of the methods

[39] to

[41] , wherein the daily application dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[43] The Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant strain derived from these strains, by any of the methods

[39] to

[42] .

[0020]

[44] A method for reducing advanced glycation end products and dimethylarginine metabolites, comprising a procedure for orally administering a composition containing the genus Hindrixia to the target.

[45] The method of

[44] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[46] The method of

[44] or

[45] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[47] The fungus of the genus Hindrixia is Hindrixia coagulans, by any of the methods of

[44] to

[46] .

[48] ​​Any of the methods

[44] to

[47] wherein the daily dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0021]

[49] A method for reducing dimethylarginine metabolites, comprising a procedure for orally administering a composition containing the genus Hindrixia.

[50] The method of

[49] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[51] The fungus of the genus Hindrixia is Hindrixia coagulans, by either

[49] or

[50] .

[52] Any of the methods

[49] to

[51] , wherein the daily application dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0022]

[53] Any method of

[39] to

[52] wherein the composition is a food.

[54] Any method of

[39] to

[52] wherein the composition is a beverage.

[55] Any method of

[39] to

[52] wherein the composition is a supplement.

[56] Any method of

[39] to

[52] wherein the composition is a feed, a feed additive, or a pet food composition.

[0023]

[57] Compositions for treating, alleviating, or preventing diseases or symptoms caused by advanced glycation end products, comprising the genus Hindrixia.

[58] The composition of

[57] , wherein the fungus of the genus Hindrixia is Hindrixia coagulans.

[59] The composition of

[57] or

[58] wherein the disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, etc.

[60] A composition according to any one of

[57] to

[59] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[61] Any of the compositions

[57] to

[60] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

[62] A composition of any of

[57] to

[61] wherein the Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant derived from these strains.

[0024]

[63] Compositions for treating, alleviating, or preventing diseases or symptoms caused by advanced glycation end products and dimethylarginine metabolites, including those of the genus Hindrixia.

[64] The composition of

[63] wherein the disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, vascular endothelial dysfunction, arteriosclerosis, etc.

[65] The composition of

[63] or

[64] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[66] A composition according to any one of

[63] to

[65] , wherein the dimethylarginine metabolite is selected from the group consisting of SDMA and ADMA.

[67] The Hindrixia species is Hindrixia coagulans, one of the compositions of

[63] to

[66] .

[68] Any of the compositions

[63] to

[67] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

[0025]

[69] Compositions for treating, alleviating, or preventing diseases or symptoms caused by dimethylarginine metabolites, including those of the genus Hindrixia.

[70] The composition of

[69] wherein the disease or symptom is chronic kidney disease, heart disease, vascular disease, vascular endothelial dysfunction, arteriosclerosis, etc.

[71] The composition of

[69] or

[70] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[72] The Hindrixia fungus is Hindrixia coagulans, any composition of

[69] to

[71] .

[73] Any of the compositions

[69] to

[72] wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

[0026]

[74] Any of the compositions from

[57] to

[73] , administered orally.

[75] A food composition of any of

[57] to

[74] .

[76] A beverage, one of the compositions of

[57] to

[74] .

[77] A supplement, which is one of the compositions of

[57] to

[74] .

[78] A pharmaceutical composition of any of

[57] to

[74] .

[79] Any composition of

[57] to

[74] , which is a feed, feed additive, or pet food composition.

[0027]

[80] A method for treating, alleviating, or preventing a disease or condition caused by advanced glycation end products, comprising a procedure for orally administering a composition containing a fungus of the genus Hindrixia.

[81] The Hindrixia fungus is Hindrixia coagulans, by the method of

[80] .

[82] The method of

[80] or

[81] , wherein the disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, etc.

[83] The method according to any one of

[80] to

[82] , wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[84] Any of the methods

[80] to

[83] , wherein the daily dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[85] The Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant strain derived from these strains, according to any of the methods in

[80] to

[84] .

[0028]

[86] A method for treating, alleviating, or preventing a disease or condition caused by advanced glycation end products and dimethylarginine metabolites, comprising a procedure for orally administering a composition containing a fungus of the genus Hindrixia.

[87] The method of

[86] , wherein the disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, vascular endothelial dysfunction, arteriosclerosis, etc.

