Composition for improving inflammation of brain tissue

Abstract

This composition comprises a lactic acid bacteria belonging to the genus Lactobacillus, and intake of the composition by a subject improves inflammation in the brain tissue of the subject.

Description

Composition for ameliorating inflammation in brain tissue REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to an earlier filed Japanese patent application, Patent Application No. 2020-208555 (filing date: December 16, 2020), the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a composition for ameliorating inflammation in brain tissue.

[0003] The brain is the center of the nervous system in animals and is the organ that controls the animal's vital activities. It is known that abnormalities in the brain can disrupt not only physical activity but also mental activity. Inflammation of brain tissue is known to be one of the causes of brain abnormalities, and research is underway to identify the causes of inflammation and ways to improve it.

[0004] Inflammation of brain tissue may affect various brain functions, and may be a factor in brain dysfunction such as a decline in higher brain functions and the induction of mental disorders and mood disorders (e.g., Non-Patent Document 1).

[0005] On the other hand, research and development of various therapeutic drugs for these brain dysfunctions is underway, but most of these are symptomatic treatments for the causes of organic brain damage, and the current situation is that they cannot be said to be sufficient methods for improving or ameliorating these brain dysfunctions.

[0006] Although there has been some knowledge about the relationship between lactic acid bacteria and improvement of brain function (e.g., Patent Documents 1 to 3), there has been no report on the relationship between lactic acid bacteria and changes in the amount of cytokines in brain tissue, particularly inflammatory cytokines that cause inflammation, and the relationship between the two was essentially unknown. In particular, it was not known that ingestion of lactic acid bacteria can reduce the amount of inflammatory cytokines in the brain tissue of a subject, or that it can improve brain dysfunction such as a decline in higher brain function, mental disorders, and mood disorders in the subject.

[0007] Inflammation of brain tissue can be a factor in brain dysfunction such as a decline in higher brain function, mental disorders, and mood disorders, and therefore there is a need for a method for effectively ameliorating inflammation of brain tissue.

[0008] International Publication No. 2017 / 179602 Special Publication No. 2018-531595 Special Publication No. 2015-526085

[0009] Akira Moji, Special Feature: The Frontiers of Pathological Research on Psychiatry: Neuroinflammatory Hypothesis of Psychiatry, Journal of Psychiatry and Neurology, Vol. 114, No. 2, pp. 124-133, 2012

[0010] An object of the present invention is to provide a composition useful for ameliorating inflammation in a subject, particularly a composition useful for ameliorating inflammation in brain tissue of a subject.

[0011] As a result of intensive research, the present inventors have found that when lactic acid bacteria belonging to the genus Lactobacillus are administered to a subject, the amount of cytokines that are suggested to be related to inflammation can be effectively reduced in the subject, particularly in the brain tissue of the subject.The present invention is based on these findings.

[0012] The present invention provides the following: [1] A composition for suppressing inflammation in brain tissue, comprising lactic acid bacteria belonging to the genus Lactobacillus. [2] The composition according to [1], wherein the brain tissue is hippocampus. [3] The composition according to [1] or [2], which is for improving a disorder caused by inflammation in brain tissue. [4] The composition according to [3], wherein the disorder is at least one disorder selected from the group consisting of psychiatric disorders and mood disorders. [5] The composition according to [3], wherein the disorder is a higher brain dysfunction disorder. [6] The composition according to [5], wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function. [7] The composition according to [5] or [6], which is for improving a disease caused by the higher brain dysfunction. [8] The composition according to [7], wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder. [9] The composition according to any one of [1] to [8], wherein the lactic acid bacterium has activity to reduce the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemotactic factor-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue.

[10] The composition according to [9], wherein the brain tissue is hippocampus.

[11] A composition for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemotactic factor-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue, comprising lactic acid bacteria belonging to the genus Lactobacillus.

[12] The composition according to

[11] , wherein the brain tissue is hippocampus.

[13] A composition for reducing the amount of interleukin-17, comprising lactic acid bacteria belonging to the genus Lactobacillus.

[14] A composition for improving at least one disorder selected from the group consisting of psychiatric disorders, mood disorders, and higher brain dysfunction, comprising lactic acid bacteria belonging to the genus Lactobacillus.

[15] The composition described in

[14] , wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function.

[16] The composition described in

[14] or

[15] , for improving a disease caused by the higher brain dysfunction.

[17] The composition described in

[16] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[18] The composition described in any of [1] to

[17] , wherein the lactic acid bacteria comprise lactic acid bacteria belonging to Lactobacillus plantarum.

[19] The composition according to any one of [1] to

[18] , wherein the lactic acid bacterium has a 16S rRNA gene that is 90% or more identical to the base sequence represented by SEQ ID NO: 1.

[20] The composition according to any one of [1] to

[19] , wherein the lactic acid bacterium is Lactobacillus plantarum OLL2712 strain deposited under accession number FERM BP-11262.

[21] The composition according to any one of [1] to

[20] , wherein the lactic acid bacterium comprises killed cells of the lactic acid bacterium.

[22] The composition according to any one of [1] to

[21] , wherein the lactic acid bacterium comprises heat-killed cells.

[23] The composition according to any one of [1] to

[22] , wherein the composition is a food composition.

[24] The composition according to any one of [1] to

[22] , wherein the composition is a pharmaceutical composition.

[25] A method for suppressing inflammation in brain tissue of a subject, comprising administering to the subject an effective amount of lactic acid bacteria belonging to the genus Lactobacillus.

[26] A method for improving damage caused by inflammation in brain tissue of a subject, comprising having the subject ingest an effective amount of lactic acid bacteria belonging to the genus Lactobacillus.

