Method for producing composition containing d-enantiomer compound as HCA3 agonist, method for producing food and beverage composition containing d-enantiomer compound, method for producing d-enantiomer compound, and composition for selective synthesis of d-enantiomer compound

Abstract

To provide a novel technique by which a D-enantiomer compound exhibiting high ligand activity among HCA3 agonists and a composition containing the D-enantiomer compound are efficiently produced using lactic acid bacteria.SOLUTION: A method for producing a D-enantiomer compound-containing composition being an HCA3 agonist, comprises a culturing step of culturing at least one lactic acid bacterium selected from the group consisting of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, Ligilactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and Limosilactobacillus reuteri in a medium, and a recovering step of recovering a culture containing the D-enantiomer compound from the medium.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a composition containing a D-form compound that is an HCA3 agonist, a method for producing a food or drink composition containing a D-form compound, a method for producing a D-form compound, and a composition for selectively synthesizing a D-form compound. [Background technology]

[0002] Aromatic lactic acids, such as indolelactic acid, phenyllactic acid, and hydroxyphenyllactic acid, are produced by the deamination of aromatic amino acids to aromatic pyruvic acid, followed by the reverse reaction catalyzed by dehydrogenases. In addition to its antibacterial and antioxidant activities, aromatic lactic acid acts as a ligand for aromatic receptors and hydroxycarboxylic acid receptors (HCA) 3 (hereinafter referred to as HCA3). HCA3 is activated by various hydroxycarboxylic acid metabolites in the blood and has been reported to be an important receptor involved in regulating metabolic homeostasis and the differentiation and function of immune cells (Non-Patent Document 1). It has also been reported that lactic acid bacteria produce aromatic lactic acid (Non-Patent Document 2).

[0003] Leucine acid, like aromatic lactic acid, is an amino acid metabolite and acts as an HCA3 ligand. Non-Patent Document 3 and Patent Document 1 disclose that certain Bifidobacterium bacteria produce leucine acid. The same documents also show that the D-isomers of aromatic lactic acid and leucine acid have higher ligand activity for HCA3 than the L-isomers. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2023-53860 [Non-patent literature]

[0005] [Non-Patent Document 1] Front Endocrinol (Lausanne) 2011, 2, 51. [Non-patent document 2] PLoS Genet 2019, 15, e1008145. [Non-patent document 3] Microorganisms. 2021 Nov 21;9(11):2397. Summary of the Invention [Problem to be solved by the invention]

[0006] Lactic acid bacteria have long been used in the production of fermented foods, and as described above, they are known to produce useful metabolic products such as aromatic lactic acid. Therefore, methods for easily and efficiently producing useful components using lactic acid bacteria have attracted attention.

[0007] In view of the above circumstances, an objective of the present invention is to provide a novel technology for efficiently producing, using lactic acid bacteria, D-form compounds that have high ligand activity among HCA3 agonists, and compositions containing the D-form compounds.

[0008] Another objective of the present invention is to provide a novel technique for efficiently synthesizing a D-form compound, which is an HCA3 agonist, using lactic acid bacteria. [Means for solving the problem]

[0009] The present invention for solving the above problems and its preferred embodiments are as follows. [1] A method for producing a composition containing a D-isomer compound, comprising the steps of: the D-form compound is an HCA3 agonist; a culturing step of culturing one or more lactic acid bacteria selected from the group consisting of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri in a medium; a recovery step of recovering a culture containing the D-form compound from the medium; A method for producing a composition containing a D-form compound, comprising:

[0010] According to the above-described method for producing a D-form compound-containing composition of the present invention, a composition containing a D-form compound that is an HCA3 agonist can be produced efficiently and simply.

[0011] [2] The method according to [1], wherein the D-form compound is one or more selected from the group consisting of D-indole-3-lactic acid, D-leucine acid, D-hydroxyphenyllactic acid, and D-phenyllactic acid. The above-mentioned aspect of the present invention makes it possible to produce a composition containing the D-form compound described above.

[0012] [3] The method according to [1] or [2], wherein the D-form compound is D-indole-3-lactic acid.

[0013] [4] The method according to any one of [1] to [3], wherein the culture produces at least one D-form compound selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid, and the ratio of the amount of D-form compound produced to the total amount of L-form compound and D-form compound produced is 50% or more. According to the above aspect of the present invention, a D-form compound that is an HCA3 agonist can be efficiently produced.

[0014] [5] The manufacturing method described in any one of [1] to [4], wherein the total amount of the D-form compounds produced is 40% or more of the total amount of all HCA3 agonist compounds produced in the culture. According to the above aspect of the present invention, a D-form compound that is an HCA3 agonist can be efficiently produced.

[0015] [6] The method according to any one of [1] to [5], wherein the D-form compound-containing composition is a food or drink composition or a pharmaceutical composition.

[0016] Furthermore, the present invention for solving the above problems may be in the following form. [7] A method for producing a food or drink composition containing a D-isomer compound, the D-form compound is an HCA3 agonist; a mixing step of mixing one or more lactic acid bacteria selected from the group consisting of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri with a food or beverage raw material; and a D-compound production step of producing the D-compound in a state where the obtained lactic acid bacteria and the food or beverage raw material are mixed. A method for producing a food or beverage composition containing a D-isomer compound. According to the above-described method for producing a D-form compound-containing composition of the present invention, a food or drink composition containing a D-form compound that is an HCA3 agonist can be produced efficiently and simply.

[0017] Furthermore, the present invention for solving the above problems may be in the following form. [8] A method for producing a D-form compound, comprising the steps of: the D-form compound is an HCA3 agonist; a culturing step of culturing one or more lactic acid bacteria selected from the group consisting of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri in a medium; a separation step of separating the D-form compound from the culture obtained from the medium; A method for producing a D-isomer compound, comprising: According to the above-mentioned method for producing a D-form compound of the present invention, a D-form compound that is an HCA3 agonist can be produced efficiently and simply.