[88] The method of

[86] or

[87] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[89] Any method of

[86] to

[88] wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[90] The fungus of the genus Hindrixia is Hindrixia coagulans, by any of the methods of

[86] to

[89] .

[91] Any of the methods

[86] to

[90] wherein the daily application dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0029]

[92] A method for treating, alleviating, or preventing a disease or condition caused by a dimethylarginine metabolite, comprising a procedure for orally administering a composition containing a fungus of the genus Hindrixia.

[93] The method of

[92] , wherein the disease or symptom is chronic kidney disease, heart disease, vascular disease, vascular endothelial dysfunction, arteriosclerosis, etc.

[94] The method of

[92] or

[93] , wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[95] The fungus of the genus Hindrixia is Hindrixia coagulans, by any of the methods of

[92] to

[94] .

[96] Any of the methods

[92] to

[95] , wherein the daily dose of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0030]

[97] Any method of

[80] to

[96] wherein the composition is a food.

[98] Any method of

[80] to

[96] wherein the composition is a beverage.

[99] Any method of

[80] to

[96] wherein the composition is a supplement.

[0100] The method according to any of

[80] to

[96] , wherein the composition is a pharmaceutical product.

[0101] The method according to any of

[80] to

[96] , wherein the composition is a feed, a feed additive, or a pet food composition.

[0031]

[0102] Use of Hindrixia bacteria in the manufacture of pharmaceuticals used in methods for reducing advanced glycation end products.

[0103] The aforementioned Hindrixia species is Hindrixia coagulans, as used in

[0102] .

[0104] Use of

[0102] or

[0103] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[0105] The use of any of

[0102] to

[0104] in which the daily application amount of Hindrixia coagulans in the above method is 1 to 2 billion cfu in terms of viable cells.

[0106] The use of any of

[0102] to

[0105] , wherein the Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant strain derived from these strains.

[0032]

[0107] Use of Hindrixia bacteria in the manufacture of pharmaceuticals used in methods for reducing advanced glycation end products and dimethylarginine metabolites.

[0108] The use of

[0107] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[0109] Use of

[0107] or

[0108] wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[0110] The aforementioned Hindrixia species is Hindrixia coagulans, using any of the following

[0107] to

[0109] .

[0111] The use of any of

[0107] to

[0110] , wherein the daily application amount of Hindrixia coagulans in the above method is 1 to 2 billion cfu in terms of viable cells.

[0033]

[0112] Use of Hindrixia bacteria in the manufacture of pharmaceuticals used in methods for reducing dimethylarginine metabolites.

[0113] Use of

[0112] wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[0114] The aforementioned Hindrixia species is Hindrixia coagulans, using

[0112] or

[0113] .

[0115] The method described above uses any of [112 to

[0114] , wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable cells.

[0034]

[0116] Use of Hindrixia species in the manufacture of pharmaceuticals used in methods for treating, alleviating, or preventing diseases or symptoms caused by advanced glycation end products.

[0117] The aforementioned Hindrixia species is Hindrixia coagulans,

[0116] .

[0118] Use of

[0116] or

[0117] when the aforementioned disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, etc.

[0119] The use of any of

[0116] to

[0118] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[0120] The use of any of

[0116] to

[0119] , wherein the daily application amount of Hindrixia coagulans in the above method is 1 to 2 billion cfu in terms of viable cells.

[0121] The use of any of the following strains of Hindrixia coagulans: SANK70258, P-22, lilac-01, SIM-7 DSM14043, C101, NBRC12583, GBI-1, GBI-20, GBI-30, GBI-40, or mutant strains derived from these strains.

[0035]

[0122] Use of Hindrixia bacteria in the manufacture of pharmaceuticals used in methods for treating, alleviating, or preventing diseases or symptoms caused by advanced glycation end products and dimethylarginine metabolites.

[0123] Use of

[0122] when the aforementioned disease or symptom is diabetic retinopathy, diabetic neuropathy, diabetic cataract, diabetic nephropathy or other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation / aging, vascular endothelial dysfunction, arteriosclerosis, etc.

[0124] Use of

[0122] or

[0123] wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

[0125] The use of any of

[0122] to

[0124] wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[0126] The aforementioned Hindrixia species is Hindrixia coagulans, using any of

[0122] to

[0125] .

[0127] The use of any of

[0122] to

[0126] in which the daily application amount of Hindrixia coagulans in the above method is 1 to 2 billion cfu in terms of viable cells.

