Composition for promoting the production of aromatic lactic acid compounds

Abstract

The present invention addresses the problem of providing: a composition that can be applied to a specific use such as a composition for promoting the production of aromatic lactic acid compounds or a composition for obtaining effects based on promoting the production of aromatic lactic acid compounds. The foregoing problem is solved by a composition containing: a nucleic acid metabolite such as hypoxanthine; and Bifidobacterium bacteria such as Bifidobacterium breve.

Description

[Technical Field]

[0001] The present invention relates to compositions that can be used for specific applications, such as compositions for promoting the production of aromatic lactic acid compounds or for obtaining effects based on the promotion of aromatic lactic acid compound production. [Background technology]

[0002] Indole-3-lactic acid (ILA), a type of aromatic lactic acid compound, can be produced, for example, by strains of Bifidobacterium species commonly isolated from the intestines of human infants (e.g., Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis, Bifidobacterium breve, and Bifidobacterium bifidum) (Non-Patent Literature 1). ILA may have functions such as improving neurite outgrowth (Non-Patent Literature 2). ILA may also have functions such as regulating immune balance (Non-Patent Literature 3). Furthermore, ILA may act as an agonist of aryl hydrocarbon receptors (AhR) in intestinal epithelial cells and nerve cells, thereby exerting anti-inflammatory effects, etc. (Non-Patent Literature 2 and 4).

[0003] It is known that culturing Bifidobacterium bacteria in a culture medium containing one or more selected from the group consisting of casein protein hydrolysate, whey protein hydrolysate, and reducing agents can increase the amount of aromatic lactic acid produced by the bacteria (Patent Document 1). [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2022-57336 [Non-patent literature]

[0005] [Non-Patent Document 1] Sakurai T. et al. Production of Indole-3-Lactic Acid by Bifidobacterium Strains Isolated from Human Infants. Microorganisms. 2019 Sep 11;7(9). [Non-Patent Document 2] Chyn Boon Wong et al. Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-Induced Neurite Outgrowth in PC12 Cells. Microorganisms. 2020 Mar; 8(3): 398. [Non-Patent Document 3] Bethany M. Henrick et al. Bifidobacteria-mediated immune system imprinting early in life, Cell. 2021 July; 184: 1-15. [Non-Patent Document 4] Ehrlich et al. Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells. BMC Microbiology. 2020 20:357. [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] An object of the present invention is to provide a composition that can be used for a specific use such as a composition for promoting the production of an aromatic lactic acid compound or a composition for obtaining an effect based on the promotion of the production of an aromatic lactic acid compound. [Means for Solving the Problems]

[0007] The inventors diligently conducted research to solve the above problems. As a result, the inventors discovered that the production of aromatic lactic acid compounds such as indole-3-lactic acid (ILA) and 3-phenyllactic acid (PLA) is promoted by using nucleic acids or nucleic acid metabolites in combination with Bifidobacterium bacteria such as Bifidobacterium breve, and thus completed the present invention.

[0008] In other words, the present invention can provide the following: A composition for promoting the production of aromatic lactic acid compounds, containing the following components (A) and (B): (A) nucleic acids or nucleic acid metabolites; (B) Bacteria of the genus Bifidobacterium.

[0009] In the above composition, it is preferable that the aromatic lactic acid compound is indole-3-lactic acid or 3-phenyllactic acid. Furthermore, in a preferred embodiment, the composition is characterized in that the nucleic acid metabolite is a nucleic acid metabolite having a purine skeleton or a nucleic acid metabolite having a pyrimidine skeleton. Furthermore, the composition preferably includes xanthine, hypoxanthine, adenosine, inosine, or uracil as the nucleic acid metabolite. Furthermore, the composition preferably contains Bifidobacterium breve or Bifidobacterium longum subsp. infantis. Furthermore, the composition preferably contains Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623. Furthermore, it is preferable that the composition is a food or beverage composition. Furthermore, it is preferable that the composition is a pharmaceutical composition.

[0010] Furthermore, the present invention can provide a method for producing aromatic lactic acid compounds, which includes culturing bacteria of the genus Bifidobacterium in a culture medium containing nucleic acid metabolites. In the above-mentioned manufacturing method, it is preferable that the aromatic lactic acid compound is indole-3-lactic acid or 3-phenyllactic acid. Furthermore, the manufacturing method preferably involves the nucleic acid metabolite being a nucleic acid metabolite having a purine skeleton or a nucleic acid metabolite having a pyrimidine skeleton. Furthermore, the manufacturing method preferably involves the nucleic acid metabolite being xanthine, hypoxanthine, adenosine, inosine, or uracil. Furthermore, the manufacturing method preferably uses the Bifidobacterium breve or Bifidobacterium longum subsp. infantis as the Bifidobacterium breve. Furthermore, the manufacturing method preferably uses the following characteristics: the Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623.

[0011] Furthermore, the present invention can provide a method for increasing the production of aromatic lactic acid compounds by Bifidobacterium bacteria, which includes culturing Bifidobacterium bacteria in a culture medium containing nucleic acid metabolites. [Effects of the Invention]

[0012] According to the present invention, it is possible to provide compositions that can be used for specific applications, such as compositions for promoting the production of aromatic lactic acid compounds or for obtaining effects based on the promotion of aromatic lactic acid compound production. [Brief explanation of the drawing]

[0013] [Figure 1] This figure shows the results of indole-3-lactic acid (ILA) production using various nucleic acid metabolites in combination with Bifidobacterium breve MCC1274 (FERM BP-11175) in culture. [Figure 2] This figure shows the results of 3-phenyllactic acid (PLA) production using various nucleic acid metabolites in combination with Bifidobacterium breve MCC1274 (FERM BP-11175) in culture. [Figure 3] This figure shows the results of indole-3-lactic acid (ILA) production using the combined use of nucleic acid metabolite (hypoxanthine) and Bifidobacterium longum subspecies infantis M-63 (NITE BP-02623) in culture. [Figure 4] This figure shows the results of indole-3-lactic acid (ILA) production using the combined use of nucleic acid metabolite (hypoxanthine) and Bifidobacterium breve M-16V (NITE BP-02622) in culture. [Figure 5] This figure shows the results of 3-phenyllactic acid (PLA) production using the combined use of nucleic acid metabolite (hypoxanthine) and Bifidobacterium breve M-16V (NITE BP-02622) in culture. [Modes for carrying out the invention]

[0014] The present invention will be described in detail below. <1> Active ingredients In this invention, the following components (A) and (B) are used as active ingredients: (A) nucleic acids or nucleic acid metabolites; (B) Bacteria of the genus Bifidobacterium.

[0015] In other words, components (A) and (B) are collectively referred to as the "active ingredient." The active ingredient can be used, for example, in vivo. That is, the active ingredient can be used, for example, by administering it to a subject.

[0016] By utilizing the active ingredient, specifically by administering the active ingredient to a target, the production of aromatic lactic acid compounds may be promoted in the target, that is, an effect of promoting the production of aromatic lactic acid compounds may be obtained. This effect is also called the "aromatic lactic acid compound production promoting effect." Specifically, by utilizing the active ingredient, an effect of promoting the production of aromatic lactic acid compounds may be obtained compared to when the active ingredient is not utilized. Cases where the active ingredient is not utilized include cases where neither component (A) nor (B) is utilized, or cases where only one of component (A) or (B) is utilized. Cases where the active ingredient is not utilized include cases where neither component (A) nor (B) is utilized. The production of aromatic lactic acid compounds may be promoted, for example, in the intestines of the target. Examples of intestines include the small intestine and the large intestine. Aromatic lactic acid compounds may be produced, for example, by administered Bifidobacterium bacteria. That is, by using it in combination with nucleic acids or nucleic acid metabolites, for example, the production of aromatic lactic acid compounds by administered Bifidobacterium bacteria may be promoted. Aromatic lactic acid compounds may be produced in the intestines of the subject by administered Bifidobacterium bacteria. Alternatively, aromatic lactic acid compounds may be produced by bacteria that naturally inhabit the intestines of the subject. That is, administration of the active ingredient may promote the production of aromatic lactic acid compounds by bacteria that naturally inhabit the intestines of the subject. The effect of promoting the production of aromatic lactic acid compounds can be confirmed, for example, by confirming an increase in the amount of aromatic lactic acid compounds in the subject after administration of the active ingredient. Specifically, the effect of promoting the production of aromatic lactic acid compounds can be confirmed, for example, when the amount of aromatic lactic acid compounds in a sample obtained from the subject after administration of the active ingredient is greater than the amount of aromatic lactic acid compounds in a sample obtained from the subject before administration of the active ingredient. Preferably, the subject before administration of the active ingredient is the same individual as the subject to which the active ingredient is administered, but before administration of the active ingredient. However, the subject before administration of the active ingredient may be, for example, a different individual from the subject to which the active ingredient is administered, and has not been administered the active ingredient. Alternatively, the subject before administration of the active ingredient may be, for example, a group of subjects that have not been administered the active ingredient.The samples used to confirm the effect of promoting the production of aromatic lactic acid compounds are not particularly limited, as long as they contain aromatic lactic acid compounds. Examples of samples used to confirm the effect of promoting the production of aromatic lactic acid compounds include blood samples such as whole blood and plasma, and feces.

[0017] "Aromatic lactic acid compounds" refer to lactic acid compounds containing cyclic unsaturated hydrocarbons. More specifically, "aromatic lactic acid compounds" may refer to lactic acid compounds having a benzene ring. Examples of aromatic lactic acid compounds include indole-3-lactic acid (ILA), 4-hydroxyphenyllactic acid (HPLA), and 3-phenyllactic acid (PLA). Preferably, indole-3-lactic acid (ILA) and 3-phenyllactic acid (PLA) are used as aromatic lactic acid compounds. The amount of aromatic lactic acid compounds can be measured, for example, by known methods for measuring the amount of compounds. Such methods include HPLC, UPLC, LC / MS, and GC / MS. The active ingredient may promote the production of one aromatic lactic acid compound, or the production of two or more aromatic lactic acid compounds. The active ingredient may promote the production of one or more aromatic lactic acid compounds selected from ILA, HPLA, and PLA, for example. Preferably, the active ingredient may promote the production of ILA and / or PLA.

[0018] Furthermore, by utilizing the active ingredient, specifically by administering the active ingredient to the target, effects based on the promotion of aromatic lactic acid compound production may be obtained. Effects based on the promotion of aromatic lactic acid compound production include effects on symptoms and diseases that can be prevented, improved, and / or treated by aromatic lactic acid compounds. Specifically, effects based on the promotion of aromatic lactic acid compound production include effects that prevent, improve, and / or treat symptoms and diseases that can be prevented, improved, and / or treated by aromatic lactic acid compounds.