[0018] Furthermore, the present invention for solving the above problems may be in the following form. [9] Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri. A composition for selectively synthesizing a D-form compound that is an HCA3 agonist, comprising one or more lactic acid bacteria selected from the group consisting of Lactobacillus reuteri as an active ingredient.

[0019]

[10] The composition described in [9], wherein the D-form compound is D-indole-3-lactic acid and / or D-leucine acid. [Effects of the Invention]

[0020] According to the present invention, a novel technique can be provided for efficiently producing, using lactic acid bacteria, D-form compounds of HCA3 agonists that have high ligand activity, and compositions containing the D-form compounds.

[0021] According to a preferred embodiment of the present invention, one or more compounds selected from the group consisting of D-indole-3-lactic acid, D-leucine acid, D-hydroxyphenyllactic acid, and D-phenyllactic acid, and a composition containing at least one of said compounds, can be efficiently produced.

[0022] Furthermore, the present invention can provide a novel technique for selectively synthesizing D-form compounds that are HCA3 agonists using lactic acid bacteria. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 shows the results of LC-MS / MS analysis using a chiral column when an indole-3-lactic acid (ILA) culture supernatant was used in an example. DETAILED DESCRIPTION OF THE INVENTION

[0024] In this specification, the symbol "to" used between numerical ranges includes the upper and lower limits of the range.

[0025] 1. Method for producing a composition containing a D-isomer compound The method for producing a D-form compound-containing composition of the present invention is a method for producing a composition containing a D-form compound that is an HCA3 agonist. The D-form compound of the present invention is a compound that has the effect of activating HCA3. In this specification, the simple expression "D-form compound" also refers to a D-form compound that is an HCA3 agonist.

[0026] The D-form compound according to the present invention is preferably a D-aromatic lactic acid. Preferred examples of D-aromatic lactic acid include D-indole-3-lactic acid, D-hydroxyphenyl lactic acid, and D-phenyl lactic acid. The D-form compound of the present invention can also be D-leucine acid.

[0027] In a preferred embodiment, the D-compound-containing composition can be a composition containing one or more, more preferably two or more, even more preferably three or more, and even more preferably all four selected from the group consisting of D-indole-3-lactic acid, D-leucine acid, D-hydroxyphenyllactic acid, and D-phenyllactic acid.

[0028] In one embodiment, the D-form compound-containing composition can be a D-indole-3-lactic acid-containing composition. In another embodiment, the D-form compound-containing composition can be a D-hydroxyphenyl lactic acid-containing composition. In another embodiment, the D-form compound-containing composition can be a D-phenyl lactic acid-containing composition. In another embodiment, the D-form compound-containing composition can be a D-leucine acid-containing composition.

[0029] <1> manufacturing process The method for producing a D-form compound-containing composition of the present invention comprises a culturing step of culturing lactic acid bacteria in a medium and a recovering step of recovering a culture containing the D-form compound from the medium. Furthermore, the method for producing a D-form compound-containing composition of the present invention may include a processing step after the recovery step. Each step will be described in detail below.

[0030] (1)Culture process Lactic acid bacteria previously classified as the Lactobacillus genus were reclassified in 2020 by the International Journal of Systematic and Evolutionary Microbiology (IJSEM) in accordance with the rules (ICNP) of the International Committee on Prokaryotic Nomenclature (ICSP). Therefore, this specification lists the new names of the reclassified lactic acid bacteria. In the culturing step, specific lactic acid bacteria are cultured in a medium. In the present invention, Lacticaseibacillus paracasei (formerly classified as Lactobacillus paracasei), Lacticaseibacillus rhamnosus (formerly classified as Lactobacillus rhamnosus), Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius (formerly classified as Lactobacillus salivarius), Lacticaseibacillus casei (formerly classified as Lactobacillus casei), Lactobacillus delbrueckii subsp. lactis (Lactobacillus delbrueckii subsp. It is preferable to culture one or more lactic acid bacteria selected from the group consisting of Lactobacillus reuteri (formerly Lactobacillus reuteri), Lactobacillus spp. (Lactobacillus spp.), and Limosi Lactobacillus reuteri (formerly Lactobacillus reuteri).

[0031] As the Lacticase Bacillus paracasei, it is preferable to use one or more species selected from Lactobacillus paracasei NITE BP-01633, Lactobacillus paracasei FERM BP-11313, and Lactobacillus paracasei ATCC25302.

[0032] As the Lacticase Bacillus rhamnosus, Lacticase Bacillus rhamnosus JCM1136 can be preferably used.

[0033] As the Lacticase Bacillus casei, it is preferable to use Lactobacillus casei ATCC393.

[0034] As Lactobacillus delbrueckii subsp. bulgaricus, it is preferable to use Lactobacillus delbrueckii subsp. bulgaricus ATCC11842.

[0035] As Lactobacillus delbrueckii subsp. lactis, it is preferable to use Lactobacillus delbrueckii subsp. lactis ATCC7830.

[0036] As the Risilactobacillus salivarius, it is preferable to use Risilactobacillus salivarius JCM1231.

[0037] As the Rimosylated Lactobacillus reuteri, it is preferable to use Rimosylated Lactobacillus reuteri JCM1112.

[0038] Lactobacillus paracasei NITE BP-01633 was deposited on June 6, 2013, at the National Patent Microorganism Depositary (NPMD) of the National Institute of Technology and Evaluation, Biotechnology Center (Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan) under the accession number NITE BP-01633, and was transferred to international deposit under the Budapest Treaty on January 31, 2014, and has been assigned the accession number NITE BP-01633.