[0036]

[0128] Use of Hindrixia bacteria in the manufacture of pharmaceuticals used in methods for treating, alleviating, or preventing diseases or symptoms caused by dimethylarginine metabolites.

[0129] Use of

[0128] when the aforementioned disease or symptom is chronic kidney disease, heart disease, vascular disease, vascular endothelial dysfunction, arteriosclerosis, etc.

[0130] Use of

[0128] or

[0129] wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

[0131] The aforementioned Hindrixia species is Hindrixia coagulans, using any of the following

[0128] to

[0130] .

[0132] The use of any of

[0128] to

[0131] , wherein the daily application amount of Hindrixia coagulans in the above method is 1 to 2 billion cfu in terms of viable cells.

[0037] This specification includes the contents described in the specification of Japanese Patent Application No. 2024-102888, filed on 26 June 2025, which forms the basis of the priority claim of this application. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety. [Effects of the Invention]

[0038] According to the present invention, it is possible to provide a novel probiotic that is less susceptible to the effects of gastric acid and bile acid, and that can reduce the amount of multiple advanced glycation end products and / or the amount of dimethylarginine metabolites. [Brief explanation of the drawing]

[0039] [Figure 1] Figure 1 is a graph showing the relative quantitative results of (A) Nε-(carboxymethyl)lysine, (B) SDMA, (C) Nω-carboxymethylarginine, and (D) pyraline in feces at weeks 0 and 8 for the placebo group and the test food group. Each graph shows the mean and standard error. [Figure 2]Figure 2 shows two graphs: (A) the average change in ADMA measurements (relative quantitative) in plasma from week 0 to week 8 for the placebo group and the test food group, and (B) the sum of the average changes in ADMA and SDMA from week 0 to week 8. [Modes for carrying out the invention]

[0040] The following describes preferred embodiments for carrying out the present invention. The embodiments described below are merely examples of typical embodiments of the present invention, and this should not be interpreted as narrowing the scope of the invention.

[0041] The genus Hendrickxia is a rod-shaped bacterium belonging to the family Heyndrickxiaceae of the order Bacillales. In the present invention, any Hendrickxia species capable of reducing advanced glycation end products and / or dimethylarginine metabolites can be used. Examples of Hendrickxia species usable in the present invention include Hendrickxia coagulans, Hendrickxia oleronia, Hendrickxia acidicola, Hendrickxia sporothermodurans, and Hendrickxia vini, and one or more selected from these can be used in combination. Preferably, in the present invention, the Hendrickxia species is Hendrickxia coagulans.

[0042] Hindrixia coagulans is a lactic acid bacterium belonging to the spore-forming lactic acid bacterium group. It is highly resistant to dryness, heat, and acid, and even when ingested orally, it reaches the intestines without being killed by stomach acid or bile, where it germinates to become vegetative cells, further proliferates, and produces lactic acid. Due to these characteristics, Hindrixia coagulans is more resistant than Lactobacillus bacteria, and is expected to produce sufficient effects even with relatively small doses. It should be noted that Hindrixia coagulans has several synonyms, such as Bacillus coagulans and Weitzmania coagulans. However, in this invention, "Hindrixia coagulans" is a concept that encompasses these conventionally known synonyms, as well as further synonyms resulting from the change in species name.

[0043] Examples of Hindrixia coagulans include strains SANK70258, P-22, lilac-01, SIM-7 DSM14043, C101, NBRC12583, GBI-1, GBI-20, GBI-30, and GBI-40. Among these, strain SANK70258 of Hindrixia coagulans is preferred due to its stable supply and ease of availability. Furthermore, any mutant strain derived from these strains may be used, as long as it has the effect of reducing advanced glycation end products and / or dimethylarginine metabolites.

[0044] Hindrixia coagulans can be commercially available (for example, Mitsubishi Chemical Corporation's "Lacris-S", "Lacris-15", and "Lacris-10 for Feed", as well as products from Kerry Inc., SABINSA, AtelioBio, UNIQUEBIOTECH, Asahi Biocycle, Jiangsu Wecare Biotechnology Co., Ltd. / Wecare Probiotics Co., Ltd., etc.). These may be cultured in a suitable medium as appropriate before use.