[0019] ILA may have a function that improves neurite outgrowth, for example (Non-patent Literature 2: Chyn Boon Wong et al. Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-Induced Neurite Outgrowth in PC12 Cells. Microorganisms. 2020 Mar; 8(3): 398.). Therefore, by promoting the production of aromatic lactic acid compounds, for example, an effect of improving neurite outgrowth may be obtained in subjects in which the production of aromatic lactic acid compounds is promoted (i.e., subjects to which the active ingredient is administered). This effect is also called the "neurite outgrowth improvement effect." In other words, the effect of improving neurite outgrowth can be cited as an effect based on the promotion of the production of aromatic lactic acid compounds.

[0020] Improvement in neurite outgrowth may be an indicator of neuronal differentiation. Therefore, by utilizing the active ingredient, specifically by administering the active ingredient to the target area, neuronal differentiation may be promoted, that is, an effect of promoting neuronal differentiation may be obtained. This effect is also called the "neuronal differentiation promoting effect." In other words, the neuronal differentiation promoting effect can be cited as an effect based on the promotion of aromatic lactic acid compound production. To put it another way, improvement in neurite outgrowth may be obtained by promoting neuronal differentiation. In other words, the neurite outgrowth improvement effect may be an example of the neuronal differentiation promoting effect. The neuronal differentiation promoting effect can be confirmed, for example, by confirming the neurite outgrowth improvement effect.

[0021] The neuronal differentiation-promoting effect can also be confirmed, for example, by observing an increase in acetylcholinesterase (AchE) activity in the subject. Specifically, the neuronal differentiation-promoting effect can be confirmed, for example, when the AchE activity in a sample obtained from the subject after administration of the active ingredient is greater than the AchE activity in a sample obtained from the subject before administration of the active ingredient. AchE activity can be measured, for example, using the Amplite Fluorimetric Acetylcholinesterase Assay Kit (AAT Bioquest, Sunnyvale, CA, USA). The sample used to confirm the neuronal differentiation-promoting effect is not particularly limited as long as it contains nerve cells. The sample can be obtained, for example, by biopsy from the subject.

[0022] Furthermore, by utilizing the active ingredient, specifically by administering the active ingredient to the target area, effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth may be obtained. The promotion of neuronal differentiation and / or improvement of neurite outgrowth may, for example, protect and / or improve nerve function. That is, the promotion of neuronal differentiation and / or improvement of neurite outgrowth may, for example, prevent, improve, and / or treat symptoms associated with nerve disorders. In other words, effects based on the promotion of aromatic lactic acid compound production (specifically, effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth) include effects that protect nerve function, improve nerve function, and prevent, improve, and / or treat symptoms associated with nerve disorders. Symptoms associated with nerve disorders may or may not be diseases. In other words, symptoms associated with nerve disorders may or may not be caused by diseases. Examples of symptoms associated with nerve disorders include neurodegenerative diseases, or, in other words, symptoms caused by neurodegenerative diseases. Neurodegenerative diseases include those that involve impaired neuronal differentiation or impaired neurite outgrowth.Neurodegenerative diseases include, specifically, Alzheimer's disease (AD), dementia (such as Lewy body dementia (DLB)), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Huntington's disease, dystonia, transmissible spongiform encephalopathy (TSE), chorea-acanthocytosis (ChAc), adrenoleukodystrophy (ALD), multiple system atrophy (MSA), and spinocerebellar degeneration (Spinocerebellar degeneration). Examples include degeneration (SCD), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), spinal and bulbar muscular atrophy (SBMA), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and Batten disease.

[0023] It has been reported that kynurenine, a tryptophan metabolite, can cross the blood-brain barrier (Psychoneuroendocrinology. 2018;94:1-10.doi:10.1016 / j.psyneuen.2018.04.019.). Therefore, aromatic lactic acid compounds such as ILA are expected to be able to cross the blood-brain barrier.

[0024] ILA may have the function of regulating the immune balance of newborns by, for example, promoting the production of immunomodulatory galectin-1, thereby reducing Th2 and Th17 cytokines and inducing Th1 cytokines such as interferon-β (Bethany M. Henrick et al. Bifidobacteria-mediated immune system imprinting early in life, Cell. 2021 July; 184: 1-15.). Therefore, by promoting the production of aromatic lactic acid compounds, for example, immune function may be improved in subjects in whom the production of aromatic lactic acid compounds is promoted (i.e., subjects to whom the active ingredient is administered), that is, an effect of improving immune function may be obtained. This effect is also called the "immune function improvement effect." In other words, an effect based on the promotion of aromatic lactic acid compound production is the immune function improvement effect. The immune function improvement effect may be obtained, for example, in infants. By improving immune function, for example, an effect of preventing, improving, and / or treating symptoms and diseases involving immune abnormalities may be obtained. In other words, the effects based on the promotion of aromatic lactic acid compound production (specifically, the effect of improving immune function) include the prevention, improvement, and / or treatment of symptoms and diseases involving immune abnormalities. Symptoms and diseases involving immune abnormalities include allergies and autoimmune diseases. Allergies include atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma, food allergies, drug allergies, and urticaria. Autoimmune diseases include Graves' disease, rheumatoid arthritis, Hashimoto's thyroiditis, type 1 diabetes, systemic lupus erythematosus, and vasculitis.

[0025] ILA is known to act as an agonist of aryl hydrocarbon receptors (AhR) in intestinal epithelial cells and nerve cells, thereby exerting anti-inflammatory effects (Ehrlich et al. Indole-3-lactic acid associated with Bifidobacterium-dominated microbiota significantly decreases inflammation in intestinal epithelial cells. BMC Microbiology. 2020 20:357. and Wong et al. Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-Induced Neurite Outgrowth in PC12 Cells. Microorganisms. 2020 Mar; 8(3): 398.). Therefore, by promoting the production of aromatic lactic acid compounds, anti-inflammatory, antioxidant, and / or antibacterial effects may be obtained in subjects in which the production of aromatic lactic acid compounds is promoted (i.e., subjects to which the active ingredient is administered). In other words, the effects based on the promotion of aromatic lactic acid compound production include anti-inflammatory, antioxidant, and antibacterial effects. These anti-inflammatory, antioxidant, and / or antibacterial effects may, for example, prevent, improve, and / or treat inflammation and inflammatory diseases. Specifically, the effects based on the promotion of aromatic lactic acid compound production (specifically, anti-inflammatory, antioxidant, or antibacterial effects) may include prevent, improve, and / or treat inflammation and inflammatory diseases. Inflammation and inflammatory diseases include encephalitis, osteomyelitis, meningitis, neuritis, dermatitis, myositis, hepatitis, pancreatitis, inflammation of the blood vessels (arteritis, phlebitis, capillary inflammation, etc.), inflammation of the heart (endocarditis, myocarditis, pericarditis, etc.), inflammation of the eyes (dacryoadenitis, keratitis, retinitis, conjunctivitis, etc.), inflammation of the ears (otitis externa, otitis media, otitis interna, etc.), inflammation of the respiratory system (sinusitis, rhinitis, pharyngitis, laryngitis, bronchitis, pneumonia, etc.), inflammation of the oral cavity (stomatitis, glossitis, tonsillitis, etc.), inflammation of the digestive system (esophagitis, gastritis, enteritis, appendicitis, etc.), and inflammation of the urinary system (nephritis, cystitis, prostatitis, etc.).

[0026] The present invention may provide the use of active ingredients to obtain the effects exemplified above. That is, the present invention may provide the use of active ingredients for promoting the production of aromatic lactic acid compounds, promoting neuronal differentiation, improving neurite outgrowth, preventing, improving, and / or treating symptoms associated with neurological disorders, improving immune function, anti-inflammatory, antioxidant, and / or antibacterial effects. The present invention may also provide the use of active ingredients for producing compositions for promoting aromatic lactic acid compound production, promoting neuronal differentiation, improving neurite outgrowth, preventing, improving, and / or treating symptoms associated with neurological disorders, improving immune function, anti-inflammatory, antioxidant, and / or antibacterial effects.

[0027] The present invention may provide active ingredients used to obtain the effects exemplified above. Specifically, the present invention may provide active ingredients used for promoting the production of aromatic lactic acid compounds, promoting neuronal differentiation, improving neurite outgrowth, preventing, improving, and / or treating symptoms associated with neurological disorders, improving immune function, anti-inflammatory, antioxidant, and / or antibacterial effects. Furthermore, the present invention may provide active ingredients used for producing compositions for promoting aromatic lactic acid compound production, promoting neuronal differentiation, improving neurite outgrowth, preventing, improving, and / or treating symptoms associated with neurological disorders, improving immune function, anti-inflammatory, antioxidant, and / or antibacterial effects.

[0028] The active ingredient may be used for therapeutic purposes or for non-therapeutic purposes. In other words, unless otherwise specified, the effects exemplified above may be obtained for therapeutic purposes or for non-therapeutic purposes.

[0029] "Therapeutic purpose" may refer to a concept that includes, for example, medical procedures, and more specifically, a concept that includes treatments performed on the human body. When the active ingredient is used for therapeutic purposes, it may be administered to non-healthy individuals. Examples of non-healthy individuals include those with the neurodegenerative diseases mentioned above, those with allergies, those with autoimmune diseases, and those with inflammation or inflammatory diseases. When the active ingredients are used for therapeutic purposes, they may be able to improve or treat conditions such as neurodegenerative diseases, allergies, autoimmune diseases, inflammation, and inflammatory diseases.

[0030] "Non-therapeutic purposes" can refer to a concept that does not include medical procedures, and more specifically, a concept that does not include treatments or procedures on the human body. Examples of non-therapeutic purposes include health promotion and cosmetic purposes. When the active ingredient is used for non-therapeutic purposes, it may be administered to healthy individuals. Healthy individuals may include those who do not have the neurodegenerative diseases mentioned above, those who do not have allergies, those who do not have autoimmune diseases, and those who do not have inflammation or inflammatory diseases. When the active ingredient is used for non-therapeutic purposes, it may be used to further promote the production of aromatic lactic acid compounds in the bodies of healthy individuals. When the active ingredient is used for non-therapeutic purposes, it can be expected to have preventive effects against conditions such as neurodegenerative diseases, allergies, autoimmune diseases, inflammation, and inflammatory diseases in healthy individuals.

[0031] "Prevention of symptoms or disease" may mean, for example, preventing and / or delaying the onset of symptoms or disease, or reducing the likelihood of developing symptoms or disease. "Improvement of symptoms or disease" or "treatment of symptoms or disease" may mean, for example, an improvement in symptoms or disease, prevention or delaying the worsening of symptoms or disease, or prevention or delaying the progression of symptoms or disease. "Improvement of symptoms or disease" may mean, in particular, these events that are obtained for non-therapeutic purposes. "Treatment of symptoms or disease" may mean, in particular, these events that are obtained for therapeutic purposes.