[27] A method for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in the brain tissue of a subject, comprising administering to the subject an effective amount of lactic acid bacteria belonging to the genus Lactobacillus.

[28] A method for improving at least one disorder selected from the group consisting of psychiatric disorders, mood disorders, and higher brain dysfunction in a subject, comprising administering to the subject an effective amount of lactic acid bacteria belonging to the genus Lactobacillus.

[29] The method according to

[28] , wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function.

[30] The method according to

[28] or

[29] , for improving a disease caused by the higher brain dysfunction.

[31] The method according to

[30] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[32] Use of lactic acid bacteria belonging to the genus Lactobacillus for the manufacture of a composition for suppressing inflammation in brain tissue.

[33] The use according to

[32] , wherein the brain tissue is hippocampus.

[34] The use according to

[32] or

[33] , wherein the composition is for ameliorating disorders caused by inflammation in brain tissue.

[35] The use according to

[34] , wherein the disorder is at least one disorder selected from the group consisting of psychiatric disorders and mood disorders.

[36] The use according to

[35] , wherein the disorder is a higher brain dysfunction disorder.

[37] The use according to

[36] , wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention function, cognitive function, memory function, executive function, and learning function.

[38] The use described in

[36] or

[37] , wherein the composition is a composition for improving a disease caused by the higher brain dysfunction.

[39] The use according to

[38] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[40] The use of any of

[32] to

[39] , wherein the lactic acid bacterium has activity to reduce the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue.

[41] The use of the lactic acid bacterium according to

[40] , wherein the brain tissue is hippocampus.

[42] Use of lactic acid bacteria belonging to the genus Lactobacillus for the manufacture of a composition for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue.

[43] Use of the lactic acid bacteria according to

[42] , wherein the brain tissue is hippocampus.

[44] Use of lactic acid bacteria belonging to the genus Lactobacillus for the manufacture of a composition for reducing the amount of interleukin-17.

[45] Use of lactic acid bacteria belonging to the genus Lactobacillus for the manufacture of a composition for ameliorating disorders caused by inflammation in brain tissue.

[46] Use of lactic acid bacteria belonging to the genus Lactobacillus for the manufacture of a composition for ameliorating at least one disorder selected from the group consisting of psychiatric disorders, mood disorders, and higher brain dysfunction.

[47] The use according to

[46] , wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention function, cognitive function, memory function, executive function, and learning function.

[48] The use according to

[46] or

[47] , wherein the composition is a composition for ameliorating a disease caused by the higher brain dysfunction.

[49] The use according to

[48] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[50] A lactic acid bacterium belonging to the genus Lactobacillus for suppressing inflammation in brain tissue.

[51] A lactic acid bacterium belonging to the genus Lactobacillus for ameliorating disorders caused by inflammation in brain tissue.

[52] A lactic acid bacterium belonging to the genus Lactobacillus for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue.

[53] A lactic acid bacterium belonging to the genus Lactobacillus for ameliorating at least one disorder selected from the group consisting of psychiatric disorders, mood disorders, and higher brain dysfunction.

[54] The lactic acid bacterium of the genus Lactobacillus according to

[53] , wherein the higher brain dysfunction is a dysfunction of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function.

[55] The lactic acid bacterium of the genus Lactobacillus according to

[53] or

[54] , for ameliorating a disease caused by the higher brain dysfunction.

[56] The lactic acid bacterium of the genus Lactobacillus according to

[55] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[57] Use of lactic acid bacteria of the genus Lactobacillus for suppressing inflammation in brain tissue.

[58] Use of lactic acid bacteria of the genus Lactobacillus for ameliorating a disorder caused by inflammation in brain tissue.

[59] Use of lactic acid bacteria belonging to the genus Lactobacillus for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue.

[60] Use of lactic acid bacteria belonging to the genus Lactobacillus for improving at least one disorder selected from the group consisting of psychiatric disorders, mood disorders, and higher brain dysfunction.

[61] Use of the lactic acid bacteria belonging to the genus Lactobacillus according to

[60] , wherein the higher brain dysfunction is a disorder of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function.

[62] Use of the lactic acid bacteria belonging to the genus Lactobacillus according to

[60] or

[61] , for improving a disease caused by the higher brain dysfunction.

[63] Use of the lactic acid bacteria belonging to the genus Lactobacillus according to

[62] , wherein the disease is selected from the group consisting of Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, and memory disorder.

[0013] According to the present invention, by administering lactic acid bacteria belonging to the genus Lactobacillus to a subject, the amount of specific cytokines that are suggested to be related to inflammation in the subject, particularly in the brain tissue of the subject, can be effectively reduced.Therefore, according to the present invention, inflammation in the subject, particularly in the brain tissue of the subject, can be effectively suppressed. Specific Description of the Invention

[0014] Composition for suppressing inflammation in brain tissue According to one aspect of the present invention, a composition for suppressing inflammation in brain tissue (hereinafter also referred to as the "composition of the present invention") is provided, which comprises lactic acid bacteria belonging to the genus Lactobacillus (hereinafter also referred to as "Lactobacillus lactic acid bacteria" or "lactic acid bacteria").

[0015] According to one embodiment of the present invention, the subject to which the composition of the present invention is applied is not particularly limited as long as the effects of the present invention are achieved, and may be, for example, mammals such as humans, monkeys, chimpanzees, cattle, horses, sheep, and goats, preferably humans. The subject may also be a subject experiencing inflammation, particularly inflammation in brain tissue, or a subject in which inflammation in brain tissue should be prevented. In one embodiment, when the subject to which the composition of the present invention is applied is a human, the age of the subject is not particularly limited, but is preferably 45 years of age or older, more preferably 50 years of age or older, even more preferably 60 years of age or older, and particularly preferably 65 years of age or older. In another embodiment, the subject to which the composition of the present invention is applied may be a human with mild cognitive impairment (MCI). In this case, the age of the subject to which the composition of the present invention is applied is not particularly limited.