[0045] In the present invention, the genus Hendrixia, preferably Hendrixia coagulans, can be used in the form of bacterial cells, their components, contents or secretions, or a culture composition of spore-forming bacteria. The bacterial cells may be dead, live, or a mixture thereof, but live is preferred.

[0046] Examples of advanced glycation end products include Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, pyralin, pentosidine, argupyrimidine, N-carboxyethyllysine, crosulin, GA-pyridine, glucospan, GOLD (glyoxal-lysine dimer), MOLD (methylglyoxal-lysine dimer), MG-H1 (N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine), 3DG-H (3-deoxyglucosone hydroimidazolone), etc. Preferably, it contains one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyralin, and more preferably, one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyralin.

[0047] Dimethylarginine metabolites are metabolic products released during protein degradation after arginine residues in proteins are enzymatically methylated. Examples of dimethylarginine metabolites include ADMA (Asymmetric Dimethylarginine) and SDMA (Symmetric Dimethylarginine). Reducing dimethylarginine metabolites is expected to alleviate the burden on the renal and vascular systems, thereby reducing cardiovascular risk and the risk of renal dysfunction.

[0048] SDMA is a type of dimethylarginine metabolite that is primarily excreted via the kidneys. Because its blood concentration increases particularly with a decrease in glomerular filtration rate (GFR), SDMA is attracting attention as a biomarker that sensitively reflects declining renal function. In addition to its application in the early diagnosis of chronic kidney disease (CKD) in humans, SDMA is also used in veterinary medicine for the early detection and monitoring of kidney disease in pets such as dogs and cats, making it a highly useful indicator in clinical practice. Reducing SDMA levels is expected to contribute to reducing the renal excretion burden and maintaining renal function.

[0049] ADMA is also a dimethylarginine metabolite, primarily metabolized in the liver by dimethylarginine dimethylaminohydrolase (DDAH), although some excretion via the kidneys is also involved. ADMA inhibits nitric oxide (NO) synthase (NOS), and numerous studies have reported its association with vascular endothelial dysfunction, arteriosclerosis, and cardiovascular disease. Therefore, reducing ADMA may contribute to maintaining vascular endothelial function and mitigating cardiovascular risk.

[0050] The mechanism by which oral ingestion / administration of Hindrixia bacteria or compositions containing Hindrixia bacteria can reduce advanced glycation end products and dimethylarginine metabolites is not clear, but it is presumed to be due to overall changes in metabolic pathways resulting from an improvement in the intestinal environment.

[0051] Oral ingestion / administration of the composition for reducing advanced glycation end products and / or dimethylarginine metabolites according to the present invention, and an agent for reducing advanced glycation end products and / or dimethylarginine metabolites (hereinafter also referred to as "the composition, etc. according to the present invention") results in a reduction in the amount of advanced glycation end products and / or dimethylarginine metabolites in the subject.

[0052] The subjects include not only humans but also animals such as pets, livestock, and poultry. Examples of animals include, but are not limited to, mammals (dogs, cats, pigs, cows, goats, sheep, horses, donkeys, rats, mice, guinea pigs, hamsters, rabbits, etc.), birds (e.g., chickens, quail, turkeys, ducks, mallards, parrots, parakeets, etc.), reptiles (e.g., crocodiles, snakes, lizards, turtles, etc.), amphibians, and fish. Preferably, the subjects are mammals including humans, and more preferably humans.

[0053] A reduction in the amount of advanced glycation end products and / or dimethylarginine metabolites may be observed no later than 8 weeks after ingestion / administration of the composition according to the present invention. However, the time it takes for a reduction in the amount of advanced glycation end products and / or dimethylarginine metabolites to be observed after ingestion / administration of the composition may vary depending on the increase or decrease in the amount applied.

[0054] The amount of advanced glycation end products (AGEs) and / or dimethylarginine metabolites in the target population may be reduced to 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, or 40% or less after 8 weeks post-ingestion / administration compared to the amount at the start of ingestion / administration (week 0; 100%). However, the extent of reduction in the amount of AGEs and / or dimethylarginine metabolites may vary depending on the increase or decrease in the applied dose and / or the type of AGEs and / or dimethylarginine metabolites.