[0032] Examples of nucleic acids include deoxyribonucleic acid and ribonucleic acid. The nucleic acid may be derived from cells, from foods such as vegetables and fish, or synthesized by known methods, but it is particularly preferable to use nucleic acid derived from food. It is known that nucleic acids are metabolized in the human body to produce nucleic acid metabolites such as xanthine and hypoxanthine (Reference: MEDICINAL 2012 Vol.2 No.7 pp.108-109). Therefore, by combining nucleic acid as component (A) with Bifidobacterium bacteria as component (B), the aromatic lactic acid compound production promoting effect of the present invention can be expected. Furthermore, the aromatic lactic acid compound production promoting effect of the present invention can be expected by the cooperation of nucleic acid as component (A) present in the intestines with Bifidobacterium bacteria as component (B). As for the nucleic acid, one type of nucleic acid may be used, or two types of nucleic acids may be used in combination.

[0033] Nucleic acid metabolites include those having a purine skeleton and those having a pyrimidine skeleton. In this specification, nucleic acid metabolites refer to xanthine, hypoxanthine, adenosine, inosine, uracil, uridine, xanthosine, adenine, guanosine, guanine, cytidine, thymidine, thymine, adenylic acid (adenosine monophosphate (AMP)), inosinic acid (inosine monophosphate (IMP)), xanthylic acid (xanthosine monophosphate (XMP)), guanylic acid (guanosine monophosphate (GMP)), cytidylic acid (cytidine monophosphate (CMP)), uridylic acid (uridine monophosphate (UMP)), thymidylic acid (thymidine monophosphate (dTMP)), or urea, and salts thereof. Among these, nucleic acid metabolites containing a purine skeleton are xanthine, hypoxanthine, adenosine, inosine, xanthosine, adenine, guanosine, guanine, AMP, IMP, XMP, and GMP. Furthermore, nucleic acid metabolites that have a pyrimidine skeleton include uracil, uridine, cytidine, thymidine, thymine, CMP, UMP, and dTMP. Preferably, nucleic acid metabolites have a purine skeleton. More preferably, xanthine or hypoxanthine is included. One nucleic acid metabolite may be used, or two or more nucleic acid metabolites may be used in combination.

[0034] Component (A) may consist of nucleic acids alone, nucleic acid metabolites alone, or a combination of nucleic acids and nucleic acid metabolites.

[0035] As nucleic acid metabolites, commercially available products may be used, or products obtained by appropriate manufacturing may be used. Examples of commercially available hypoxanthine include hypoxanthine manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. The method for producing nucleic acid metabolites is not particularly limited. Nucleic acid metabolites can be produced, for example, by known methods. Specifically, nucleic acid metabolites can be produced, for example, by chemical synthesis, enzymatic reaction, or extraction. For example, hypoxanthine can be obtained by culturing microorganisms capable of producing hypoxanthine in adenine-supplemented medium (Japanese Patent Publication No. 10-028593, Japanese Patent Publication No. 2001-224393, Japanese Patent Publication No. 2005-333814, etc.). Nucleic acid metabolites may or may not be purified to a desired degree. That is, purified products may be used as nucleic acid metabolites, or materials containing nucleic acid metabolites may be used. The content of nucleic acid metabolites in the material may be, for example, 1% or more by weight, 5% or more by weight, 10% or more by weight, 30% or more by weight, 50% or more by weight, 70% or more by weight, or 90% or more by weight, relative to the dry weight of the material.

[0036] When using materials containing nucleic acid metabolites, the amount of nucleic acid metabolites (for example, the content in the composition of the present invention or the dosage in the method of the present invention) shall be calculated based on the amount of nucleic acid metabolites themselves contained in the material.

[0037] Bifidobacterium species include Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium bifidum, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium dentium, Bifidobacterium pseudocatenulatum, Bifidobacterium animalis, and Bifidobacterium pseudolongum. Examples include Bifidobacterium pseudolongum and Bifidobacterium thermophilum. In particular, Bifidobacterium breve is a notable example of a Bifidobacterium bacterium. A single Bifidobacterium species may be used, or a combination of two or more species may be used.

[0038] The term "Bifidobacterium longum" includes strains classified as any subspecies of Bifidobacterium longum, such as Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis, and Bifidobacterium longum subsp. suis. The term "Bifidobacterium animalis" includes strains classified as any subspecies of Bifidobacterium animalis, such as Bifidobacterium animalis subsp. lactis. The term "Bifidobacterium pseudolongum" includes strains classified as any subspecies of Bifidobacterium pseudolongum, such as Bifidobacterium pseudolongum subsp. globosum and Bifidobacterium pseudolongum subsp. pseudolongum. Note that Bifidobacterium longum subspecies longum is sometimes simply referred to as Bifidobacterium longum, and Bifidobacterium longum subspecies infantis is sometimes simply referred to as Bifidobacterium infantis.

[0039] Bifidobacterium bacteria may be, for example, bacteria capable of producing aromatic lactic acid compounds such as ILA. Bifidobacterium bacteria may, for example, produce aromatic lactic acid compounds from a carbon source and / or tryptophan. Specifically, Bifidobacterium bacteria may be bacteria capable of producing aromatic lactic acid compounds in a subject when administered to that subject. More specifically, Bifidobacterium bacteria may be bacteria capable of producing aromatic lactic acid compounds in the intestines of a subject when administered to that subject. For example, infant-type human-resident bifidobacteria (HRB) have been reported to produce significantly higher concentrations of ILA compared to adult-type HRB and non-HRB (Sakurai et al, Production of Indole-3-Lactic Acid by Bifidobacterium Strains Isolated from Human Infants. Microorganisms. 2019 Sep 11;7(9)). Therefore, infant-type HRB is particularly noteworthy among Bifidobacterium species. Examples of infant-type HRB include Bifidobacterium longum (Bifidobacterium longum subspecies longum and Bifidobacterium longum subspecies infantis, etc.), Bifidobacterium breve, and Bifidobacterium bifidum.

[0040] Examples of Bifidobacterium longum include BB536 (NITE BP-02621), ATCC 15697, ATCC 15707, ATCC 25962, ATCC 15702, ATCC 27533, M-63 (NITE BP-02623), BG7, DSM 24736, SBT 2928, NCC 490 (CNCM I-2170), and NCC 2705 (CNCM I-2618). One strain of Bifidobacterium longum may be used, or a combination of two or more strains may be used.

[0041] Examples of Bifidobacterium breve include M-16V (NITE BP-02622), MCC1274 (FERM BP-11175), ATCC 15700, B632 (DSM 24706), Bb99 (DSM 13692), ATCC 15698, DSM 24732, UCC2003, YIT4010, YIT4064, BBG-001, BR-03, C50, and R0070. In particular, M-16V (NITE BP-02622) and MCC1274 (FERM BP-11175) are mentioned. One strain of Bifidobacterium breve may be used, or a combination of two or more strains may be used.

[0042] Examples of Bifidobacterium bifidum include ATCC 29521, MCC1092 (NITE BP-02429), MCC1319 (NITE BP-02431), OLB6378, and BF-1. Examples of Bifidobacterium adolescentis include ATCC 15703. Examples of Bifidobacterium denthium include DSM 20436. Examples of Bifidobacterium animalis include DSM 10140, Bb-12, DN-173 010, GCL2505, and CNCM I-3446. Examples of Bifidobacterium pseudorhondongum include JCM 5820 and ATCC 25526. A specific example of Bifidobacterium thermophyllum is ATCC 25525.

[0043] Bifidobacterium longum BB536 (NITE BP-02621) was internationally deposited with the National Institute of Technology and Evaluation (NITE) Patent Microorganism Depositary Center (Postal Code: 292-0818, Address: Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) on January 26, 2018, under the Budapest Convention, and has been assigned the accession number NITE BP-02621.

[0044] Bifidobacterium infantis M-63 (NITE BP-02623) was internationally deposited with the National Institute of Technology and Evaluation (NITE) Patent Microorganism Depositary Center (Postal Code: 292-0818, Address: Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) on January 26, 2018, under the Budapest Convention, and has been assigned the accession number NITE BP-02623.

[0045] Bifidobacterium breve M-16V (NITE BP-02622) was internationally deposited with the National Institute of Technology and Evaluation (NITE) Patent Microorganism Depositary Center (Postal Code: 292-0818, Address: Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) on January 26, 2018, under the Budapest Convention, and has been assigned the accession number NITE BP-02622.

[0046] Bifidobacterium bifidum MCC1092 (NITE BP-02429) was internationally deposited with the National Institute of Technology and Evaluation (NITE) Patent Microorganism Depositary Center (Postal Code: 292-0818, Address: Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) on February 21, 2017, under the Budapest Convention, and has been assigned the accession number NITE BP-02429.

[0047] Bifidobacterium bifidum MCC1319 (NITE BP-02431) was internationally deposited with the National Institute of Technology and Evaluation (NITE) Patent Microorganism Depositary Center (Postal Code: 292-0818, Address: Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) on February 21, 2017, under the Budapest Convention, and has been assigned the accession number NITE BP-02431.

[0048] Bifidobacterium breve MCC1274 (FERM BP-11175) was internationally deposited on August 25, 2009 (Heisei 21) at the Patent Organism Depository Center of the National Institute of Advanced Industrial Science and Technology (now the Patent Organism Depository Center of the National Institute of Technology and Evaluation (IPOD), postal code: 292-0818, address: Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan) under the Budapest Convention, and was assigned the accession number FERM BP-11175.

[0049] These strains can be obtained, for example, from the American Type Culture Collection (ATCC, Address: 10801 University Boulevard Manassas, VA 20110, United States of America), the Belgian Coordinated Collections of Microorganisms (BCCM, Address: Rue de la Science 8, 1000 Brussels, Belgium), the German Collection of Microorganisms and Cell Cultures (DSMZ, Address: Inhoffenstr.7B, D38124 Braunschweig, Germany), the Japan Collection of Microorganisms (JCM, Postal Code: 305-0074, Address: Microbial Materials Development Laboratory, RIKEN BioResource Research Center, 3-1-1 Takanodai, Tsukuba City, Ibaraki Prefecture, Japan), or from the depositary institutions where each strain is deposited.