[0039] Lactobacillus paracasei FERM BP-11313 was internationally deposited on November 5, 2010, under the accession number FERM BP-11313, at the National Institute of Advanced Industrial Science and Technology (currently the National Institute of Technology and Evaluation (IPOD) (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818)) in accordance with the Budapest Treaty.

[0040] Lactic acid bacteria assigned JCM numbers (Lacticaseibacillus rhamnosus JCM1136, Risilictobacillus salivarius JCM1231, and Risilictobacillus reuteri JCM1112) can be obtained from the Japan Collection of Microorganisms (Microbial Materials Development Division, RIKEN BioResource Center, 3-1-1 Takanodai, Tsukuba, Ibaraki 305-0074, Japan).

[0041] Lactic acid bacteria with ATCC numbers (Lactobacillus paracasei ATCC 25302, Lactobacillus casei ATCC 393, Lactobacillus delbrueckii subsp. bulgaricus ATCC 11842, Lactobacillus delbrueckii subsp. lactis ATCC 7830) can be obtained from the American Type Culture Collection (Address: 10801 University Boulevard, Manassas, VA 20110, United States of America).

[0042] The aforementioned strains of lactic acid bacteria are not limited to the strains deposited or registered under the bacterial name at a designated institution (hereinafter, for convenience of explanation, also referred to as "deposited strains"), but also include strains substantially equivalent thereto (also referred to as "derived strains" or "derived strains"). In other words, the term is not limited to the strains deposited at the depository institution under the above-mentioned accession numbers, but also includes strains substantially equivalent thereto. Regarding bacteria, "a strain substantially equivalent to the deposited strain" refers to a strain that belongs to the same species as the deposited strain, has a genome sequence similarity (average nucleotide identity value) with the deposited strain of preferably 99.0% or more, more preferably 99.5% or more, and even more preferably 100% identity, and preferably has the same bacteriological properties as the deposited strain. Regarding bacteria, a strain substantially equivalent to the deposited strain may be, for example, a derivative strain derived from the deposited strain. Derivative strains include strains bred from the deposited strain and strains that have arisen naturally from the deposited strain. Breeding methods include modification by genetic engineering techniques and modification by mutation treatment. Mutation treatments include irradiation with X-rays, irradiation with ultraviolet light, and treatment with mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine, ethyl methanesulfonate, and methyl methanesulfonate. Strains naturally arising from the deposited strain include strains that arise naturally during use of the deposited strain. Such strains include mutant strains that arise naturally through culturing (e.g., subculturing) of the deposited strain. Derivative strains may be constructed by one type of modification, or by two or more types of modifications.

[0043] The lactic acid bacteria contained in the D-form compound-containing composition of the present invention may be commercially available products, or may be obtained by appropriate production, or may be obtained by culturing the aforementioned bacteria. The lactic acid bacteria used may also be in the form of a dried product such as a freeze-dried product.

[0044] The culture method is not particularly limited as long as it allows the lactic acid bacteria to grow. For example, a method commonly used for culturing lactic acid bacteria can be used as is or with appropriate modifications.

[0045] The culture temperature may be, for example, 25 to 50°C, preferably 35 to 42°C, and more preferably 35 to 40°C.

[0046] The lactic acid bacteria can be cultured until they grow to a desired extent. In one embodiment, the culture period is preferably 10 hours or more, more preferably 13 hours or more, even more preferably 15 hours or more, and even more preferably 17 hours or more. The culture period is preferably 30 hours or less, more preferably 25 hours or less, and even more preferably 20 hours or less. The culture period is preferably 10 to 30 hours, more preferably 13 to 25 hours, even more preferably 15 to 20 hours, and still more preferably 17 to 20 hours. By setting the culture period within the above range, the lactic acid bacteria can produce a sufficient amount of D-isomer compounds.

[0047] Lactic acid bacteria can be cultured preferably under anaerobic conditions, for example, while aerating with anaerobic gas such as carbon dioxide. Alternatively, the culture can be performed under microaerobic conditions such as liquid static culture.

[0048] The medium used for the culture is not particularly limited as long as it allows the growth of lactic acid bacteria. For example, a medium commonly used for culturing lactic acid bacteria can be used as is or with appropriate modifications. Specifically, sugars such as galactose, glucose, fructose, mannose, cellobiose, maltose, lactose, sucrose, trehalose, starch, starch hydrolysates, and blackstrap molasses can be used as carbon sources depending on the assimilation ability. Nitrogen sources include ammonium salts such as ammonia, ammonium sulfate, ammonium chloride, and ammonium nitrate, as well as nitrates. Inorganic salts include sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, and ferrous sulfate. Organic components such as peptone, soybean flour, defatted soybean meal, meat extract, and yeast extract can also be used. Specific examples of media commonly used for culturing lactic acid bacteria include reinforced clostridial medium, de Man, Rogosa, and Sharpe (MRS) medium, modified MRS (mMRS) medium, TOS propionate (TOSP) medium, TOS propionate mupirocin (TOSP Mup) medium, Gifu Anaerobic Medium (GAM), and Yeast Extract-casein Hydrolysate Acid (YCFA) medium. In the present invention, it is preferable to use MRS medium.

[0049] (2) Recovery process In the recovery step, a culture containing the D-form compound is recovered from the medium that has been subjected to the culture step. The culture containing the D-form compound may be the culture itself, bacterial cells, or culture supernatant. The method for recovering the culture containing the D-compound is not particularly limited, and the culture may be recovered as is, or may be recovered after filtration, centrifugation, or the like. The culture collected in the collection step contains a D-form compound with high ligand activity for HCA3.