[0055] The effect of the compositions according to the present invention on reducing the amount of advanced glycation end products and / or dimethylarginine metabolites can be evaluated by comparing the amounts of advanced glycation end products and / or dimethylarginine metabolites in samples taken from subjects before and after ingestion / administration of the compositions according to the present invention. The quantitative determination of advanced glycation end products and / or dimethylarginine metabolites in the samples can be performed using methods commonly used for protein purification and quantification, such as ammonium sulfate precipitation, precipitation separation, filtration, chromatography (column chromatography, high-performance liquid chromatography (HPLC), etc.), capillary electrophoresis, mass spectrometry, enzyme immunosorbent assay (ELISA), Western blotting, flow cytometry, etc., by combining one or more methods selected from these.

[0056] The sample may contain advanced glycation end products and / or dimethylarginine metabolites, and examples include blood, serum, plasma, saliva, tears, urine, feces, etc., collected from the subject, with feces being preferred.

[0057] The compositions and the like according to the present invention may contain bacteria other than those of the genus Heindrixia. Examples of other bacteria include lactic acid bacteria, butyrate-producing bacteria, bifidobacteria, Bacillus bacteria, natto bacteria, Aspergillus oryzae, and yeast. Examples of lactic acid bacteria include bacteria of the genera Lactobacillus and Lactococcus.

[0058] Examples of bacteria belonging to the genus Lactobacillus include Lactobacillus casei, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus gaceli, Lactobacillus plantrum, and Lactobacillus pentosus.

[0059] Examples of bacteria belonging to the genus Lactococcus include Lactococcus lactis, Lactococcus plantrum, Lactococcus garvieae, and Lactococcus raffinolactis.

[0060] If bacteria other than those of the genus Hindrixia are present, the proportion of Hindrixia, preferably Hindrixia coagulans, to the total amount of bacteria is usually 1% by weight or more, preferably 10% by weight or more, preferably 50% by weight or more, and usually 100% by weight or less.

[0061] The compositions according to the present invention include salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; amino acids such as lysine, methionine, threonine, tryptophan, and valine; organic acids such as tannic acid; and vitamins A, D, E, K, B1, B2, B6, and B1. 12 It may also contain vitamins such as niacin, pantothenic acid, biotin, folic acid, and ascorbic acid.

[0062] The compositions according to the present invention may optionally contain stabilizers, excipients, pH adjusters, etc. Examples of stabilizers include anhydrous silicic acid, and examples of excipients include cereals such as corn, wheat, soybeans, and milo; sugars such as lactose, sucrose, and glucose; vegetable oils such as soybean meal, corn gluten meal, sesame oil meal, corn farm meal, rapeseed oil meal, and distilled grain residue; bran products such as wheat bran, rice bran, defatted rice bran, and corn gluten feed; animal materials such as fish meal; vegetable oils such as coconut oil, lard, and corn oil; starches such as corn starch and potato starch; minerals such as calcium carbonate; vitamins such as vitamin E; dextrin, corn steam liquor, paprika extract, and alfalfa meal.

[0063] The compositions according to the present invention are preferably to be taken orally, and can take the form of pharmaceuticals, foods, beverages, and supplements as specific oral compositions. The advanced glycation end products and / or dimethylarginine metabolite reducers according to the present invention can also be added to foods, beverages, and supplements for oral intake / administration.

[0064] In this invention, the "pharmaceutical" may take any form, including tablets, granules, powders, sugar-coated tablets, capsules, syrups, suspensions, liquids, emulsions, etc. Furthermore, to protect it from stomach acid and allow it to act in the intestines, it may be an enteric-coated substance with different solubility at different pH levels.

[0065] In this invention, "food" includes health foods, functional foods, health functional foods (foods for specified health uses, nutrient function foods, foods with functional claims, etc.), health supplements, and nutritional supplements. The form of the food can be selected as appropriate, such as solid, liquid, or paste.

[0066] In this invention, "beverage" includes soft drinks, dairy beverages, and alcoholic beverages.

[0067] The "supplement" in the present invention may have any shape, and may be tablets, granules, powders, dragees, capsules, syrups, suspensions, solutions, emulsions, etc. Further, in order to protect from gastric acid and act in the intestine, it may be an enteric solvent having differences in solubility with respect to different pHs.

[0068] In addition, the above-mentioned pharmaceuticals, foods, beverages and supplements include not only those for humans but also those for animals. For example, the composition according to the present invention can take the form of feed, feed additives, or pet food compositions, and the advanced glycation end products and / or dimethylarginine metabolite reducing agents according to the present invention can be added to feeds, feed additives, or pet food compositions.