[0050] The strains identified by the strain names exemplified above are not limited to the strains themselves that have been deposited or registered with a designated institution under those strain names (hereinafter, for convenience of explanation, also referred to as "deposited strains"), but also include strains that are substantially equivalent to said deposited strains (hereinafter, also referred to as "inducible strains"). In other words, for example, "Bifidobacterium breve MCC1274 (FERM BP-11175)" is not limited to the strain itself deposited with the above depositary institution under the depositary number FERM BP-11175, but also includes strains that are substantially equivalent to the deposited strain. A "strain substantially equivalent to the deposited strain" means a strain that belongs to the same species as the deposited strain, has the function of an active ingredient (i.e., the function of promoting the production of aromatic lactic acid compounds when used in combination with nucleic acids or nucleic acid metabolites), whose 16S rRNA gene base sequence is preferably 99.86% or more, more preferably 99.93% or more, and even more preferably 100% identical to the 16S rRNA gene base sequence of the deposited strain, and preferably has the same biological properties as the deposited strain. A strain substantially equivalent to the deposited strain may be, for example, a derivative strain obtained using the deposited strain as the parent plant. Examples of derivative strains include strains bred from the deposited strain and strains that arose naturally from the deposited strain. Breeding methods include modification using genetic engineering techniques and modification through 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 (MNNG), ethyl methanesulfonate (EMS), and methyl methanesulfonate (MMS)). Strains that arise naturally from deposited strains include strains that arise naturally when deposited strains are used. Use of deposited strains includes culturing deposited strains (e.g., subculturing). Derived strains may be constructed by one modification, or by two or more modifications.

[0051] As for Bifidobacterium bacteria, commercially available products may be used, or those that are manufactured and obtained as appropriate may be used. Examples of commercially available Bifidobacterium bacteria include Bifidobacterium longum subspecies longum BB536, Bifidobacterium breve M-16V, Bifidobacterium breve MCC1274, and Bifidobacterium longum subspecies infantis M-63, all manufactured by Morinaga Milk Industry Co., Ltd.

[0052] The active ingredient "Bifidobacterium bacteria" may refer to the bacterial cells of the genus Bifidobacterium. Bifidobacterium bacterial cells can be easily obtained by culturing Bifidobacterium bacteria. The culturing method is not particularly limited as long as the Bifidobacterium bacteria can grow. As a culturing method, for example, the method normally used for culturing Bifidobacterium bacteria can be used as is or modified as appropriate. The culturing temperature may be, for example, 25 to 50°C, and preferably 35 to 42°C. Culturing can preferably be carried out under anaerobic conditions, for example, by aerating with an anaerobic gas such as carbon dioxide. Alternatively, culturing can be carried out under microaerophilic conditions such as liquid static culture. Culturing can be carried out, for example, until the Bifidobacterium bacteria have grown to the desired extent.

[0053] The culture medium used is not particularly limited as long as it allows Bifidobacterium bacteria to grow. For example, a culture medium commonly used for culturing Bifidobacterium bacteria can be used as is or modified as appropriate. The culture medium may contain, for example, a carbon source, a nitrogen source, inorganic salts, organic components, milk components, or a combination thereof. Examples of carbon sources include sugars such as galactose, glucose, fructose, mannose, cellobiose, maltose, lactose, sucrose, trehalose, starch, starch hydrolysates, and molasses, and any of these sugars can be used depending on the assimilation capacity of Bifidobacterium bacteria. Examples of nitrogen sources include ammonia and ammonium salts or nitrates such as ammonium sulfate, ammonium chloride, and ammonium nitrate. Examples of inorganic salts include sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, and ferrous sulfate. Organic components include peptone, soy flour, defatted soybean meal, meat extract, and yeast extract. Milk components include milk proteins. Milk proteins include casein, whey, and their hydrolysates. These components may be used individually or in appropriate combinations. Specific culture media that can be used for culturing Bifidobacterium bacteria include reinforced Clostridial medium, MRS medium (de Man, Rogosa, and Sharpe medium), mMRS medium (modified MRS medium), TOSP medium (TOS propionate medium), and TOSP Mup medium (TOS propionate mupirocin medium).

[0054] As the Bifidobacterium bacteria, either the bacterial cells themselves or fractions containing them can be used. That is, as the Bifidobacterium bacteria, for example, the culture solution of Bifidobacterium bacteria may be used as is, or bacterial cells recovered from the culture solution may be used. In addition, the bacterial cells or fractions containing them may be used after being subjected to treatment. The treatment is not particularly limited as long as it does not impair the desired effect, such as the effect of promoting the production of aromatic lactic acid compounds. Preferably, the treatment does not significantly reduce the viability of the bacterial cells. Treatments include dilution, concentration, freezing, and drying. That is, as the Bifidobacterium bacteria (specifically the bacterial cells of Bifidobacterium bacteria), examples include the culture solution of Bifidobacterium bacteria, bacterial cells recovered from the culture solution, and processed products thereof (diluted products, concentrated products, frozen products, dried products, etc.). Specific treatments include freezing of the culture solution, spray drying, freeze-drying, and the oil drop method. The bacterial cells may contain live cells. The bacterial cells may also contain dead cells, or they may not.

[0055] <2> Composition of the present invention The composition of the present invention is a composition containing an active ingredient.

[0056] In other words, the composition of the present invention is a composition containing the following components (A) and (B): (A) nucleic acids or nucleic acid metabolites; (B) Bacteria of the genus Bifidobacterium.

[0057] The compositions of the present invention can be used by administering them to a subject. Specifically, the compositions of the present invention can be administered to a subject as described in the method of the present invention. The compositions of the present invention can be used, for example, to obtain the effects exemplified above.

[0058] By utilizing the composition of the present invention, specifically by administering the composition to a target, the production of aromatic lactic acid compounds may be promoted in the target, that is, an effect of promoting the production of aromatic lactic acid compounds may be obtained. In other words, the composition of the present invention may be, for example, a composition for promoting the production of aromatic lactic acid compounds. Furthermore, the composition of the present invention may be, for example, a composition for use in promoting the production of aromatic lactic acid compounds.

[0059] Furthermore, by utilizing the composition of the present invention, specifically by administering the composition of the present invention to a target, effects based on the promotion of production of aromatic lactic acid compounds may be obtained, for example. That is, the composition of the present invention may be, for example, a composition for obtaining effects based on the promotion of production of aromatic lactic acid compounds. The composition for obtaining effects based on the promotion of production of aromatic lactic acid compounds may be an example of a composition for promoting the production of aromatic lactic acid compounds.

[0060] By utilizing the composition of the present invention, specifically by administering the composition of the present invention to a subject, for example, neurite outgrowth may be improved in the subject, that is, a neurite outgrowth improvement effect may be obtained. In other words, the composition of the present invention may be, for example, a composition for improving neurite outgrowth. Furthermore, the composition of the present invention may be, for example, a composition for use in improving neurite outgrowth. A composition for improving neurite outgrowth may be an example of a composition for promoting the production of aromatic lactic acid compounds.

[0061] By utilizing the composition of the present invention, specifically by administering the composition of the present invention to a target, for example, neuronal cell differentiation may be promoted, that is, a neuronal cell differentiation promoting effect may be obtained. In other words, the composition of the present invention may be, for example, a composition for promoting neuronal cell differentiation. Furthermore, the composition of the present invention may be, for example, a composition for use in promoting neuronal cell differentiation. A composition for improving neurite extension may be an example of a composition for promoting neuronal cell differentiation. A composition for improving neurite extension may be an example of a composition for promoting aromatic lactic acid compound production.

[0062] By utilizing the composition of the present invention, specifically by administering the composition of the present invention to a target, effects based on, for example, the promotion of neuronal differentiation and / or improvement of neurite outgrowth may be obtained. That is, the composition of the present invention may be, for example, a composition for obtaining effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth. Furthermore, the composition of the present invention may be, for example, a composition for use in achieving effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth. Specifically, the composition of the present invention may be, for example, a composition for the prevention, improvement, and / or treatment of symptoms related to neurological disorders. Furthermore, the composition of the present invention may be, for example, a composition for use in the prevention, improvement, and / or treatment of symptoms related to neurological disorders. A composition for obtaining effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth (such as a composition for the prevention, improvement, and / or treatment of symptoms related to neurological disorders) may be an example of a composition for promoting neuronal differentiation and / or a composition for improving neurite outgrowth. A composition for obtaining effects based on the promotion of neuronal cell differentiation and / or improvement of neurite outgrowth (such as a composition for the prevention, improvement, and / or treatment of symptoms related to neurological disorders) may be an example of a composition for promoting the production of aromatic lactic acid compounds.

[0063] By utilizing the composition of the present invention, specifically by administering the composition to a target, for example, immune function may be improved, that is, an immune function improvement effect may be obtained. In other words, the composition of the present invention may be, for example, an immune function improving composition. Furthermore, the composition of the present invention may be, for example, a composition for use in improving immune function. An immune function improving composition may be an example of a composition for promoting the production of aromatic lactic acid compounds.

[0064] By utilizing the composition of the present invention, specifically by administering the composition to a target, for example, anti-inflammatory effects, antioxidant effects, and / or antibacterial effects may be obtained. That is, the composition of the present invention may be, for example, an anti-inflammatory, antioxidant, and / or antibacterial composition. Furthermore, the composition of the present invention may be, for example, a composition for use in anti-inflammatory, antioxidant, and / or antibacterial applications. The anti-inflammatory, antioxidant, and / or antibacterial composition may be an example of a composition for promoting the production of aromatic lactic acid compounds.

[0065] The description of the subject to whom the composition of the present invention is administered can be applied mutatis mutandis to the subject to whom the active ingredient in the method of the present invention is administered.