[0016] As used herein, "brain tissue" refers to the entire brain or a partial region of the brain to which the composition of the present invention is applied. According to a preferred embodiment of the present invention, the "brain tissue" includes the hippocampus. That is, according to a preferred embodiment of the present invention, the composition for inhibiting inflammation in brain tissue of the present invention is a composition for ameliorating inflammation in the hippocampus.

[0017] As used herein, "suppression" of inflammation includes "treatment" and "prevention" of inflammation. "Treatment" of inflammation includes not only stopping, alleviating, or delaying the progress or worsening of inflammation through medical intervention, but also stopping, alleviating, or delaying the progress or worsening of inflammation through non-medical intervention. "Prevention" of inflammation also includes preparing in advance for anticipated worsening of inflammation and preventing the onset or recurrence of inflammation through medical or non-medical intervention.

[0018] According to a preferred embodiment of the present invention, the Lactobacillus lactic acid bacteria contained in the composition of the present invention have activity to reduce the level of at least one of inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-9, IL-12, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), and tumor necrosis factor-α (TNF-α). According to another preferred aspect, the Lactobacillus lactic acid bacteria contained in the composition of the present invention have activity to reduce the level of at least one of the above-mentioned inflammatory cytokines in brain tissue. According to yet another aspect, the Lactobacillus lactic acid bacteria contained in the composition of the present invention have activity to reduce the level of at least one of the above-mentioned inflammatory cytokines in the hippocampus.

[0019] In this specification, "having reducing activity" in relation to inflammatory cytokine means that when a subject is stimulated with Lactobacillus lactic acid bacteria or a composition comprising said lactic acid bacteria, the amount of inflammatory cytokines in the stimulated subject, particularly in the brain tissue of said subject, tends to be reduced, preferably statistically significantly (i.e., beyond the margin of error), compared with the subject that has not been stimulated.In addition, the measurement of the amount of inflammatory cytokines and the determination of whether or not there is the activity of reducing the amount of inflammatory cytokines can be carried out, for example, by the method shown in Examples.In addition, the statistical analysis of the amount of inflammatory cytokines can be carried out by using statistical analysis methods known to those skilled in the art.Specifically, the statistical analysis of the amount of inflammatory cytokines can be carried out by t-test.

[0020] The composition for suppressing inflammation in brain tissue of the present invention can effectively suppress inflammation in brain tissue, and therefore can be used to improve disorders and diseases caused by inflammation in brain tissue, particularly disorders and diseases caused by inflammation in the hippocampus. Therefore, according to another aspect of the present invention, there is provided a composition for improving disorders and diseases caused by inflammation in brain tissue, such as a decline in higher brain functions, mental disorders, and mood disorders, as described below.

[0021] Composition for improving higher brain dysfunction According to one aspect of the present invention, there is provided a composition for improving a decline in higher brain function (i.e., higher brain dysfunction), comprising Lactobacillus lactic acid bacteria.

[0022] The subject to which the composition for improving higher brain dysfunction of the present invention is applied can be the same as that described for the composition for suppressing inflammation in brain tissue of the present invention. Furthermore, the subject to which the composition is applied may be a subject with normal higher brain function, or a subject with impaired higher brain function (a subject with a disorder in higher brain function).

[0023] As used herein, "improving higher brain function disorders" encompasses not only "improving higher brain function," but also "maintaining higher brain function" and "preventing decline in higher brain function." Furthermore, "improving higher brain function" encompasses promoting recovery from a state in which higher brain function has declined due to inflammation associated with aging or brain disease (e.g., ischemic strokes such as cerebral infarction and transient ischemic attack, hemorrhagic strokes such as cerebral hemorrhage and subarachnoid hemorrhage, and traumatic diseases such as concussion and cerebral contusion). Furthermore, "maintaining higher brain function" encompasses maintaining higher brain function in a healthy state. Furthermore, "preventing decline in higher brain function" encompasses preventing decline in healthy higher brain function and preventing further decline in declined higher brain function. Examples of higher brain functions include selective attention, cognitive function, memory function, executive function, learning, language, and calculation function. In addition, disorders caused by a decline in higher brain function include, for example, unilateral somatosensory agnosia, topographical disorder, agnosia, aphasia, memory disorder, mild cognitive impairment, apraxia, attention disorder, executive dysfunction, and behavioral and emotional disorders.

[0024] The composition for improving higher brain dysfunction of the present invention can improve higher brain dysfunction and therefore can be used to improve diseases caused by higher brain dysfunction. Examples of diseases caused by disorders of higher brain function include dementia such as Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, as well as amnesic syndrome, generalized attention disorder, social behavior disorder, and memory impairment. As used herein, "improvement" of a disease or disorder encompasses "treatment" and "prevention" of the disease or disorder. Furthermore, "treatment" of a disease or disorder encompasses not only stopping, alleviating, or delaying the progression or worsening of the disease or disorder through medical intervention, but also stopping, alleviating, or delaying the progression or worsening of the disease or disorder through non-medical intervention. Furthermore, "prevention" of a disease or disorder encompasses preparing for anticipated worsening of the disease or disorder and preventing the onset or recurrence of the disease or disorder through medical or non-medical intervention.