[0050] In the present invention, with respect to at least one type of acid selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid contained in the culture, the ratio of the amount of D-compound produced to the total amount of L-compound and D-compound produced (hereinafter also referred to as the D-compound content) is preferably 40% or more, more preferably 43% or more, more preferably 45% or more, more preferably 50% or more, more preferably 53% or more, more preferably 55% or more, and more preferably 57% or more. The content of the D-form compound may be 60% or more, preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more.

[0051] In one embodiment, it is preferable that the content of D-form compounds in the culture satisfies the above-mentioned numerical range for two or more, more preferably three or more, and more preferably all four types selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid.

[0052] The content of the D-form compound can be calculated by applying the peak area of ​​the HCA3 agonist obtained by liquid chromatography tandem mass spectrometry of the culture recovered in the recovery step to the following formula A. (Formula A) Content of D-form compound (%) = Peak area of ​​D-form compound ÷ (Peak area of ​​D-form compound + Peak area of ​​L-form compound) × 100

[0053] In the present invention, the total amount of D-form compounds produced relative to the total amount of all HCA3 agonist compounds contained in the culture (hereinafter also referred to as the content of D-form compounds (total)) is preferably 40% or more, more preferably 43% or more, more preferably 45% or more, more preferably 50% or more, more preferably 53% or more, more preferably 55% or more, more preferably 60% or more, more preferably 65% ​​or more, and even more preferably 70% or more.

[0054] The content of D-form compounds (total) can be calculated by applying the peak area of ​​the HCA3 agonist obtained by liquid chromatography tandem mass spectrometry for the culture recovered in the recovery step to the following formula B. (Equation B) Content (%) of D-form compounds (total) = Total peak area of ​​D-form compounds ÷ (Total peak area of ​​D-form compounds + Total peak area of ​​L-form compounds) × 100

[0055] In addition, in formula B, the sum of the peak area of ​​the D-form compound and the peak area of ​​the L-form compound refers to the sum of the peak areas of compounds that are HCA3 agonists.

[0056] For liquid chromatography tandem mass spectrometry in measuring the total content of D-form compounds and the content of D-form compounds for each type of compound, a Vanquish HPLC connected to an LC-MS / MS; TSQ-FORTIS can be suitably used. Specifically, it is preferable to apply the culture supernatant of lactic acid bacteria to high-performance liquid chromatography (HPLC) using preparative reverse-phase chromatography, and further analyze the fraction containing the target compound using an LC-MS / S system using a chiral column to quantify the D- and L-isomer compounds.

[0057] (3) Processing process In the processing step, the culture containing the D-form compound obtained in the recovery step is processed by any method to obtain a processed product. The processing method for the culture is not particularly limited as long as the HCA3 ligand activity is not lost, and can be performed by appropriately combining one or more methods selected from dilution, concentration, purification, heating, freeze-drying, spray-drying, crushing, fractionation, and sterilization. The processed product refers to a culture that has been subjected to these processing methods.

[0058] In one embodiment, the recovered culture containing the D-form compound is preferably dried by spray drying or freeze drying in the processing step, whereby a processed product in the form of a dry powder is obtained, and the composition obtained by the production method of the present invention can be made into a dry powder composition containing a D-form compound. The culture to be spray-dried or freeze-dried is preferably one or more selected from bacterial cells and culture supernatant.

[0059] In one embodiment, in the processing step, the culture or a processed product of the culture may be mixed with other ingredients to produce a food or beverage composition or a pharmaceutical composition. Specific examples of food and drink compositions and their preferred forms will be described later.

[0060] In the D-compound-containing composition obtained in this manner, the solid content of the D-compound (total including the bacterial cells when bacterial cells are included) is preferably 0.001 to 99% by mass, and more preferably 0.01 to 90% by mass.

[0061] <2> Specific Examples of Preferred Embodiments As described above, a preferred embodiment of the method for producing a D-form compound-containing composition of the present invention has been shown. Specific embodiments will now be described.

[0062] As shown in the Examples, Lacticase Bacillus paracasei, Lacticase Bacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-indole-3-lactic acid than L-indole-3-lactic acid. That is, in one embodiment, the method for producing a D-indole-3-lactic acid-containing composition can be such that the lactic acid bacteria cultured in the culture step are one or more species selected from Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus.

[0063] In addition, Lactobacillus salivarius, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-phenyllactic acid than L-phenyllactic acid. That is, in one embodiment, the method for producing a D-phenyllactic acid-containing composition can be such that the lactic acid bacteria cultured in the culture step are one or more species selected from the group consisting of Lactobacillus salivarius, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus.

[0064] In addition, Lactobacillus salivarius, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus, Lacticaseibacillus paracasei, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-hydroxyphenyllactic acid than L-hydroxyphenyllactic acid. That is, in one embodiment, the method for producing a D-hydroxyphenyllactic acid-containing composition can be one or more species selected from the group consisting of resilient Lactobacillus salivarius, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus, Lacticaseibacillus paracasei, Lactobacillus delbrueckii subsp. lactis, limosiliactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus.

[0065] In addition, Lacticaceae Bacillus paracasei, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-leucine than L-leucine. That is, in one embodiment, the method for producing a D-leucine acid-containing composition can be such that the lactic acid bacteria cultured in the culture step are one or more species selected from Lacticaceae Bacillus paracasei, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus.

[0066] In addition, Lacticase Bacillus paracasei, Lacticase Bacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-isomers of ILA and PLA than L-isomers. That is, in one embodiment, the method for producing a D compound-containing composition may be such that the lactic acid bacteria cultured in the culture step are one or more species selected from Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus delbrueckii subsp. bulgaricus, and the D compounds are D-indole-3-lactic acid and D-phenyllactic acid.