[0066] The compositions of the present invention may be, for example, food and beverage compositions, pharmaceutical compositions, or animal feed compositions. In particular, the compositions of the present invention may be food and beverage compositions or pharmaceutical compositions. That is, the compositions of the present invention may be, for example, food and beverage compositions for obtaining the effects exemplified above (e.g., for promoting the production of aromatic lactic acid compounds, for promoting neuronal differentiation, for improving neurite outgrowth, for preventing, improving, and / or treating symptoms related to neurological disorders, for improving immune function, for anti-inflammatory, antioxidant, and / or antibacterial purposes). Furthermore, the compositions of the present invention may be food and beverage compositions for use in achieving the effects exemplified above (e.g., for use in promoting the production of aromatic lactic acid compounds, for use in promoting neuronal differentiation, for use in improving neurite outgrowth, for use in preventing, improving, and / or treating symptoms related to neurological disorders, for use in improving immune function, for anti-inflammatory, antioxidant, and / or antibacterial purposes). Furthermore, the compositions of the present invention may be, for example, pharmaceutical compositions for obtaining the effects exemplified above (e.g., for promoting the production of aromatic lactic acid compounds, for promoting neuronal differentiation, for improving neurite outgrowth, for preventing, improving, or treating symptoms related to neurological disorders, for improving immune function, for anti-inflammatory, antioxidant, and / or antibacterial purposes). Furthermore, the compositions of the present invention may be, for example, pharmaceutical compositions for use in achieving the effects exemplified above (e.g., for promoting the production of aromatic lactic acid compounds, for promoting neuronal differentiation, for improving neurite outgrowth, for preventing, improving, and / or treating symptoms related to neurological disorders, for improving immune function, for anti-inflammatory, antioxidant, and / or antibacterial purposes). Furthermore, the compositions of the present invention may be, for example, feed compositions for obtaining the effects exemplified above (e.g., for promoting the production of aromatic lactic acid compounds, for promoting neuronal differentiation, for improving neurite outgrowth, for preventing, improving, and / or treating symptoms related to neurological disorders, for improving immune function, for anti-inflammatory, antioxidant, and / or antibacterial purposes).Furthermore, the compositions of the present invention may be, for example, feed compositions for use in achieving the effects exemplified above (e.g., use in promoting the production of aromatic lactic acid compounds, use in promoting neuronal cell differentiation, use in improving neurite outgrowth, use in preventing, improving, and / or treating symptoms associated with neurological disorders, use in improving immune function, use in anti-inflammatory applications, use in antioxidant applications, and / or antimicrobial applications). The compositions of the present invention, which are food and beverage compositions, pharmaceutical compositions, or feed compositions, are also referred to as "food and beverage compositions of the present invention," "pharmaceutical compositions of the present invention," or "feed compositions of the present invention," respectively.

[0067] The composition of the present invention may consist of an active ingredient, or it may contain additional ingredients in addition to the active ingredient.

[0068] The additional components are not particularly limited, as long as they do not impair the desired effects, such as the effect of promoting the production of aromatic lactic acid compounds. The additional components can be those that are acceptable depending on how the composition of the present invention is used. Examples of additional components include those that can be incorporated into food and beverages, pharmaceuticals, or animal feed. Specifically, examples of additional components include those exemplified in the food and beverage compositions, pharmaceutical compositions, or animal feed compositions described later. The additional components may be a single component, or a combination of two or more components.

[0069] The content and ratio of the components (i.e., the active ingredient and optionally additional components) in the composition of the present invention are not particularly limited, as long as the desired effect, such as the effect of promoting the production of aromatic lactic acid compounds, is achieved. The content and ratio of the components in the composition of the present invention can be appropriately set according to various conditions such as the type of active ingredient, the type of additional components, the type of composition of the present invention, the dosage form and method of use, the type of recipient, age, and health condition.

[0070] The total content of the active ingredient in the composition of the present invention is greater than 0% by weight and 100% by weight or less. The total content of the active ingredient in the composition of the present invention may be, for example, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 5% by weight or more, 10% by weight or more, 30% by weight or more, 50% by weight or more, 70% by weight or more, or 90% by weight or more, or 100% by weight or less, 99.99% by weight or less, 99% by weight or less, 90% by weight or less, 70% by weight or less, 50% by weight or less, 30% by weight or less, 10% by weight or less, 5% by weight or less, or 1% by weight or less, and may be within a range of non-inconsistent combinations thereof.

[0071] The content of component (A) in the composition of the present invention may be, for example, 0.1% by weight or more, 0.3% by weight or more, 0.5% by weight or more, 1% by weight or more, 5% by weight or more, 10% by weight or more, 30% by weight or more, 50% by weight or more, 70% by weight or more, or 90% by weight or more, or 99.99% by weight or less, 99% by weight or less, 90% by weight or less, 70% by weight or less, 50% by weight or less, 30% by weight or less, 10% by weight or less, 5% by weight or less, or 1% by weight or less, and may be within a range of non-inconsistent combinations thereof. Specifically, the content of component (A) in the composition of the present invention may be, for example, 0.1 to 50% by weight, preferably 0.3 to 20% by weight, and more preferably 0.5 to 10% by weight.

[0072] The content of component (B) in the composition of the present invention is, for example, 1 × 10⁻⁶, when converted to the number of viable Bifidobacterium bacteria. 4 cells / g or more, 1×10 5 cells / g or more, 1×10 6 cells / g or more, 1×10 7 cells / g or more, or 1 × 10⁶ 8 It may be more than 1 × 10 13 cells / g or less, 1×10 12 cells / g or less, or 1 × 10⁻⁶ 11It may be below 1×10 cells / g or within the range of their combinations. Specifically, the content of component (B) in the composition of the present invention, when converted to the viable cell count of Bifidobacterium bacteria, is, for example, 1×10 4 ~1×10 13 cells / g, 1×10 5 ~1×10 13 cells / g, 1×10 6 ~1×10 12 cells / g, preferably 1×10 7 ~1×10 11 cells / g, more preferably 1×10 8 ~1×10 10 cells / g. "Cells" in the dosage ranges exemplified above may be read as "cfu". "Cfu" represents colony forming unit.

[0073] The content of the active ingredient in the composition of the present invention may be set, for example, so that the dosage of the active ingredient mentioned in the method of the present invention is achieved.

[0074] The shape of the composition of the present invention is not particularly limited. As the shape of the composition of the present invention, those acceptable according to the usage mode of the composition of the present invention can be adopted. Specifically, as the shape of the composition of the present invention, the shapes exemplified for the food and drink composition, pharmaceutical composition, or feed composition described later can be mentioned.

[0075] <Food and Drink Composition> The food and drink composition of the present invention is not particularly limited as long as it contains an active ingredient. The food and drink composition may be provided in any shape such as liquid, paste, solid, powder, etc.

[0076] Food and beverage compositions may be, for example, food and beverages themselves, or materials used in the manufacture of food and beverages. Such materials include seasonings, food additives, and other food ingredients. Specifically, food and beverage compositions include wheat flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, dairy products (fermented milk, cheese, infant formula, etc.), oils and fats, basic seasonings, compound seasonings, frozen foods, confectionery, beverages, and other commercially available food and beverages. Dairy products such as fermented milk are particularly noteworthy as food and beverage compositions. Specifically, food and beverage compositions also include health foods, functional foods, enteral nutrition foods, foods for special dietary uses, health functional foods (foods for specified health uses, nutrient function foods, foods with functional claims, etc.), nutritional supplements, and quasi-drugs. Food and beverage compositions may also include supplements such as tablet supplements.

[0077] The food and beverage composition of the present invention can be manufactured, for example, by combining an active ingredient with additional ingredients. The operation of combining an active ingredient with additional ingredients is also called "addition of the active ingredient." The method of manufacturing the food and beverage composition of the present invention is not particularly limited. The food and beverage composition of the present invention can be manufactured, for example, using the same raw materials as ordinary food and beverages and using the same methods as ordinary food and beverages, except for the addition of the active ingredient. The same applies when the food and beverage composition of the present invention is manufactured as a material used in the manufacture of food and beverages. The addition of the active ingredient may be carried out at any stage of the manufacturing process of the food and beverage composition. The addition of the active ingredient may be carried out, for example, during or after the manufacture of the food and beverage composition. That is, for example, the food and beverage composition of the present invention may be manufactured by adding the active ingredient to a pre-prepared food or beverage. Furthermore, the food and beverage composition of the present invention may be manufactured through a fermentation process using the active ingredient (specifically, a fermentation process using ingredient (B)). Examples of food and beverage compositions manufactured through a fermentation process include fermented milk and probiotic beverages. That is, the active ingredient (specifically, ingredient (B)) may be used, for example, as a starter for the manufacture of fermented products. Naturally, the active ingredients can also be added to pre-prepared fermented products.

[0078] Furthermore, other food and beverage compositions can be manufactured using the food and beverage compositions of the present invention. That is, for example, if the food and beverage compositions of the present invention are provided as materials used in the manufacture of food and beverages (seasonings, food additives, other food and beverage ingredients, etc.), other food and beverage compositions may be manufactured by adding the food and beverage compositions of the present invention. Such other food and beverage compositions are also examples of food and beverage compositions of the present invention. The description of the addition of active ingredients in the manufacture of food and beverage compositions can be applied mutatis mutandis to the addition of the food and beverage compositions of the present invention in the manufacture of food and beverage compositions.

[0079] The food and beverage composition of the present invention may be used for the non-therapeutic purposes described above. The food and beverage composition of the present invention may be provided and sold as a food or beverage labeled with intended uses (including health uses) such as promoting aromatic lactic acid compound production, promoting nerve cell differentiation, improving neurite outgrowth, preventing symptoms associated with nerve disorders, improving immune function, anti-inflammatory, antioxidant, and / or antibacterial. The food and beverage composition of the present invention may be provided and sold as a food or beverage labeled with intended target.

[0080] "Display" includes all actions taken to inform consumers of the aforementioned use, and any expression that can evoke or infer the aforementioned use constitutes a "display," regardless of the purpose, content, object, or medium of the display. In particular, the display may be carried out using an expression that allows consumers to directly recognize the aforementioned use.

[0081] Specifically, examples of indications include transferring, delivering, displaying for transfer or delivery, or importing products relating to the food and beverage composition of the present invention or products with the aforementioned uses described on the packaging; displaying or distributing advertisements, price lists, or transaction documents relating to the product with the aforementioned uses described on them; or providing information containing these materials by electromagnetic means (such as the Internet). Examples of indications include indications on packaging, containers, catalogs, brochures, promotional materials at sales sites (such as POP displays), or other documents.

[0082] Examples of labeling include labels for health foods, functional foods, enteral nutrition foods, foods for special dietary uses, health functional foods (foods for specified health uses, nutrient function foods, foods with functional claims, etc.), nutritional supplements, and quasi-drugs. Preferably, the labeling may be approved by the government or other authorities (for example, labels approved under various systems established by the government and made in accordance with such approval). Examples of labels approved by the government or other authorities include labels approved by the Consumer Affairs Agency. Examples of labels approved by the government or other authorities (for example, the Consumer Affairs Agency) include labels approved under the health functional food system (foods for specified health uses, nutrient function foods, foods with functional claims, etc.) and similar systems. Specifically, examples of labels approved by the Consumer Affairs Agency include labels as foods for specified health uses, labels as conditionally specified health uses, labels indicating an effect on the structure or function of the body, labels indicating a reduction in disease risk, and labels indicating scientifically based functionality. More specifically, the labels approved by the Consumer Affairs Agency include labels for Foods for Specified Health Uses (especially labels for health purposes) as defined in the Cabinet Office Ordinance concerning the Permission for Special Use Labeling under the Health Promotion Act (Cabinet Office Ordinance No. 57 of August 31, 2009) and similar labels. Specific examples of such labels include: "The combination of Bifidobacterium and nucleic acids or nucleic acid metabolites promotes ILA production in the intestines," "Promotes the production of ILA, which is known to regulate immune balance," and "The combination of Bifidobacterium and purines promotes ILA production in the intestines."