[0069] The appropriate dosage of the genus Helicobacter, preferably Helicobacter coglans, is 1×10 7 colony forming units (cfu) or more per day in terms of viable cell count, preferably 1×10 8 cfu or more, and the upper limit is preferably 5×10 10 cfu. More specifically, the appropriate dosage of the genus Helicobacter, preferably Helicobacter coglans, is about 1×10 8 cfu to 2×10 9 cfu per day in terms of viable cell count.

[0070] The genus Helicobacter, preferably Helicobacter coglans, in the composition etc. according to the present invention can be appropriately set according to the above-mentioned appropriate dosage. For example, it is 1.0×10 <00​​​​​​​​​​The duration of ingestion / administration of Hindrixia bacteria, preferably Hindrixia coagulans, is not particularly limited, but as a guideline for obtaining the effect of reducing advanced glycation end products and / or dimethylarginine metabolites, it is 4 weeks or more, preferably 8 weeks or more, more preferably 12 weeks or more, and there is no upper limit to the duration of ingestion.

[0072] The compositions, etc., according to the present invention can be used to treat, alleviate, or prevent diseases or symptoms caused by advanced glycation end products and / or dimethylarginine metabolites. Advanced glycation end products and / or dimethylarginine metabolites are irreversible reaction products, and once they are produced or taken into the body, they accumulate in tissues, abnormally altering the structure and function of the tissues and causing various diseases and symptoms such as diabetic retinopathy, diabetic neuropathy, diabetic cataracts, diabetic nephropathy and other diabetic complications, diabetes, chronic kidney disease, heart disease, vascular disease, glycation and aging. By orally ingesting / administering the compositions, etc., according to the present invention to a subject as described above, and reducing the amount of advanced glycation end products and / or dimethylarginine metabolites in the subject, various diseases and symptoms caused by advanced glycation end products and / or dimethylarginine metabolites can be treated, alleviated, or prevented. The present invention will be described below with reference to examples, but the present invention is not limited to these examples. [Examples]

[0073] The following tests were conducted to investigate the changes in the levels of AGEs and dimethylarginine metabolites in feces and plasma following the ingestion of Hindrixia coagulans.

[0074] I. Method <Test Method> Eighty Japanese women aged 30 to under 65 who reported experiencing skin problems were selected through a screening study. Forty women were randomly assigned to either a placebo group or a group receiving a test food containing Hindrixia coagulans (test food group). A placebo-controlled, randomized, double-blind, parallel-group comparative study was conducted with eight weeks of continuous intake of Hindrixia coagulans. <Subjects> Healthy adult women (ages 30 to under 65): 40 participants for the test food (1 discontinued / dropped out / excluded, 39 valid data points), 40 participants for the control food (4 discontinued / dropped out / excluded, 36 valid data points). <Intake period> 8 weeks <Test Food> The composition is shown in Table 1 below. Both groups took one capsule per day. Hindrixia coagulans was taken using Mitsubishi Chemical Corporation's "Lacris-15" at a viable bacterial count of 1 billion cfu / day.

[0075] [Table 1] <Collection of fecal samples> Fecal samples were collected from participants at the start of the study, at 4 weeks, and at 8 weeks. Comprehensive fecal metabolite measurements were performed to determine the levels of AGEs and dimethylarginine metabolites in the feces of both the placebo and test food groups. The specific methods are described below.

[0076] <Collection of fecal samples for metabolite analysis and measurement of metabolites> Participants collected a marble-sized stool sample at home using a spoon-shaped collection container 1 to 3 days prior to the test date and froze it in their home freezer. They brought the frozen sample to the test site and submitted it to the test administrator. The test administrator then sent the frozen sample to HMT (Human Metabolome Technologies, Inc., Japan). <Comprehensive analysis of metabolites> For the comprehensive analysis of metabolites (feces), we commissioned HMT Corporation to perform the measurements. Metabolites contained in feces were comprehensively measured and data obtained using CE-TOFMS or LC-MS (Soga T, Heiger DN: Amino acid analysis by capillary electrophoresis electrospray ionization mass spectrometry. Anal. Chem. 2000, 72:1236-1241.; Soga T, Ohashi Y, Ueno Y, Naraoka H, ​​Tomita M, Nishioka T: Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J. Proteome Res. 2003, 2:488-494). Specifically, the metabolite measurement results were obtained using the following methods.