[0067] Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus produce more D-forms of indole-3-lactic acid, phenyllactic acid, hydroxyphenyllactic acid, and leucine acid than L-forms. That is, in one embodiment, the method for producing a D-compound-containing composition can be such that the lactic acid bacteria cultured in the culture step are one or more species selected from Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus, and the D compounds are D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid.

[0068] In the method for producing a D-form compound-containing composition of the present invention, a composition containing a D-form compound can be easily obtained by culturing the specific lactic acid bacteria described above and recovering the resulting culture. Furthermore, because the lactic acid bacteria used are capable of selectively synthesizing D-form compounds, there is no need for isomerization treatment or the like. That is, the present invention can be implemented in a form in which an L-form compound of an HCA3 agonist is not separately added to a medium for culturing lactic acid bacteria. Note that this form does not exclude a form in which an L-form-containing composition is mixed with a D-form-containing composition, and the produced D-form-containing composition may be a form in which an L-form compound synthesized by lactic acid bacteria together with the D-form compound is mixed.

[0069] <3> Composition containing D-form compound The D-form compound-containing composition obtained by the production method of the present invention is preferably for oral administration. Furthermore, the D-form compound-containing composition can be in the form of a food or beverage composition, a pharmaceutical composition, or a quasi-drug. From the viewpoint of facilitating continuous intake, the D-form compound-containing composition is preferably a food or beverage composition. In the present invention, the food and drink compositions include not only foods and drinks ingested by humans but also feeds ingested by animals other than humans. The D-form compound-containing food and drink compositions will be described in detail in the method for producing the food and drink compositions below.

[0070] When the food or beverage is prepared in the form of a food or beverage composition, the food or beverage can be produced, for example, by appropriately blending a culture containing a D-form compound with a base, carrier, or additive that is acceptable from a food hygiene standpoint, or other known ingredients or materials used as food additives, and processing the mixture.

[0071] Food and drink compositions include tablet confectionery, liquid food, feed (including for pets), etc., regardless of whether they are in liquid, paste, solid, powder, etc. form, as well as, for example, flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, complex seasonings and foods, frozen foods, confectionery, beverages, and other commercially available foods.

[0072] The D-form compound-containing composition of the present invention is preferably formulated as a dairy product, and particularly preferably as fermented milk, which allows the user to enjoy the high nutritional value of dairy products in addition to the physiological effects of the D-form compounds. Examples of dairy products include fermented milk, milk drinks, lactic acid bacteria drinks, sweetened condensed milk, skim milk powder, sweetened milk powder, modified milk powder, cream, cheese, butter, and ice cream.

[0073] When the D-form compound-containing composition is in the form of a food or beverage composition (including feed), the D-form compound-containing composition is preferably provided or sold as a food or beverage composition labeled with uses such as promoting HCA3 activation.

[0074] Such "indication" acts include all acts for informing consumers of the aforementioned uses, and any expression that can recall or infer the aforementioned uses falls under the category of "indication" acts in this invention, regardless of the purpose of the indication, the content of the indication, the object or medium on which it is displayed, etc. Furthermore, it is preferable that the "labeling" be done in an expression that allows consumers to directly recognize the intended use. Specific examples include the act of transferring, delivering, displaying for the purpose of transferring or delivering, or importing a food or beverage composition product or product packaging on which the intended use is stated, displaying or distributing advertisements, price lists, or transaction documents related to the product and including the intended use, or providing information containing the above content by electromagnetic means (such as the Internet).

[0075] On the other hand, it is preferable that the content of the labeling be one approved by the government, etc. (for example, a labeling approved based on various systems established by the government and made in a manner based on such approval.) It is also preferable that such content of the labeling be affixed to promotional materials at the point of sale, such as packaging, containers, catalogs, pamphlets, POP displays, and other documents.

[0076] "Labeling" also includes labeling as health food, functional food, enteral nutritional food, special dietary food, health functional food, food for specified health uses, food with nutrient functions, food with functional claims, quasi-drug, etc. Among these, labeling approved by the Consumer Affairs Agency, such as labeling approved under systems related to foods for specified health uses, foods with nutrient functions, or foods with functional claims, or similar systems, can be cited. Specific examples include labeling as a food for specified health uses, labeling as a conditional food for specified health uses, labeling that indicates an effect on the structure or function of the body, labeling that reduces disease risk, and labeling of functionality based on scientific evidence. More specifically, typical examples include labeling as a food for specified health uses (especially labeling of health uses) and similar labeling as defined in the Cabinet Office Ordinance on Permission for Labeling for Special Uses Provided in the Health Promotion Act (Cabinet Office Ordinance No. 57 of August 31, 2009).

[0077] When the D-form compound-containing composition of the present invention is in the form of a pharmaceutical composition, the pharmaceutical composition can be produced by formulating a culture containing the D-form compound using any additives, such as a pharmaceutically acceptable excipient. For oral administration, the pharmaceutical composition may be in the form of a solid preparation such as a powder, granules, tablets, or capsules, or a liquid preparation such as a solution, syrup, suspension, or emulsion. The pharmaceutical composition may also be in the form of a preparation for enteral or parenteral administration, such as a suppository or spray for parenteral administration.

[0078] As pharmaceutical carriers and additives, various conventional organic or inorganic carriers can be used depending on the dosage form. In the case of solid preparations, examples include excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, etc.

[0079] The uses, D-form compound content, and dosage forms of the above-mentioned food and beverage compositions and pharmaceutical compositions are as described for the D-form compound-containing compositions.

[0080] <4> Method for producing food and drink composition In one embodiment, the food and beverage composition can be produced by a method for producing a food and beverage composition containing a D-form compound, which includes a mixing step of mixing lactic acid bacteria with food and beverage ingredients, and a D-form compound production step of producing the D-form compound in the resulting mixture of the lactic acid bacteria and the food and beverage ingredients.