[0083] The content of the active ingredient in the food and beverage composition of the present invention may be, for example, within the range described above. The content of component (B) in the food and beverage composition of the present invention may be, in particular, 1 × 10⁻⁶, when converted to the number of viable Bifidobacterium bacteria. 4 ~1 × 10 13 cells / g, 1 × 10⁻⁶ 5 ~1 × 10 13 cells / g, 1 × 10⁻⁶ 6 ~1 × 10 12 cells / g, preferably 1 × 10⁶ 7 ~1 × 10 11 cells / g, more comfortably 1×108 ~1 × 10 10 It can be expressed as cells / g.

[0084] <Pharmaceutical composition> The pharmaceutical composition of the present invention is not particularly limited as long as it contains an active ingredient. The pharmaceutical composition of the present invention can be used for the therapeutic purposes described above.

[0085] The pharmaceutical composition of the present invention may be formulated into any desired dosage form. The dosage form of the pharmaceutical composition of the present invention is not particularly limited. The dosage form of the pharmaceutical composition of the present invention can be appropriately selected according to various conditions such as the method of administration. The pharmaceutical composition of the present invention may be for oral administration or for parenteral administration. The pharmaceutical composition of the present invention may be particularly for oral administration. In the case of oral administration, the dosage form may be a solid preparation such as powders, granules, tablets, or capsules, or a liquid preparation such as a solution, syrup, suspension, or emulsion. In the case of parenteral administration, the dosage form may be a suppository or ointment.

[0086] The method of formulation is not particularly limited. Formulation can be carried out, for example, by known methods depending on the dosage form. Physiologically acceptable additives can be used in formulation. Examples of additives include various organic and inorganic components. Specifically, examples of additives include excipients, binders, disintegrants, lubricants, stabilizers, flavoring and odor-correcting agents, pH adjusters, colorants, diluents, surfactants, and solvents. These additives can be appropriately selected, for example, depending on various conditions such as the dosage form.

[0087] Excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.

[0088] In addition to the above-mentioned excipients, other examples of binders include gelatin, polyvinylpyrrolidone, and macrogol.

[0089] In addition to the above-mentioned excipients, disintegrants include chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone.

[0090] Examples of lubricants include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beecam and gayl wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate; and starch derivatives.

[0091] Examples of stabilizers include para-hydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; and sorbic acid.

[0092] Flavoring and odor-modifying agents include sweeteners, acidulants, and flavorings.

[0093] The content of the active ingredient in the pharmaceutical composition of the present invention may be, for example, within the range described above. The content of component (B) in the pharmaceutical composition of the present invention may be, in particular, 1 × 10⁻⁶, when converted to the number of viable Bifidobacterium bacteria. 4 ~1 × 10 13 cells / g, 1 × 10⁻⁶ 5 ~1 × 10 13 cells / g, 1 × 10⁻⁶ 6 ~1 × 10 12 cells / g, preferably 1 × 10⁶ 7 ~1 × 10 11 cells / g, more comfortably 1×10 8 ~1 × 10 10 It can be expressed as cells / g.

[0094] <Feed composition> The feed composition of the present invention is not particularly limited as long as it contains an active ingredient. Examples of feed compositions include pet food and livestock feed. The feed composition may be provided in any form, such as powder, granules, crumble, pellets, cubes, paste, or liquid. The feed composition of the present invention can be used for either the therapeutic or non-therapeutic purposes described above.

[0095] The feed composition of the present invention can be manufactured, for example, by combining an active ingredient with additional ingredients. The operation of combining an active ingredient with additional ingredients is also called "addition of the active ingredient." The method of manufacturing the feed composition of the present invention is not particularly limited. The feed composition of the present invention can be manufactured, for example, using the same raw materials as ordinary feed and in the same manner as ordinary feed, except for the addition of the active ingredient. The addition of the active ingredient may be carried out at any stage of the manufacturing process of the feed composition. The addition of the active ingredient may be carried out, for example, during or after the manufacturing of the feed composition. That is, for example, the feed composition of the present invention may be manufactured by adding the active ingredient to a pre-prepared feed. Furthermore, the feed composition of the present invention may be manufactured through a fermentation process using the active ingredient (specifically, a fermentation process using ingredient (B)). Silage is an example of a feed composition manufactured through a fermentation process.

[0096] <3> Method of the present invention The present invention relates to a method that includes administering an active ingredient to a target. This step is also referred to as the "administration step." The target to which the active ingredient is administered is also referred to as the "administration target."

[0097] In other words, the method of the present invention is a method comprising administering the following components (A) and (B) to the target: (A) nucleic acids or nucleic acid metabolites; (B) Bacteria of the genus Bifidobacterium.

[0098] The method of the present invention can be carried out, for example, to obtain the effects exemplified above.

[0099] By utilizing the method of the present invention, specifically by administering the active ingredient to a target, the production of aromatic lactic acid compounds in that target may be promoted, that is, an effect of promoting the production of aromatic lactic acid compounds may be obtained. In other words, the method of the present invention may be, for example, a method for promoting the production of aromatic lactic acid compounds.

[0100] Furthermore, by utilizing the method of the present invention, specifically by administering the active ingredient to a target, effects based on the promotion of aromatic lactic acid compound production may be obtained, for example. That is, the method of the present invention may be, for example, a method for obtaining effects based on the promotion of aromatic lactic acid compound production. A method for obtaining effects based on the promotion of aromatic lactic acid compound production may be an example of a method for promoting the production of aromatic lactic acid compound.

[0101] By utilizing the method of the present invention, specifically by administering the active ingredient to a target, for example, neurite outgrowth may be improved in the target, that is, a neurite outgrowth improvement effect may be obtained. In other words, the method of the present invention may be, for example, a method for improving neurite outgrowth. A method for improving neurite outgrowth may be an example of a method for promoting the production of aromatic lactic acid compounds.

[0102] By utilizing the method of the present invention, specifically by administering the active ingredient to a target, for example, nerve cell differentiation may be promoted, that is, a nerve cell differentiation promoting effect may be obtained. In other words, the method of the present invention may be, for example, a method for promoting nerve cell differentiation. A method for improving neurite outgrowth may be an example of a method for promoting nerve cell differentiation. A method for promoting nerve cell differentiation may be an example of a method for promoting the production of aromatic lactic acid compounds.

[0103] By utilizing the method of the present invention, specifically by administering the active ingredient to a target, effects based on, for example, the promotion of neuronal differentiation and / or improvement of neurite outgrowth may be obtained. That is, the method of the present invention may be, for example, a method for obtaining effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth. Specifically, the method of the present invention may be, for example, a method for preventing, improving, and / or treating symptoms related to neurological disorders. A method for obtaining effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth (such as a method for preventing, improving, and / or treating symptoms related to neurological disorders) may be an example of a method for promoting neuronal differentiation or improving neurite outgrowth. A method for obtaining effects based on the promotion of neuronal differentiation and / or improvement of neurite outgrowth (such as a method for preventing, improving, and / or treating symptoms related to neurological disorders) may be an example of a method for promoting the production of aromatic lactic acid compounds.

[0104] By utilizing the method of the present invention, specifically by administering the active ingredient to a target, for example, immune function may be improved, that is, an immune function improvement effect may be obtained. In other words, the method of the present invention may be, for example, a method for improving immune function. A method for improving immune function may be, for example, a method for promoting the production of aromatic lactic acid compounds.

[0105] By utilizing the method of the present invention, specifically by administering an active ingredient to a target, for example, anti-inflammatory effects, antioxidant effects, and / or antibacterial effects may be obtained. That is, the method of the present invention may be, for example, a method for anti-inflammatory, antioxidant, and / or antibacterial effects. A method for anti-inflammatory, antioxidant, and / or antibacterial effects may be an example of a method for promoting the production of aromatic lactic acid compounds.

[0106] Furthermore, the phrase "administering the active ingredient to a subject" can be used interchangeably or equivalently with "allowing the subject to ingest the active ingredient." Ingestion may be voluntary (i.e., ad libitum) or compulsory (i.e., forced ingestion). That is, the administration process may be, for example, a process of supplying the subject with the active ingredient (which may be incorporated into food, beverage, or feed) so that the subject can ingest the active ingredient ad libitum. Administration may be oral or parenteral. Administration is typically oral. Parenteral administration includes enteral, rectal, and intranasal administration.

[0107] The administration conditions for the active ingredient (e.g., target recipient, duration of administration, number of administrations, dosage, and other administration-related conditions) are not particularly limited, as long as the desired effect, such as the promotion of aromatic lactic acid compound production, is achieved. The administration conditions for the active ingredient can be appropriately set according to various conditions such as the type of active ingredient, the type of recipient, age, and health condition.

[0108] The subjects of administration are not particularly limited, as long as the desired effects, such as the promotion of aromatic lactic acid compound production, are achieved. Examples of subjects of administration include mammals. Examples of mammals include primates such as humans, monkeys, and chimpanzees, rodents such as mice, rats, hamsters, and guinea pigs, and various other mammals such as rabbits, horses, cattle, sheep, goats, pigs, dogs, and cats. Humans are particularly noteworthy as mammals. Subjects of administration (e.g., mammals) may be, for example, pet animals, livestock, or laboratory animals. Subjects of administration may be male or female. Subjects of administration may be of any age, for example, infants, children, adults, middle-aged and elderly people. Subjects of administration may be, for example, healthy subjects or unhealthy subjects. Examples of unhealthy subjects include subjects exhibiting symptoms related to neurological disorders. Subjects of administration may be selected, for example, those who require prevention, improvement, and / or treatment of symptoms related to neurological disorders.

[0109] The dosage of component (A) may be, for example, 0.1 mg / kg body weight / day or more, 0.5 mg / kg body weight / day or more, 1 mg / kg body weight / day or more, 5 mg / kg body weight / day or more, 10 mg / kg body weight / day or more, 50 mg / kg body weight / day or more, 100 mg / kg body weight / day or more, 200 mg / kg body weight / day or more, or 300 mg / kg body weight / day or less, 200 mg / kg body weight / day or less, 100 mg / kg body weight / day or less, 50 mg / kg body weight / day or less, 10 mg / kg body weight / day or less, 5 mg / kg body weight / day or less, or 1 mg / kg body weight / day or less, and may be within a range of non-inconsistent combinations thereof. Specifically, the dosage of the active ingredient may be, for example, 0.1 to 300 mg / kg body weight / day, preferably 1 to 300 mg / kg body weight / day, more preferably 10 to 100 mg / kg body weight / day.