[0077] (Extraction of metabolites from feces) Approximately 30 mg of fecal matter was mixed with 500 μL of Milli-Q water containing an internal standard substance (H3304-1002, HMT Corporation, Tsuruoka City, Yamagata Prefecture). The mixture was centrifuged at 2,300 × g at 4°C for 5 minutes, and 350 μL of the supernatant was filtered by centrifugation through a Millipore 5 kDa cutoff filter (ULTRAFREE MC PLHCC, HMT Corporation) at 9,100 × g at 4°C for 120 minutes to remove polymers. 80 μL of the filtrate was mixed with 20 μL of Milli-Q water and used for measurement.

[0078] <Collection of plasma samples> Plasma samples were collected from the subjects at the start of the study and again 8 weeks later. Comprehensive plasma metabolite measurements were performed to determine the levels of AGEs and dimethylarginine metabolites in the plasma of both the placebo and test food groups. The specific methods are described below.

[0079] <Collection of plasma samples for metabolite measurement> The subjects had their blood drawn at the testing site. (Processing of specimens) A 5mL EDTA-2K blood collection tube was used. After blood collection at the testing site, the tube was thoroughly mixed by inverting it, and then immediately placed in a test tube rack filled with ice to rapidly cool it. Within 6 hours of blood collection, centrifugation (1500g x 15 minutes) was performed, and multiple 0.5mL tubes of plasma were collected. These were then immediately frozen and stored at -20°C. The frozen samples were sent to HMT (Human Metabolome Technologies, Inc., Japan).

[0080] (Extraction of metabolites from plasma) 50 μL of plasma was added to a 200 μL methanol solution prepared to a concentration of 20 μM of the internal standard substance (H3304-1002, HMT Co., Ltd., Tsuruoka City, Yamagata Prefecture) and mixed. 150 μL of Milli-Q water was added to this and stirred, and the entire volume was transferred to a Millipore 5kDa cutoff filter (ULTRAFREE MC PLHCC, HMT). The solution was centrifuged at 9,100 × g at 4°C for 120 minutes, then ultrafiltered. The resulting liquid was allowed to dry, redissolved in Milli-Q water, and subjected to measurement.

[0081] (Measurement and analysis of metabolites) Metabolites were measured using the aforementioned fecal and plasma samples. Metabolite analysis was performed using a capillary electrophoresis time-of-flight mass spectrometer (CE-TOFMS) in accordance with HMT's Basic Scan package, following the method described previously (Ohashi Y, Hirayama A, Ishikawa T, Nakamura S, Shimizu K, Ueno Y, Tomita M, Soga T: Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS. Mol. Biosyst. 2008, 4:135-147.). CE-TOFMS analysis was performed using an Agilent 6210 time-of-flight mass spectrometer (Agilent Technologies, Inc.) connected to an Agilent CE capillary electrophoresis system. The system was controlled by Agilent G2201AA ChemStation software version B.03.01 (Agilent Technologies) and connected to a fused silica capillary (50 μm id × 80 cm total length) using commercially available electrophoresis buffer (H3301-1001 for cation analysis, HMT) as the electrolyte. The spectrometer was scanned from m / z 50 to 1,000, and peaks were extracted using the automated integration software MasterHands (Keio University, Tsuruoka City, Yamagata Prefecture). Peak information such as m / z, peak area, and migration time (MT) was obtained (Sugimoto M, Wong DT, Hirayama A, Soga T, Tomita M: Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast, and pancreatic cancer-specific profiles. Metabolomics 2010, 6:78-95.). Signal peaks corresponding to known metabolite isotopomers, adduct ions, and other product ions were excluded, and the remaining peaks were annotated based on m / z values ​​and MT according to the HMT metabolite database. The relative quantitative values ​​for each metabolite were calculated by normalizing the area of ​​the annotated peaks with an internal standard and sample volume, and then determining the relative concentration of each metabolite.