[0081] In the mixing step, the same lactic acid bacteria as those used in the above-mentioned method for producing a D-compound-containing composition can be used. In the mixing step, one or more of the above-mentioned lactic acid bacteria can be mixed.

[0082] In one embodiment, the food and drink composition produced is preferably a fermented food, such as fermented milk or a lactic acid bacteria drink.

[0083] The food and beverage raw materials to be mixed with lactic acid bacteria are not particularly limited, and may be selected appropriately from raw materials added to fermented foods, for example. Examples of food and beverage raw materials include dairy raw materials such as skim milk, concentrated skim milk, skim milk powder, concentrated milk, whole milk powder, cream, butter, whey protein concentrate (WPC), whey protein isolate (WPI), milk protein concentrate (MPC), micellar casein concentrate (MCC), and milk protein isolate (MPI), as well as additives such as sweeteners, flavorings, pH adjusters, and antioxidants.

[0084] In the D-compound production process, D-compounds are produced in a mixture of lactic acid bacteria and food and beverage ingredients. In the D-compound production step, by synthesizing the D-compound with lactic acid bacteria in a mixture state, food and drink compositions containing the D-compound can be easily produced.

[0085] In a preferred embodiment of the present invention, the step of producing a D-compound is a step of fermenting a mixture of lactic acid bacteria and a food or beverage raw material. By using such a form, a fermented food containing a D-isomer compound can be easily produced.

[0086] Fermentation with lactic acid bacteria can be carried out by a known method, for example, by adding fermentation bacteria to the raw material liquid and carrying out the fermentation at 25 to 45°C for 3 to 24 hours until the pH reaches about 3.8 to 4.8.

[0087] Furthermore, in one embodiment, for at least one selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid in the fermented product after the fermentation step, the ratio of the amount of D-compound produced to the total amount of L-compound and D-compound produced (D-compound content) is preferably 40% or more, more preferably 43% or more, more preferably 45% or more, more preferably 50% or more, more preferably 53% or more, more preferably 55% or more, and more preferably 57% or more. The content of the D-form compound may be 60% or more, preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more.

[0088] In a more preferred embodiment, the content of D-form compounds in the food and beverage composition after the D-form compound production process satisfies the above numerical range for two or more, more preferably three or more, and more preferably all four types selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid.

[0089] In one embodiment, the total amount of D-form compounds produced (content of D-form compounds (total)) relative to the total amount of all HCA3 agonist compounds produced in the food and beverage composition after the D-form compound production process is preferably 40% or more, more preferably 43% or more, more preferably 45% or more, more preferably 50% or more, more preferably 53% or more, more preferably 55% or more, more preferably 60% or more, more preferably 65% ​​or more, and even more preferably 70% or more.

[0090] The total content of the D-form compounds and the content of each type of D-form compound in the food or beverage composition can be measured under the same conditions as in the production method of the D-form compound-containing composition. In such cases, the "culture product recovered in the recovery step" can be read as the "food or beverage composition after the D-form compound production step."

[0091] 2. Method for producing D-isomer compounds The method for producing a D-form compound of the present invention is a method for producing a D-form compound that is an HCA3 agonist. The D-form compound produced by the method of the present invention for producing a D-form compound is preferably D-aromatic lactic acid. Preferred examples of D-aromatic lactic acid are as described above. The D-form compound can also be D-leucine acid.

[0092] The method for producing a D-form compound of the present invention comprises a culturing step of culturing lactic acid bacteria in a medium and a separation step of separating the D-form compound from the resulting culture.

[0093] As for a preferred embodiment of the culturing step in the method for producing a D-compound, the description of (1) the culturing step in the method for producing a D-compound-containing composition can be cited.

[0094] The separation step is a step of separating the D-form compound from the culture obtained in the culture step. Specifically, a preferred example of this step is to remove lactic acid bacteria from the obtained culture and then recover a fraction containing the D-form compound.

[0095] Methods for removing lactic acid bacteria from the culture include, for example, membrane filtration and centrifugation. The membrane may be either a flat membrane or a hollow fiber membrane. When filtration is performed using a hollow fiber membrane, separation of D-form compounds from lactic acid bacteria and recovery of a fraction containing D-form compounds from the culture can be performed simultaneously.

[0096] Examples of the step of recovering a fraction containing a D-form compound from the culture after removal of the microorganism include various types of chromatography (e.g., ion exchange, gel filtration, reversed-phase chromatography), salting out, crystallization, and solvent precipitation. These methods can be appropriately selected depending on the type of the target D-form compound. The chromatography may be low-pressure or high-pressure (HPLC), but high-pressure (HPLC) is preferred.

[0097] The fraction containing the D-form compound is not particularly limited as long as it does not impair the HCA3 ligand activity of the D-form compound, and may contain medium components or may be fully or partially purified. The purification of the D-form compound can be carried out by appropriately combining the above methods for recovering fractions containing the D-form compound. The form of the fraction containing the D-form compound is not particularly limited, and it may be a liquid or a powder obtained by freeze-drying or the like.

[0098] The fraction containing the D-form compound may also contain the L-form compound as long as the HCA3 ligand activity of the D-form compound is not impaired, but the D-form compound alone may be separated and purified using a known separation and purification method. Separation of the D-form compound and the L-form compound can be carried out, for example, by appropriately selecting a diastereomeric method, an enzymatic method, or chromatography, or by a combination of these methods.

[0099] The chromatography may be appropriately selected from known methods for separating optical isomers. For example, D-isomer compounds can be separated and purified by appropriately combining a chiral stationary phase method in which a diastereomeric complex is formed with an optically active component bound to a stationary phase to separate and collect the desired enantiomer; a chiral mobile phase method in which an appropriate optically active compound is added to a mobile phase solvent; and a chiral derivatization method in which an enantiomer is converted into a diastereomer by reacting it with an appropriate optically active derivatization reagent and then subjected to a conventional separation system.