[0110] The dosage of component (B) is, for example, converted to the number of viable Bifidobacterium bacteria, 1 × 10⁻⁶. 6 cells / kg body weight / day or more, 1 x 10 7 cells / kg body weight / day or more, or 1 × 10⁻⁶8 It may be more than 1 × 10 12 cells / kg body weight / day or less, 1 x 10 11 cells / kg body weight / day or less, or 1 × 10⁻⁶ 11 The dose may be less than or equal to cells / kg body weight / day, or within a range of non-inconsistent combinations thereof. Specifically, the dose of component (B) may be, for example, converted to the number of viable Bifidobacterium bacteria, 1 × 10⁻⁶. 6 ~1 × 10 12 cells / kg body weight / day, preferably 1 × 10 7 ~1 × 10 11 cells / kg body weight / day, more comfortably 1 × 10 8 ~1 × 10 10 It may also be expressed as cells / kg body weight / day. In the dosage ranges exemplified above, "cells" may be read as "cfu".

[0111] The duration of administration of the active ingredient may be, for example, 1 day or more, 3 days or more, 1 week or more, 2 weeks or more, 4 weeks or more, 2 months or more, 3 months or more, 4 months or more, 6 months or more, 9 months or more, or 12 months or more, or 10 years or less, 5 years or less, 1 year or less, or 6 months or less, or within a range of non-inconsistent combinations thereof. The active ingredient may be administered, for example, throughout the subject's lifetime, or for a period of the subject's lifetime. The active ingredient may be administered, for example, at least until a desired effect is achieved, such as promoting the production of aromatic lactic acid compounds. The active ingredient may be administered, for example, daily, or once every few days. The active ingredient may be administered daily in particular. The dose of the active ingredient at each administration may be constant or not. The active ingredients (A) and (B) may be administered simultaneously or not. The active ingredients (A) and (B) may be administered simultaneously in particular.

[0112] The active ingredient may be administered directly to the subject, for example, or it may be prepared as a composition such as a food or beverage composition, a pharmaceutical composition, or a feed composition containing the active ingredient and administered to the subject. The description of the composition of the present invention can be applied mutatis mutandis to compositions containing the active ingredient. The active ingredient may be administered alone or in combination with additional ingredients. Examples of additional ingredients include food and beverages, pharmaceuticals, feed, and ingredients contained therein. Furthermore, the description of additional ingredients contained in the composition of the present invention can be applied mutatis mutandis to additional ingredients used in the method of the present invention.

[0113] The active ingredient can also be administered to a subject, for example, by using the composition of the present invention (specifically, by administering the composition of the present invention to the subject). That is, one aspect of the method of the present invention may include administering the composition of the present invention to a subject. In other words, "administration of the active ingredient" also includes the administration of the composition of the present invention. The administration conditions of the composition of the present invention (for example, the subject to administration, the duration of administration, the number of administrations, the dosage, and other administration conditions) are not particularly limited as long as the desired effect, such as the effect of promoting the production of aromatic lactic acid compounds, is achieved. The administration conditions of the composition of the present invention can be appropriately set according to various conditions such as the type and content of the active ingredient, the type and content of additional ingredients, the type and dosage form of the composition, the type of subject to administration, age, and health condition. The description of the administration conditions for the active ingredient can be applied mutatis mutandis to the administration conditions of the composition of the present invention. That is, the composition of the present invention may be administered to subjects such as those exemplified above. Furthermore, the dosage of the composition of the present invention can be set so as to obtain the dosage of the active ingredient exemplified above. Furthermore, the composition of the present invention may be administered alone or in combination with additional ingredients.

[0114] <4> Method for producing aromatic lactic acid compounds The active ingredient can also be used in vitro. The active ingredient can be used, for example, in the production of aromatic lactic acid compounds. That is, another aspect of the present invention may be a method for producing aromatic lactic acid compounds, comprising culturing bacteria of the genus Bifidobacterium in a medium containing nucleic acid metabolites. The nucleic acid metabolites, Bifidobacterium bacteria, and aromatic lactic acid compounds are as described above. As the Bifidobacterium bacteria, bacteria capable of producing aromatic lactic acid compounds such as ILA may be selected.

[0115] The culture conditions are not particularly limited, as long as a culture medium containing nucleic acid metabolites is used and aromatic lactic acid compounds are produced. Regarding the culture conditions, the conditions for obtaining Bifidobacterium bacteria described above can be applied mutatis mutandis, except for the use of a culture medium containing nucleic acid metabolites. The culture medium may or may not contain carbon sources other than nucleic acid metabolites.

[0116] The concentration of nucleic acid metabolites in the culture medium is not particularly limited, as long as aromatic lactic acid compounds are produced. The concentration of nucleic acid metabolites in the culture medium may be, for example, 0.1% or more by weight, 0.2% or more by weight, 0.3% or more by weight, 0.5% or more by weight, 0.7% or more by weight, or 1% or more by weight, or 30% or less by weight, 20% or less by weight, 15% or less by weight, 10% or less by weight, 7% or less by weight, 5% or less by weight, 3% or less by weight, 2% or less by weight, or 1% or less by weight, and may be within a range of non-inconsistent combinations thereof. Specifically, the concentration of nucleic acid metabolites in the culture medium may be, for example, 0.1 to 30% by weight, preferably 0.2 to 20% by weight, and more preferably 0.5 to 10% by weight. Nucleic acid metabolites may be contained in the culture medium at the start of culture in the concentration ranges exemplified above, and / or may be added during culture to reach the concentration ranges exemplified above.

[0117] Nucleic acid metabolites may or may not be present in the culture medium for the entire duration of the culture. For example, nucleic acid metabolites may or may not be present in the culture medium at a predetermined concentration range, such as the concentration range exemplified above, for the entire duration of the culture. That is, nucleic acid metabolites may, for example, be present in the culture medium at a concentration other than the predetermined concentration range exemplified above, for a certain period. Nucleic acid metabolites may, for example, be deficient for a certain period. "Deficient" means that the required amount is not met, and for example, the concentration in the culture medium may be zero. For example, nucleic acid metabolites may or may not be present in the culture medium from the start of the culture. If nucleic acid metabolites are not present in the culture medium at the start of the culture, nucleic acid metabolites are supplied to the culture medium after the start of the culture. The timing of the supply can be appropriately set according to various conditions such as the culture time. Nucleic acid metabolites may, for example, be supplied to the culture medium after the Bifidobacterium bacteria have grown sufficiently. Also, for example, nucleic acid metabolites may be consumed during the culture and their concentration in the culture medium may become zero. "A portion of the culture period" could be, for example, 50% or less, 30% or less, 20% or less, 10% or less, 5% or less, or 1% or less of the total culture period. In this way, even if nucleic acid metabolites are deficient for a portion of the culture period, as long as there is a period of culture in a medium containing nucleic acid metabolites, it is still considered "cultivating Bifidobacterium bacteria in a medium containing nucleic acid metabolites." Nucleic acid metabolites may usually be present in the medium for at least the period during which the production of aromatic lactic acid compounds is desired.

[0118] By culturing Bifidobacterium bacteria in this manner, aromatic lactic acid compounds are produced, and a culture containing these aromatic lactic acid compounds is obtained.

[0119] The amount of aromatic lactic acid compounds produced when Bifidobacterium bacteria are cultured in a medium containing nucleic acid metabolites is, in order of increasing preference, 1.02 times or more, 1.04 times or more, 1.1 times or more, 1.15 times or more, 1.20 times or more, 1.25 times or more, 1.29 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, and 1.8 times or more, while a higher upper limit is preferable, for example, 10 times or less. For example, 1.02 times or more and 10 times or less, 1.04 times or more and 10 times or less, 1.1 times or more and 10 times or less, 1.15 times or more and 10 times or less, 1.20 times or more and 10 times or less, 1.25 times or more and 10 times or less, 1.29 times or more and 10 times or less, 1.3 times or more and 10 times or less, 1.4 times or more and 10 times or less, 1.5 times or more and 10 times or less, 1.6 times or more and 10 times or less, or 1.8 times or more and 10 times or less, etc.

[0120] The formation of aromatic lactic acid compounds can be confirmed, for example, by known methods used for the detection or identification of compounds. Such methods include HPLC, UPLC, LC / MS, GC / MS, and NMR.

[0121] Aromatic lactic acid compounds can be recovered from the culture (specifically from the culture medium) as appropriate. That is, the method for producing aromatic lactic acid compounds may further include recovering the aromatic lactic acid compounds from the culture. Recovery of aromatic lactic acid compounds can be carried out, for example, by known methods used for the separation and purification of compounds. Such methods include ion exchange resin methods, membrane treatment methods, precipitation methods, extraction methods, distillation methods, and crystallization methods. Aromatic lactic acid compounds may be purified to a desired purity.

[0122] <5> Methods to increase the production of aromatic lactic acid compounds by Bifidobacterium bacteria Another aspect of the present invention may be a method for increasing the production of aromatic lactic acid compounds by Bifidobacterium bacteria, comprising culturing Bifidobacterium bacteria in a medium containing nucleic acid metabolites. The nucleic acid metabolites, Bifidobacterium bacteria, and aromatic lactic acid compounds are as described above. As the Bifidobacterium bacteria, bacteria capable of producing aromatic lactic acid compounds such as ILA may be selected. The culture conditions and nucleic acid metabolites in the medium are as described above. The increased production of aromatic lactic acid compounds can be confirmed, for example, by comparing it to the case where Bifidobacterium bacteria are cultured in a medium that does not contain nucleic acid metabolites. The amount of aromatic lactic acid compounds produced when Bifidobacterium bacteria are cultured in a medium containing nucleic acid metabolites is, in order of increasing preference, 1.02 times or more, 1.04 times or more, 1.1 times or more, 1.15 times or more, 1.20 times or more, 1.25 times or more, 1.29 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, and 1.8 times or more, while a higher upper limit is preferable, for example, 10 times or less. For example, 1.02 times or more and 10 times or less, 1.04 times or more and 10 times or less, 1.1 times or more and 10 times or less, 1.15 times or more and 10 times or less, 1.20 times or more and 10 times or less, 1.25 times or more and 10 times or less, 1.29 times or more and 10 times or less, 1.3 times or more and 10 times or less, 1.4 times or more and 10 times or less, 1.5 times or more and 10 times or less, 1.6 times or more and 10 times or less, or 1.8 times or more and 10 times or less, etc. The formation of aromatic lactic acid compounds can be confirmed, for example, by known methods used for the detection or identification of compounds. Such methods include HPLC, UPLC, LC / MS, GC / MS, and NMR.

[0123] <6> Manufacturing methods for each composition Another aspect of the present invention may be a method for producing each application composition, comprising the steps of: culturing bacteria of the genus Bifidobacterium in a medium containing nucleic acid metabolites; recovering a fraction containing an aromatic lactic acid compound from the culture obtained in the culturing step; and formulating the fraction recovered in the recovery step as an active ingredient.