[0025] According to a preferred embodiment of the present invention, the composition for improving higher brain function disorders of the present invention is a composition for improving higher brain function disorders, treating higher brain function disorders, preventing higher brain function disorders, improving higher brain function, improving higher brain function, maintaining higher brain function, suppressing decline in higher brain function, improving diseases or disorders caused by decline in higher brain function (e.g., dementia such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder, memory disorder, etc.), treating diseases or disorders caused by decline in higher brain function, preventing diseases or disorders caused by decline in higher brain function, improving cognitive function, improving cognitive function, suppressing decline in cognitive function, suppressing an increase in the risk of dementia, reducing the risk of dementia, improving memory function, maintaining memory function, or suppressing decline in memory function.

[0026] Composition for Improving Mental Disorders According to another aspect of the present invention, there is provided a composition for improving mental disorders, comprising Lactobacillus lactic acid bacteria.

[0027] The subject to which the composition for improving a mental disorder of the present invention is applied can be the same as that described for the composition for suppressing inflammation in brain tissue of the present invention. Furthermore, the subject to which the composition is applied may be a subject with normal (healthy) mental function (mental state) (i.e., without mental function disorder) or a subject with abnormal mental function (i.e., with mental function disorder).

[0028] Mental disorders, also known as "mental illnesses," have no unified definition, but are defined, for example, as psychological syndromes accompanied by distress or abnormalities. Mental disorders refer, for example, to disorders classified among F09 to F99 in Chapter 5, "Mental and Behavioral Disorders," of the "International Statistical Classification of Diseases and Related Health Problems, 10th Edition," of the World Health Organization (WHO), particularly those classified other than F30 to F39, "Mood (Affective) Disorders." More specifically, these disorders and illnesses include schizophrenia, epilepsy, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, intellectual disability, personality disorder, eating disorders, sleep disorders, and adjustment disorders.

[0029] As used herein, "ameliorating a mental disorder" encompasses not only the meaning of "treating a mental disorder" but also the meaning of "preventing a mental disorder." Furthermore, "treating a mental disorder" encompasses promoting recovery from a mental disorder caused by inflammation associated with aging or brain disease (e.g., ischemic stroke such as cerebral infarction and transient ischemic attack, hemorrhagic stroke such as cerebral hemorrhage and subarachnoid hemorrhage, and traumatic diseases such as cerebral concussion and cerebral contusion). Furthermore, "preventing a mental disorder" encompasses maintaining normal mental function, preventing further impairment from occurring due to impaired mental function, and the like.

[0030] According to a preferred embodiment of the present invention, the composition for improving a mental disorder of the present invention is a composition for improving a mental disorder, treating a mental disorder, preventing a mental disorder, treating schizophrenia, epilepsy, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, intellectual disability, personality disorder, eating disorder, sleep disorder and / or adjustment disorder, or preventing schizophrenia, epilepsy, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, intellectual disability, personality disorder, eating disorder, sleep disorder and / or adjustment disorder.

[0031] Composition for Improving Mood Disorders According to another aspect of the present invention, there is provided a composition for improving mood disorders, comprising Lactobacillus lactic acid bacteria.

[0032] The subject to which the composition for improving mood disorders of the present invention is applied may be the same as that described for the composition for suppressing inflammation in brain tissue of the present invention. Furthermore, the subject may be a subject with a normal (healthy) mood state (emotional state) (i.e., not having a mood disorder) or a subject with an abnormal mood state (i.e., having a mood disorder).

[0033] Mood disorders, also known as "affective disorders," refer to mental disorders, particularly those related to mood. While there is no unified definition of mood disorders, they are defined, for example, as a state in which a person feels distress or experiences difficulty in daily life due to mood (emotion) disturbances that persist for a certain period of time. Examples of mood disorders include those classified as "Mood (Affective) Disorders" in Chapter 5, "Mental and Behavioral Disorders," of the WHO's "International Statistical Classification of Diseases and Related Health Problems, 10th Edition," under categories F30 to F39. More specifically, these disorders and illnesses include depression, mania, bipolar disorder, mixed episode, and substance-induced mood disorder.

[0034] As used herein, "improving mood disorders" encompasses not only the meaning of "treating mood disorders" but also the meaning of "preventing mood disorders." Furthermore, "treating mood disorders" encompasses promoting recovery from mood disorders caused by inflammation associated with aging or brain diseases (e.g., ischemic strokes such as cerebral infarction and transient ischemic attack, hemorrhagic strokes such as cerebral hemorrhage and subarachnoid hemorrhage, and traumatic diseases such as cerebral concussion and cerebral contusion). Furthermore, "preventing mood disorders" encompasses maintaining a normal mood state, preventing the onset of further disorders from a disturbed mood state, and the like.

[0035] According to a preferred embodiment of the present invention, the composition for improving mood disorders of the present invention is a composition for improving mood disorders, treating mood disorders, preventing mood disorders, improving depression, treating depression, preventing depression, suppressing an increased risk of depression, reducing the risk of depression, improving mania, improving bipolar disorder, improving mixed episodes, or improving substance-induced mood disorders.

[0036] Composition for reducing the amount of inflammatory cytokines According to another aspect of the present invention, there is provided a composition for reducing the amount of inflammatory cytokines, comprising Lactobacillus lactic acid bacteria. According to a preferred embodiment, the composition for reducing the amount of inflammatory cytokines of the present invention reduces the amount of inflammatory cytokines in brain tissue. According to a further preferred embodiment, the composition for reducing the amount of inflammatory cytokines of the present invention reduces the amount of inflammatory cytokines in the hippocampus.

[0037] Examples of inflammatory cytokines whose amounts are reduced by the composition for reducing the amount of a proinflammatory cytokine of the present invention include IL-1, IL-6, IL-9, IL-12, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1, and TNF-α. That is, according to a preferred embodiment, the composition for reducing the amount of a proinflammatory cytokine of the present invention reduces the amount of at least one of the above-mentioned inflammatory cytokines. In a preferred embodiment, the composition for reducing the amount of a proinflammatory cytokine of the present invention reduces the amount of IL-17.