[0100] The separated and purified D-form compound can be further subjected to any treatment, such as heating or drying (freeze drying or spray drying).

[0101] 3. Application The D-compound-containing composition and method for producing a D-compound of the present invention were discovered by discovering that the above-mentioned lactic acid bacteria synthesize a large amount of D-compounds among the optical isomers of HCA3 agonists. This finding can be applied to the following inventions. Furthermore, the above-mentioned methods for producing D-compounds and D-compound-containing compositions, as well as the compositions obtained by these methods, can be used to describe preferred embodiments of the following applications.

[0102] The present invention relates to Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri. The present invention can be applied to an agent for selectively synthesizing a D-form compound, which is an HCA3 agonist, comprising one or more lactic acid bacteria selected from the group consisting of Lactobacillus reuteri as an active ingredient (hereinafter also referred to as a D-form compound synthesis agent).

[0103] The present invention also relates to Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri. The composition can be used to selectively synthesize a D-form compound that is an HCA3 agonist (hereinafter also referred to as a composition for synthesizing a D-form compound), which comprises one or more lactic acid bacteria selected from the group consisting of Lactobacillus reuteri as an active ingredient.

[0104] The D-compound synthesizing agent and composition for synthesizing a D-compound of the present invention are preferably used for selectively synthesizing D-aromatic lactic acid or D-leucine acid. Preferred examples of D-aromatic lactic acids include D-indole-3-lactic acid, D-hydroxyphenyl lactic acid, and D-phenyl lactic acid.

[0105] The D-compound synthesizing agent and composition for synthesizing a D-compound of the present invention are preferably used to selectively synthesize D-indole-3-lactic acid and / or D-leucine acid. That is, in one embodiment of the composition for synthesizing a D-compound of the present invention, it can be in the form of an agent or composition for selectively synthesizing D-indole-3-lactic acid and / or D-leucine acid. In addition, the uses, content of the D-form compound, and dosage form of the D-form compound synthesizing agent and the composition for synthesizing the D-form compound are the same as those described for the D-form compound-containing composition.

[0106] The present invention also relates to Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, and LimosiLactobacillus reuteri. The present invention can be a method for selectively synthesizing a D-form compound that is an HCA3 agonist in a composition (hereinafter also referred to as a selective synthesis method), which comprises adding one or more lactic acid bacteria selected from the group consisting of Lactobacillus reuteri to the composition and culturing the composition.

[0107] In the selective synthesis method of the present invention, the preferred types of lactic acid bacteria and the preferred form of the D-form compound to be synthesized are as described above for the method for producing a D-form compound-containing composition. In addition, the preferred combination of the type of lactic acid bacteria to be cultured and the D-form compound to be synthesized in the selective synthesis method of the present invention is also described in the above-mentioned method for producing a D-form compound-containing composition (particularly, <2> ) can be adopted. [Example]

[0108] The following shows various test results that support the findings that form the basis of the present invention.

[0109] <Test Example> Analysis of Lactic Acid Bacteria Culture Supernatant Using 15 strains of lactic acid bacteria, the amounts of aromatic lactic acid and leucine acid contained in the culture supernatant were analyzed according to the procedure described below.

[0110] (1) Recovery of culture supernatant and crude purification of aromatic lactic acid and leucine acid Lactic acid bacteria were inoculated into MRS medium (BD Biosciences) at a concentration of 3% and cultured for 18 hours at 37°C under anaerobic conditions. After culture, the bacterial solution was centrifuged (10,000g, 10 minutes) and the supernatant was collected. Methanol (80%) was added to the collected supernatant, and the aggregates were removed by centrifugation (10,000g, 10 minutes). Water and methanol were then evaporated by centrifugal evaporation.

[0111] The resulting sample was dissolved in ultrapure water (containing 0.1% ammonium formate, Fujifilm / Wako Pure Chemical Industries, Ltd.) and fractionated using a column (XBridge® C18 OBD column, Waters) connected to a Waters e2695 pump to separate hydroxyphenyllactic acid (HPLA), leucine acid (LeuA), phenyllactic acid (PLA), and indole-3-lactic acid (ILA). Mobile phase A used for fractionation was ultrapure water (containing 0.1% ammonium formate), and mobile phase B was acetonitrile (containing 0.1% ammonium formate). The mobile phase B was increased from 2% to 80% over 20 min at a flow rate of 3 mL / min. The fractions containing D-indole-3-lactic acid (ILA), D-phenyllactic acid (PLA), D-hydroxyphenyllactic acid (HPLA), and D-leucine acid (LeuA) were collected at the elution times shown in Table 1 below. The mobile phase was evaporated from the obtained fractions using a centrifugal evaporator.

[0112] [Table 1]

[0113] (2) Analysis using chiral columns The fractions containing D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid were each analyzed using a chiral column (manufactured by Daicel Corporation) and an LC-MS / MS system (Vanquish HPLC and TSQ-FORTIS, both manufactured by Thermo Fisher Scientific). The mobile phase conditions and the details of the chiral column used are as shown in Tables 2 and 3.