[0124] Aromatic lactic acid compounds are produced by culturing Bifidobacterium bacteria in a medium containing nucleic acid metabolites, thereby obtaining a culture containing aromatic lactic acid compounds. The nucleic acid metabolites, Bifidobacterium bacteria, and aromatic lactic acid compounds are as described above. As the Bifidobacterium bacteria, bacteria capable of producing aromatic lactic acid compounds such as ILA may be selected. The culture conditions and nucleic acid metabolites in the medium are as described above.

[0125] Aromatic lactic acid compounds can be recovered from the culture (specifically from the culture medium) as appropriate. That is, a fraction containing aromatic lactic acid compounds can be recovered from the culture obtained in the aforementioned culturing step. The recovery of aromatic lactic acid compounds is as described above.

[0126] The fraction recovered in the recovery process described above can be formulated as an active ingredient according to conventional methods (specifically, in the form of the compositions of the present invention described above) to create various application compositions. The applications are as described above. [Examples]

[0127] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Unless otherwise specified, percentages are expressed in weight (mass).

[0128] <Test Example 1> In Test Example 1, Bifidobacterium breve MCC1274 (FERM BP-11175) cells were cultured in a bacterial medium with the composition described later, and the production of aromatic lactic acid compounds was evaluated by measuring indole-3-lactic acid (ILA) and 3-phenyllactic acid (PLA) in the culture supernatant using LC-MS / MS.

[0129] (1) Preparation of bacterial culture supernatant Bifidobacterium breve MCC1274 (FERM BP-11175) was cultured anaerobically at 37°C for 16 hours using an aneropack kettle in MRS medium supplemented with 0.05% (v / v) cysteine ​​hydrochloride. The cells were then centrifuged (1,000 g, 5 min), and the precipitated cells were washed with PBS(-). 9 The compounds were resuspended in PBS(-) to a concentration of CFU / mL. Adenosine, inosine, uridine, and uracil were dissolved in purified water, xanthine in 1N sodium hydroxide aqueous solution, and hypoxanthine in dimethyl sulfoxide (DMSO). 1% bacterial cells were added to bacterial culture medium (YC medium) containing either 200 μM of each compound or equal amounts of the solvent for each compound (control group), and incubated at 37°C for 24 hours in an anaerobic chamber. The culture medium was then centrifuged to collect the supernatant, which was stored at -80°C until ready for quantification by LC-MS / MS. YC medium was prepared by dissolving the reagent of composition 1 below in purified water, sterilizing it in an autoclave (115°C, 20 min), and then adding the mixture of composition 2 below, which had been sterilized by filtering, and MES (final concentration 100 μM), and adjusting the pH to 7.5.

[0130] [Table 1]

[0131] (2) Determination of aromatic lactic acid compounds contained in the culture supernatant The culture supernatant was purified by mixing 5.4 mL of methanol with 600 μL of culture medium and removing the precipitate by centrifugation (10,000 × g, 5 min). The culture supernatant was dried using a vacuum evaporator and dissolved in 200 μL of ammonium formate (0.5 g / L) with the addition of an internal standard substance (1-methyl-2-oxindole). 5 μL of this supernatant was used for analysis. Subsequently, ILA and PLA in the culture medium were analyzed and quantified using LC-MS / MS (Vanquish HPLC connected with TSQ-FORTIS), XBridge® C8 column (Waters Corporation, Milford, MA, USA), and SRM (Selected Reaction Monitoring). For the separation of ILA and PLA, 0.5 g / L ammonium formate (mobile phase A) and acetonitrile (mobile phase B) were used as mobile phases, and the target compounds were analyzed under the gradient elution conditions shown in the table below.

[0132] [Table 2]

[0133] The results for ILA are shown in Figure 1, and the results for PLA are shown in Figure 2. It was revealed that the combined use of nucleic acid metabolites such as hypoxanthine and Bifidobacterium breve promotes the production of aromatic lactic acid compounds such as ILA and PLA.

[0134] <Test Example 2> In Test Example 2, the bacterial cells of Bifidobacterium longum subspecies infantis M-63 (NITE BP-02623) were cultured, and the amount of aromatic lactic acid compounds produced was evaluated by measuring indole-3-lactic acid (ILA) in the culture supernatant using LC-MS / MS.

[0135] (1) Preparation of bacterial culture supernatant Bifidobacterium longum subspecies infantis M-63 (NITE BP-02623) was used as the bacterial cell. Hypoxanthine was used as the nucleic acid metabolite, dissolved in a 1N sodium hydroxide solution, and the same procedure as in Test Example 1 was followed, except that 2% of the bacterial cell was added to the culture medium.

[0136] (2) Determination of ILA contained in the culture supernatant The same procedure as in Test Example 1 was followed.

[0137] The results are shown in Figure 3. The vertical axis in Figure 3 shows the peak intensity values ​​detected under LC-MS / MS analysis conditions. It was revealed that the combined use of hypoxanthine and Bifidobacterium longum subspecies infantis promotes ILA production.

[0138] <Test Example 3> In Test Example 3, the bacterial cells of Bifidobacterium breve M-16V (NITE BP-02622) were cultured, and the production of aromatic lactic acid compounds was evaluated by measuring indole-3-lactic acid (ILA) and 3-phenyllactic acid (PLA) in the culture supernatant using LC-MS / MS.

[0139] (1) Preparation of bacterial culture supernatant Bifidobacterium breve M-16V (NITE BP-02622) was used as the bacterial cell. Hypoxanthine was used as the nucleic acid metabolite, dissolved in a 1N sodium hydroxide solution, and 2% of the bacterial cell was added to the culture medium. The procedure was the same as in Test Example 1 above, except that the incubation period was 12 hours.

[0140] (2) Determination of ILA and PLA contained in the culture supernatant The same procedure as in Test Example 1 was followed.

[0141] The results for ILA are shown in Figure 4, and the results for PLA are shown in Figure 5. The vertical axis in Figures 4 and 5 shows the peak intensity values ​​detected under LC-MS / MS analysis conditions. It was revealed that the combined use of hypoxanthine and Bifidobacterium breve promotes the production of both ILA and PLA.

[0142] The results above clearly show that the combined use of nucleic acid metabolites such as hypoxanthine and Bifidobacterium bacteria such as Bifidobacterium breve and Bifidobacterium longum subspecies infantis promotes the production of aromatic lactic acid compounds such as ILA and PLA.

[0143] <Manufacturing example> The following are examples of compositions manufactured according to the present invention, but the compositions of the present invention are not limited to those manufactured according to these examples.

[0144] [Manufacturing Example 1] Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623, in MRS liquid medium (Difco TMAdd the mixture to 3 mL of Lactobacill MRS Broth (model number 288130), culture anaerobically at 32-39°C for 5-25 hours, concentrate the culture solution, and freeze-dry it to obtain freeze-dried bacterial powder (i.e., bacterial powder). Mix the bacterial powder and whey protein concentrate (WPC) uniformly to obtain a composition. Dissolve 20 g of this composition in 200 g of water to obtain a composition containing one of the following: Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623. The obtained composition can be used as a composition to promote the production of aromatic lactic acid compounds when combined with foods such as vegetables and fish. Furthermore, by ingesting the obtained composition as is, it is expected to act with nucleic acids or nucleic acid metabolites in the intestines to promote the production of aromatic lactic acid compounds in the intestines.

[0145] [Manufacturing Example 2] The following describes the method for producing infant formula to which one of the following is added: Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623. Dissolve 10 kg of desalted milk whey protein powder (Mirai Co., Ltd.), 6 kg of milk casein powder (Fonterra Co., Ltd.), 48 kg of lactose (Mirai Co., Ltd.), 920 g of mineral mixture (Tomita Pharmaceutical Co., Ltd.), 32 g of vitamin mixture (Tanabe Seiyaku Co., Ltd.), 500 g of lactulose (Morinaga Milk Industry Co., Ltd.), 500 g of raffinose (Nippon Beet Sugar Manufacturing Co., Ltd.), and 900 g of galactooligosaccharide liquid sugar (Yakult Pharmaceutical Industry Co., Ltd.) in 300 kg of warm water, and further heat and dissolve at 90°C for 10 minutes. Then, add 28 kg of prepared fat (Taiyo Yushi Co., Ltd.) and homogenize. After that, sterilization and concentration processes are carried out and spray-dried to prepare approximately 95 kg of prepared milk powder. To this, add one of the following bacterial cells (1.8 × 10) dispersed in starch: Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623. 11 Add 100g of Bifidobacterium and oligosaccharide-containing formula milk powder (CFU / g, manufactured by Morinaga Milk Industry Co., Ltd.) to prepare approximately 95kg of formula milk powder. When the prepared formula milk powder is dissolved in water to make a formula solution with a total solids content of 14% (w / V), which is the standard formula milk concentration, the number of Bifidobacterium in the formula solution is 10 6 ~10 9 The concentration is CFU / 100mL.

[0146] The prepared milk powder containing Bifidobacterium bacteria obtained as described above can be used as a composition for promoting the production of aromatic lactic acid compounds when combined with foods such as vegetables and fish. The prepared milk powder containing Bifidobacterium bacteria obtained as described above can be further used as a composition for promoting the production of aromatic lactic acid compounds by adding nucleic acid metabolites such as sodium cytidylate, sodium inosinate, sodium guanylate, sodium uridylate, and adenylic acid. Furthermore, ingesting the prepared milk powder as is can be expected to promote the production of aromatic lactic acid compounds in the intestines by acting on nucleic acids or nucleic acid metabolites in the intestines.

Claims

1. A composition for promoting the production of aromatic lactic acid compounds, comprising the following components (A) and (B), wherein the aromatic lactic acid compound is indole-3-lactic acid or 3-phenyllactic acid: (A) Xanthine or hypoxanthine; (B) Bifidobacterium breve FERM BP-11175, Bifidobacterium breve Benite BP-02622, or Bifidobacterium longum subspecies inf FANTIS NITE BP-02623.

2. The composition according to claim 1, wherein the composition is a food or beverage composition.

3. The composition according to claim 1, wherein the composition is a pharmaceutical composition.

4. Culturing Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623 in a medium containing xanthine or hypoxanthine. A method for producing indole-3-lactic acid or 3-phenyllactic acid, including the above.

5. Culturing Bifidobacterium breve FERM BP-11175, Bifidobacterium breve NITE BP-02622, or Bifidobacterium longum subspecies infantis NITE BP-02623 in a medium containing xanthine or hypoxanthine. A method for increasing the production of indole-3-lactic acid or 3-phenyllactic acid by bacteria of the genus Bifidobacterium, including the above.

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