[0038] According to a preferred embodiment, the composition of the present invention for reducing the amount of inflammatory cytokines is a composition for suppressing the production of inflammatory cytokines in brain tissue, particularly the production of inflammatory cytokines in the hippocampus.

[0039] The inflammatory cytokines whose production is inhibited by the composition for inhibiting inflammatory cytokine production of the present invention are the same as the inflammatory cytokines described above. That is, according to a preferred embodiment, the composition for inhibiting inflammatory cytokine production of the present invention inhibits the production of at least one of the above-mentioned inflammatory cytokines. In a preferred embodiment, the composition for inhibiting inflammatory cytokine production of the present invention inhibits the production of IL-17.

[0040] Specific examples of Lactobacillus lactic acid bacteria contained in the composition of the present invention include Lactobacillus delbrueckii subsp. burgaricus, Lactobacillus delbrueckii subsp. lactis, Lactobacillus casei, Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus amylovorus, Lactobacillus gallinarum, Lactobacillus gasseri, and Lactobacillus oris. oris), Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus fermentum, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus pentosus, Lactobacillus paraplantarum, Lactobacillus paracollinoides, Lactobacillus hammesii, etc. Among these Lactobacillus lactic acid bacteria, Lactobacillus plantarum is preferably used, and Lactobacillus plantarum OLL2712 strain is more preferably used. In this specification, "lactic acid bacteria belonging to the genus Lactobacillus" meansThe article "A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Lactobacillus cereus" was published in the INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY, Volume 70, Issue 4, on April 15, 2020. The 25 genera newly established by the reorganization of lactic acid bacteria published in the "Leuconostocaceae" include the genera Lactobacillus, Paralactobacillus, Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, and Loigolactobacillus. Lacticaseibacillus genus, Lacticaseibacillus genus, Latilactobacillus genus, Dellaglioa genus, Liquorilactobacillus genus, Ligilactobacillus genus, Lactiplantibacillus genus, Furfurilactobacillus genus, Paucilactobacillus genus, Limosilactobacillus genus, Fructilactobacillus genus, Acetilactobacillus genus,It refers to lactic acid bacteria belonging to any of the genera Apilactobacillus, Levilactobacillus, Secundilactobacillus and Lentilactobacillus. Among the lactic acid bacteria belonging to the above-mentioned reorganized genera, in the present invention, preferably, lactic acid bacteria belonging to any of the genera Lactobacillus, Lacticaseibacillus, Lactiplantibacillus, Liquorilactobacillus, Limosilactobacillus and Levilactobacillus are used. Note that, according to the classification after the above-mentioned reorganization, the conventional Lactobacillus plantarum is classified into the genus Lactiplantibacillus and is called Lactiplantibacillus plantarum.

[0041] The Lactobacillus plantarum OLL2712 strain was deposited at the International Patent Organism Depositary of the National Institute of Advanced Industrial Science and Technology (6 Central, 1-1-1 Higashi, Tsukuba City, Ibaraki Prefecture, Japan) on July 2, 2010, and was subsequently transferred to international deposition and assigned the accession number FERM BP-11262. As described in Budapest Notification No. 282 (http: / / www.wipo.int / treaties / en / notifications / budapest / treaty_budapest_282.html), the National Institute of Technology and Evaluation (IPOD, NITE) has taken over the patent microorganism deposit business from the National Institute of Advanced Industrial Science and Technology (AIST), and therefore the Lactobacillus plantarum OLL2712 strain is currently deposited at the National Institute of Technology and Evaluation (IPOD, NITE) (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture) under the deposit number FERM BP-11262.

[0042] The Lactobacillus lactic acid bacteria contained in the composition of the present invention can also be substantially the same strain as the deposited strain.It is surprising to those skilled in the art that the deposited strain and substantially the same strain can reduce the amount of inflammatory cytokines in brain tissue, especially in the hippocampus.Substantially the same strain refers to, for example, the above-mentioned Lactobacillus lactic acid bacteria strain, whose 16S rRNA gene base sequence has 90% or more, preferably 95% or more, more preferably 98% or more, and even more preferably 99% or more homology with the 16S rRNA gene base sequence (SEQ ID NO: 1) of the deposited strain, and preferably has the same bacteriological properties as the above-mentioned strain.The strain with the same bacteriological properties is preferably a strain that has the same activity as the deposited strain in terms of reducing the amount of inflammatory cytokines in the brain tissue of a subject (e.g., human), especially in the hippocampus. Furthermore, the Lactobacillus lactic acid bacteria contained in the composition of the present invention may be a strain bred from a deposited strain or a strain substantially equivalent thereto by mutation treatment, genetic recombination, selection of natural mutant strains, etc., as long as the effects of the present invention are achieved.

[0043] The Lactobacillus lactic acid bacteria contained in the composition of the present invention include not only the Lactobacillus lactic acid bacteria themselves, but also, for example, cultures containing Lactobacillus lactic acid bacteria. As the Lactobacillus lactic acid bacteria, either live or killed cells can be used, but killed cells are preferred, and more preferably killed cells obtained by heat-treating live cells (heat-killed cells). That is, the Lactobacillus lactic acid bacteria contained in the composition of the present invention preferably include killed cells, more preferably heat-killed cells. In addition, the passage number of the Lactobacillus lactic acid bacteria is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 1 to 30, preferably 5 to 15, more preferably 11 to 13.