[0082] II. Results <Comparison of AGEs and dimethylarginine metabolites in feces between groups> When AGEs and dimethylarginine metabolites were extracted from the feces of more than 10 subjects, four types of AGEs and dimethylarginine metabolites were found: Nε-(carboxymethyl)lysine, SDMA, Nω-carboxymethylarginine, and pyralin. The comparative results for each group at week 0 and week 8 are shown in Figure 1.

[0083] Regarding Nε-(carboxymethyl)lysine, the relative amounts at week 8 were calculated using week 0 as the baseline for the placebo group and the test food group. The change in the placebo group was 108%, while the change in the test food group was 54% (Figure 1(A)).

[0084] Regarding SDMA, when the relative levels at week 8 were calculated using week 0 as the baseline, the change in the placebo group was 105%, while the change in the test food group was 73% (Figure 1(B)).

[0085] Regarding Nω-carboxymethylarginine, the relative amounts at week 8 for the placebo group and the test food group were calculated using week 0 as the baseline. The change in the placebo group was 87%, while the change in the test food group was 74% (Figure 1(C)).

[0086] Regarding pyralin, when the relative amounts at week 8 were calculated using week 0 as the baseline, the change in the placebo group was 114%, while the change in the test food group was 80% (Figure 1(D)).

[0087] These results show that the intake of Hindrixia coagulans has a reducing effect on all four types of AGEs and dimethylarginine metabolites in feces: Nε-(carboxymethyl)lysine, SDMA, Nω-carboxymethylarginine, and pyralin. In particular, Nε-(carboxymethyl)lysine, SDMA, and pyralin increased in the placebo group after 8 weeks, while they decreased in the Hindrixia coagulans group, demonstrating an even greater reduction effect.

[0088] <Comparison of AGEs and dimethylarginine metabolites in plasma between groups> AGEs and dimethylarginine metabolites detected in the plasma of more than 10 subjects were extracted, and SDMA and ADMA were found. Figure 2 shows a comparison of the changes in these metabolites from week 0 to week 8.

[0089] Regarding ADMA, the change in relative quantitative values ​​from week 0 to week 8 was calculated for each subject in both the placebo group and the test food group, and the average values ​​were compared. The placebo group showed an increase at week 8, while the test food group showed a decrease at week 8. If the size of the graph for the test food group is set to 1, the size of the placebo group was approximately 22.6 (Figure 2(A)).

[0090] For ADMA and SDMA, the change in relative quantitative values ​​from week 0 to week 8 was calculated for each subject in both the placebo group and the test food group. When the sum of the average values ​​was compared, the placebo group showed an increase at week 8, while the test food group showed a decrease at week 8. If the size of the graph for the test food group is set to 1, the size of the placebo group was approximately 0.8 (Figure 2(B)).

[0091] These results indicate that the intake of Hindrixia coagulans has a reducing effect on plasma levels of ADMA, as well as SDMA and ADMA.

Claims

1. A composition comprising Heyndrickxia coagulans for use in reducing advanced glycation end products (AGEs).

2. The composition according to claim 1, wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

3. The composition according to claim 1, wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu (colony formation unit) in terms of viable cell count.

4. The composition according to claim 3, wherein the Hindrixia coagulans is strain SANK70258, strain P-22, strain lilac-01, strain SIM-7 DSM14043, strain C101, strain NBRC12583, strain GBI-1, strain GBI-20, strain GBI-30, strain GBI-40, or a mutant strain derived from these strains.

5. A composition comprising Hindrixia coagulans for use in reducing advanced glycation end products and dimethylarginine metabolites.

6. The composition according to claim 5, wherein the advanced glycation end product comprises one or more selected from the group consisting of Nε-(carboxymethyl)lysine, Nω-carboxymethylarginine, and pyraline.

7. The composition according to claim 6, wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

8. The composition according to claim 5, wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

9. A composition comprising Hindrixia coagulance for use in reducing dimethylarginine metabolites.

10. The composition according to claim 9, wherein the dimethylarginine metabolite comprises one or more selected from the group consisting of SDMA and ADMA.

11. The composition according to claim 9, wherein the daily application amount of Hindrixia coagulans is 1 to 2 billion cfu in terms of viable bacteria.

12. A food product, the composition according to any one of claims 1 to 11.

13. A beverage, the composition according to any one of claims 1 to 11.

14. A supplement, the composition according to any one of claims 1 to 11.

15. The composition according to any one of claims 1 to 11, which is a feed, a feed additive, or a pet food composition.

Images