[0114] [Table 2]

[0115] [Table 3]

[0116] Next, the elution pattern of each compound was detected using the TSQ-FORTIS with SRM (see Table 2 for precursor ion, product ion, and collision energy conditions). For each compound, elution of the D-isomer was followed by elution of the L-isomer (see Table 3 and Figure 1). Using the peak areas of the D-isomer and the L-isomer obtained, the content (%) of each D-isomer and L-isomer was calculated for each compound using the following formula: (Equation A1) D-isomer content (%) = (D-isomer peak area) ÷ (D-isomer peak area + L-isomer peak area) × 100 (Equation A2) L-isomer content (%) = (L-isomer peak area) ÷ (D-isomer peak area + L-isomer peak area) × 100

[0117] [Table 4]

[0118] (3) Results As shown in Table 4, a comparison of Comparative Examples 1 to 6 with Examples 1 to 9 revealed that the culture supernatants of the lactic acid bacteria of Examples 1 to 9 contained D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid. In other words, it was revealed that D-isomer compounds, which are HCA3 agonists, can be obtained by culturing lactic acid bacteria such as Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, Lacticaseibacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, or Lactobacillus reuteri.

[0119] Furthermore, the lactic acid bacteria of Examples 1 to 9 showed a D-isomer content of 50% or more for at least one of D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid.

[0120] Focusing on D-indole-3-lactic acid, as shown in Examples 3 to 9, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus had a high D-indole-3-lactic acid content of 50% or more, and selectively produced D-indole-3-lactic acid.

[0121] Focusing on D-phenyllactic acid, as shown in Examples 1 and 3 to 9, Lactobacillus salivarius, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus had a high D-phenyllactic acid content of 50% or more, and selectively produced D-phenyllactic acid.

[0122] Focusing on D-hydroxyphenyllactic acid, as shown in Examples 1, 2, 4, and 6 to 9, Lactobacillus salivarius, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus, Lacticaseibacillus paracasei, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus had a high D-hydroxyphenyllactic acid content of 50% or more, and selectively produced D-hydroxyphenyllactic acid.

[0123] Focusing on D-leucine acid, as shown in Examples 5 and 7 to 9, Lacticase Bacillus paracasei, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus had a high D-leucine acid content of 50% or more, and selectively produced D-leucine acid.

[0124] From the above, it was found that by culturing Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus salivarius, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, or Lactobacillus reuteri, it is possible to selectively biosynthesize one or more of D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid.

[0125] Furthermore, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus showed a D-isomer content of 50% or more of the total content of L- and D-isomers for all four types of acid: D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid. These results demonstrate that Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus can selectively biosynthesize all four types of D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid.

[0126] Furthermore, Lacticase Bacillus paracasei (FERM BP-11313, NITE BP-01633), Lacticase Bacillus rhamnosus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus reuteri, and Lactobacillus delbrueckii subsp. bulgaricus contained 50% or more of the D-isomers of at least three of the following acids: D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid. Therefore, it is inferred that these bacterial species contain 50% or more of the D-isomers of HCA3 agonist compounds relative to the total amount of all compounds.

[0127] As described above, it has been shown that by culturing the above-mentioned specific species of lactic acid bacteria, it is possible to selectively synthesize D-form compounds that are HCA3 agonists, such as D-indole-3-lactic acid, D-phenyllactic acid, D-hydroxyphenyllactic acid, and D-leucine acid. [Industrial Applicability]

[0128] The present invention can be applied to the efficient synthesis of D-form compounds and the production of drugs, quasi-drugs, topical skin preparations, cosmetics, foods, food additives, feeds, etc. that contain D-form compounds. [Accession number]

[0129] NITE BP-01633 FERM BP-11313

Claims

1. A method for producing a composition containing a D-isomer compound, comprising the steps of: the D-form compound is an HCA3 agonist; Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei casei), Lactobacillus delbrueckii subsp. lactis, and Limosyl Lactobacillus reuteri; and a recovery step of recovering a culture containing the D-form compound from the medium; A method for producing a composition containing a D-isomer compound, comprising:

2. The method according to claim 1, wherein the D-form compound is at least one selected from the group consisting of D-indole-3-lactic acid, D-leucine acid, D-hydroxyphenyllactic acid, and D-phenyllactic acid.

3. The method according to claim 1 or 2, wherein the D-form compound is D-indole-3-lactic acid.

4. 3. The production method according to claim 1 or 2, wherein the culture produces at least one D-form compound selected from the group consisting of D-indole-3-lactic acid, D-hydroxyphenyllactic acid, D-leucine acid, and D-phenyllactic acid, and the ratio of the amount of the D-form compound produced to the total amount of the L-form compound and the D-form compound is 50% or more.

5. 3. The method according to claim 1, wherein the total amount of the D-form compounds produced is 40% or more of the total amount of all HCA3 agonist compounds produced in the culture.

6. The method according to claim 1 or 2, wherein the composition containing a D-form compound is a food or drink composition or a pharmaceutical composition.

7. A method for producing a food or drink composition containing a D-isomer compound, comprising: the D-form compound is an HCA3 agonist; Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei casei), Lactobacillus delbrueckii subsp. lactis, and Limosyl Lactobacillus reuteri are mixed with a food or beverage raw material; a D-form compound production step of producing the D-form compound in a state where the obtained lactic acid bacteria and the food or beverage raw material are mixed, A method for producing a food or drink composition containing a D-isomer compound.

8. A method for producing a D-isomer compound, comprising the steps of: the D-form compound is an HCA3 agonist; Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei casei), Lactobacillus delbrueckii subsp. lactis, and Limosyl Lactobacillus reuteri; and a separation step of separating the D-form compound from the culture obtained from the medium; A method for producing a D-isomer compound, comprising:

9. Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, LigiLactobacillus salivarius, Lacticaseibacillus casei A composition for selectively synthesizing a D-form compound that is an HCA3 agonist, comprising one or more lactic acid bacteria selected from the group consisting of Lactobacillus delbrueckii subsp. lactis, Lactobacillus delbrueckii subsp. lactis, and Limosilactobacillus reuteri as active ingredients.

10. The composition according to claim 9, wherein the D-form compound is D-indole-3-lactic acid and / or D-leucine acid.

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