[0044] The conditions for culturing Lactobacillus lactic acid bacteria are not particularly limited as long as the effects of the present invention are achieved, and can be the conditions commonly used for culturing lactic acid bacteria. For example, the medium may be prepared by dissolving whey powder and whey protein concentrate in sterilized water, digesting them with protease A, and then adding yeast extract, fish extract, and MnSO. ４ The medium can be used by adding various nutrients (vitamins, minerals, fatty acid esters), adjusting the pH to 6.7 with NaOH, and then sterilizing by autoclaving. The pH during cultivation can be set to 4.8 to 6.8. The pH can be adjusted by adding K ２ CO ３ The temperature during cultivation can be set to 29 to 40°C.

[0045] The heat treatment for obtaining heat-killed cells of Lactobacillus lactic acid bacteria is not particularly limited as long as the effects of the present invention are achieved, and the heat treatment is carried out under conditions that are commonly used to sterilize lactic acid bacteria.

[0046] In addition to the above-mentioned heat treatment, Lactobacillus lactic acid bacteria may also be used that have been subjected to treatments such as concentration, dilution, freezing, drying, or powdering.

[0047] The Lactobacillus lactic acid bacteria contained in the composition of the present invention may be those prepared by the above-mentioned culture or various treatments, or commercially available compositions containing Lactobacillus lactic acid bacteria may be used.

[0048] In the composition of the present invention, the number of Lactobacillus lactic acid bacteria per mass of the composition is not particularly limited as long as the effects of the present invention are exhibited. ６ ~10 １３ pieces / g, more preferably 10 ６ ~1 x 10 １２ pcs / g, more preferably 10 ７ ~10 １１ pieces / g, and even more preferably 10 ８ ~10 １１ Particularly preferably 10 pieces / g ８ ~10 １０In the composition of the present invention, the dry mass of bacterial cells per mass of solids in the composition is preferably 0.01 to 100% by mass, more preferably 1 to 80% by mass, and even more preferably 10 to 40% by mass.

[0049] The composition of the present invention may contain components other than Lactobacillus lactic acid bacteria, as long as they do not impair the effects of the present invention. Examples of components other than Lactobacillus lactic acid bacteria include medium components, additives suitable for oral tube administration, solvents such as water, carbohydrates, proteins, lipids, vitamins, minerals, biologically essential trace metals (manganese sulfate, zinc sulfate, magnesium chloride, potassium carbonate, etc.), flavorings, hygienically or pharmaceutically acceptable carriers, food additives, etc.

[0050] Examples of carbohydrates include sugars, modified starch (dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.

[0051] Examples of proteins include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lactoglobulin, α-lactalbumin, lactoferrin, soy protein, egg protein, meat protein and other animal and plant proteins, hydrolysates thereof, butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipids, lactose and other milk-derived components.

[0052] Examples of lipids include animal fats and oils such as lard, fish oil, and fractionated, hydrogenated, and interesterified oils thereof; and vegetable fats and oils such as palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated, hydrogenated, and interesterified oils thereof.

[0053] Examples of vitamins include vitamin A, carotenes, B vitamins, vitamin C, D vitamins, vitamin E, K vitamins, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, and folic acid.

[0054] Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium.

[0055] The composition of the present invention can be produced by blending the Lactobacillus lactic acid bacteria with the above-mentioned pharmaceutically acceptable carriers and / or additives, food hygiene acceptable carriers and / or additives, etc.Therefore, according to one aspect of the present invention, there is provided a method for producing a composition for suppressing inflammation of brain tissue, which comprises blending Lactobacillus lactic acid bacteria.In addition, according to another aspect of the present invention, there is provided a method for producing a composition for improving higher brain dysfunction, a composition for improving mental disorder or a composition for improving mood disorder, which comprises the same steps as above.

[0056] According to a preferred embodiment of the present invention, the composition of the present invention contains fermented milk in addition to Lactobacillus lactic acid bacteria. Ingesting both Lactobacillus lactic acid bacteria and fermented milk in a subject is particularly advantageous in reducing the amount of cytokines, which have been suggested to be related to the suppression of inflammation, in brain tissues such as the hippocampus. Such fermented milk is not particularly limited as long as it can achieve the effects of the present invention, and examples thereof include set-type yogurt (hard yogurt, solid fermented milk), soft yogurt (paste-like fermented milk), drink yogurt (liquid fermented milk), frozen yogurt, etc.

[0057] According to one embodiment of the present invention, the composition of the present invention can be provided as a food composition. The food composition of the present invention may be in any form as long as it contains lactic acid bacteria, such as a solution, suspension, emulsion, powder, paste, semi-solid product, or solid product, and may be in a form that can be taken orally or through a tube. Specific examples of the food include solid or semi-solid foods (bread, crackers, pizza crust, yogurt, cheese, infant formula, etc.), beverages (dairy drinks (milk, lactic acid bacteria drinks, dairy drinks, etc.)), liquid foods, foods for the sick, nutritional foods, frozen foods, processed foods, confectioneries (chocolate, tablets, gummies, jellies, candies, biscuits, ice cream, frozen desserts, etc.), seasonings, and other commercially available foods. However, dairy products containing lactic acid bacteria (dairy drinks, yogurt, etc.) are preferred.

[0058] The food composition of the present invention can be a food or beverage labeled with uses such as suppressing inflammation that occurs in brain tissue, ameliorating inflammation that occurs in brain tissue, suppressing the occurrence of inflammation in brain tissue, suppressing the production of inflammatory cytokines in brain tissue, suppressing inflammation that occurs in the hippocampus, ameliorating inflammation that occurs in the hippocampus, suppressing the occurrence of inflammation in the hippocampus, suppressing the production of inflammatory cytokines in the hippocampus, improving higher brain function, improving higher brain function, maintaining higher brain function, suppressing the decline of higher brain function, ameliorating diseases or disorders caused by the decline of higher brain function, ameliorating mental disorders, preventing mental disorders, ameliorating mood disorders, and preventing mood disorders. Specifically, the foods and beverages have the following claims: "for suppressing inflammation in brain tissue," "for improving inflammation in brain tissue," "for suppressing the occurrence of inflammation in brain tissue," "for suppressing the production of inflammatory cytokines in brain tissue," "for suppressing inflammation in the hippocampus," "for improving inflammation in the hippocampus," "for suppressing the occurrence of inflammation in the hippocampus," "for suppressing the production of inflammatory cytokines in the hippocampus," "for improving higher brain function," "for improving higher brain function," "for maintaining higher brain function," "for suppressing the decline of higher brain function," "for improving diseases or disorders caused by the decline of higher brain function," "for improving mental disorders," "for preventing mental disorders," "for improving mood disorders," "for preventing mood disorders," and "for improving cognitive function." The following claims may be made: "for improving function," "for preventing cognitive decline," "for supporting cognitive function," "for reducing the risk of dementia," "for improving the accuracy of memory function (or memory ability)," "for improving memory function (or memory ability)," "for maintaining memory function (or memory ability)," "for preventing decline (decline) of memory function (or memory ability)," "for supporting memory function (or memory ability)," "for preventing forgetfulness," "for improving forgetfulness," "for maintaining attention," "for improving depression," "for preventing depression," "for reducing the risk of depression," "function of maintaining a positive mood (clear mind, lively, positive mood, energized, etc.)," ​​etc. In addition, claims other than these may also be used as long as they describe the effects produced by suppressing inflammation in brain tissue (for example, suppressing inflammation in the hippocampus), reducing the amount of inflammatory cytokines in brain tissue (suppressing their production), or reducing the amount of inflammatory cytokines in the hippocampus (suppressing their production).With respect to each of the above-mentioned uses, "memory" includes the ability to encode (memorize), store (retain), retrieve (recall), and use (process) information. Examples of "memory function" or "memory ability" include the ability to memorize language (verbal memory ability), the ability to memorize numbers (digital memory ability), and the ability to memorize space (spatial cognitive ability, spatial cognitive ability; for example, the ability to grasp two-dimensional or three-dimensional positions). "Memory function" or "memory ability" includes both long-term and short-term memory function or ability, but the composition of the present invention can particularly significantly contribute to short-term memory function or ability.

[0059] In this specification, "display" means any act intended to inform consumers of the above-mentioned uses, and any display that can evoke or infer the above-mentioned uses falls under the "display" of the present invention, regardless of the purpose of the display, the content of the display, the object or medium on which it is displayed, etc. However, it is preferable to display the use in an expression that allows consumers to directly recognize the above-mentioned uses.

[0060] The labeling is preferably one approved by the government or the like (e.g., labeling approved under various government systems and made in a manner based on such approval). Examples include labeling as a health food, functional food, functional food with function claims, enteral nutritional food, special dietary food, food for patients, food with nutrient function claims, and quasi-drugs. Other examples include labeling approved by the Ministry of Health, Labor and Welfare, such as labeling as a food for specified health uses (SFU) or labeling approved under similar systems. Examples of the latter include labeling as a food for specified health uses (SFU), labeling as a conditional SFU, labeling indicating an effect on the structure or function of the body, and labeling for disease risk reduction. More specifically, labeling as a food for specified health uses (particularly labeling for health uses) as defined in the Enforcement Regulations of the Health Promotion Act (Ministry of Health, Labor and Welfare Ordinance No. 86 of April 30, 2003), and similar labeling, etc.

[0061] According to another aspect of the present invention, the composition of the present invention can be provided as a pharmaceutical composition. The pharmaceutical composition of the present invention can be produced according to the usual manufacturing procedures for the food, except for the inclusion of lactic acid bacteria. Here, the pharmaceutical composition refers to the composition of the present invention prepared as an oral or parenteral formulation according to a conventional method. The formulation may contain additives acceptable for formulation. Examples of additives acceptable for formulation include excipients, stabilizers, preservatives, humectants, emulsifiers, lubricants, sweeteners, colorants, flavorings, buffers, antioxidants, pH adjusters, etc. When the pharmaceutical composition is an oral formulation, it can take the form of solid formulations such as tablets, powders, fine granules, granules, capsules, pills, and sustained-release formulations, or liquid formulations such as solutions, suspensions, and emulsions. When the pharmaceutical composition is a parenteral formulation, it can take the form of injections, suppositories, etc. From the perspective of ease of ingestion (administration) to the recipient, oral formulations are preferred.

[0062] The intake amount of the composition of the present invention is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately adjusted depending on the age, health condition, body weight, etc. of the person taking it. Typically, it is 0.001 to 10 g / kg body weight per day, preferably 0.01 to 7 g / kg body weight, more preferably 0.5 to 5 g / kg body weight, and even more preferably 1 to 2 g / kg body weight. Furthermore, the dry mass of the lactic acid bacteria is preferably 0.001 to 1000 mg / kg body weight, more preferably 0.01 to 100 mg / kg body weight, more preferably 0.05 to 30 mg / kg body weight, and even more preferably 0.1 to 10 mg / kg body weight. Furthermore, the number of lactic acid bacteria is preferably 10 ４ ~10 １２ per kg body weight, more preferably 10 ５ ~10 １１ per kg body weight, more preferably 10 ６ ~10 １０ / kg body weight, particularly preferably 10 ６ ~10 ８ per kg of body weight.

[0063] In order to maximize the effects of the composition of the present invention, it is preferable to take (administer) it continuously for a long period of time, specifically, it is preferably taken (administered) continuously for 3 days or more, and more preferably it is taken (administered) continuously for 1 week or more. Examples of the intake (administration) period include 1 to 6 weeks, 1 to 12 weeks, 2 to 10 weeks, 4 to 10 weeks, and 4 to 12 weeks. As used herein, "continuously" means that a set amount of the composition of the present invention is taken continuously every day.

[0064] According to another aspect of the present invention, there is provided a method for suppressing inflammation in the brain tissue of a subject, comprising administering an effective amount of Lactobacillus lactic acid bacteria to the subject.According to a preferred embodiment, there is provided a method for suppressing inflammation in the hippocampus of a subject, comprising administering an effective amount of Lactobacillus lactic acid bacteria to the subject.The above-mentioned method can be a non-therapeutic method or a therapeutic method.

[0065] Furthermore, the subjects who take lactic acid bacteria are not particularly limited as long as they are subjects who need to suppress inflammation in their brain tissue, and may be healthy individuals, or individuals who are experiencing inflammation in their brain tissue or who need to prevent inflammation from occurring in their brain tissue.

[0066] In the method for suppressing inflammation in brain tissue, the dosage and ingestion period of the lactic acid bacteria are not particularly limited as long as the effects of the present invention are achieved, and can be appropriately adjusted depending on the age, health condition, weight, etc. of the subject. Typically, in the method of the present invention, the dosage and ingestion period of the lactic acid bacteria are the same as those of the lactic acid bacteria in the composition of the present invention.

[0067] As mentioned above, by having a subject ingest an effective amount of Lactobacillus lactic acid bacteria, inflammation in brain tissue, particularly in the hippocampus, can be suppressed. Therefore, in another aspect of the present invention, a method for improving disorders or diseases caused by inflammation in the brain tissue of a subject is provided, which comprises having a subject ingest an effective amount of Lactobacillus lactic acid bacteria. Disorders caused by inflammation in brain tissue include a decline in higher brain function, mental disorders, and mood disorders. Therefore, in another aspect of the present invention, a method for improving higher brain dysfunction, a method for improving mental disorders, or a mood disorder is provided, which comprises the same steps as the method for suppressing inflammation in brain tissue described above. In a preferred embodiment, a method for improving higher brain dysfunction, a method for improving mental disorders, or a mood disorder is provided, which comprises the same steps as the method for suppressing inflammation in the hippocampus described above.

[0068] According to another aspect of the present invention, there is provided a method for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue, particularly the hippocampus, of a subject, which method comprises administering to the subject an effective amount of Lactobacillus lactic acid bacteria.

[0069] According to another aspect of the present invention, there is provided a use of Lactobacillus lactic acid bacteria for suppressing inflammation in brain tissue. According to a preferred embodiment, there is provided a use of Lactobacillus lactic acid bacteria for suppressing inflammation in the hippocampus. As described above, since Lactobacillus lactic acid bacteria can suppress inflammation in brain tissue, particularly in the hippocampus, another aspect of the present invention provides a use of Lactobacillus lactic acid bacteria for improving disorders caused by inflammation in brain tissue. According to a further preferred embodiment, the lactic acid bacteria are provided as a food composition. According to yet another preferred embodiment, the lactic acid bacteria are ingested by a subject by a non-therapeutic method.

[0070] According to yet another aspect of the present invention, there is provided use of Lactobacillus lactic acid bacteria for improving higher brain dysfunction, improving mental disorders, or improving mood disorders.

[0071] According to another aspect of the present invention, there is provided use of Lactobacillus lactic acid bacteria for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue, particularly the hippocampus.

[0072] According to another aspect of the present invention, there is provided the use of Lactobacillus lactic acid bacteria for the manufacture of a composition for suppressing inflammation in brain tissue. According to a preferred embodiment, there is provided the use of Lactobacillus lactic acid bacteria for the manufacture of a composition for suppressing inflammation in the hippocampus. According to yet another aspect, there is provided the use of Lactobacillus lactic acid bacteria for the manufacture of a composition for ameliorating disorders caused by inflammation in brain tissue. According to a further preferred embodiment, the lactic acid bacteria are used for the manufacture of a food composition or a pharmaceutical composition. As described above, the composition for suppressing inflammation can also be provided as a pharmaceutical composition. Therefore, according to another aspect of the present invention, there is provided the use of Lactobacillus lactic acid bacteria for the manufacture of a medicament for suppressing inflammation in brain tissue, particularly the hippocampus. According to yet another aspect, there is provided the use of Lactobacillus lactic acid bacteria for the manufacture of a medicament for ameliorating disorders caused by inflammation in brain tissue. According to yet another preferred embodiment, the lactic acid bacteria are ingested by a subject by a non-therapeutic method.

[0073] According to another aspect of the present invention, the use of Lactobacillus lactic acid bacteria is provided for the manufacture of a composition for improving higher brain dysfunction, a composition for improving mental disorders or a composition for improving mood disorders.In a preferred embodiment, the lactic acid bacteria is used for the manufacture of food compositions or pharmaceutical compositions.As mentioned above, each of these compositions can also be provided as pharmaceutical compositions, so as another aspect of the present invention, the use of Lactobacillus lactic acid bacteria is provided for the manufacture of a medicine for improving higher brain dysfunction, mental disorders or mood disorders.

[0074] According to another aspect of the present invention, there is provided use of Lactobacillus lactic acid bacteria for the production of a composition for reducing the level of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interferon-γ, monocyte chemoattractant-1, macrophage inflammatory protein-1, and tumor necrosis factor in brain tissue, particularly the hippocampus. In a preferred embodiment, the lactic acid bacteria are used for the production of a food composition or pharmaceutical composition. As described above, the composition for reducing the level of inflammatory cytokines in brain tissue, particularly the hippocampus, according to this aspect can also be provided as a pharmaceutical composition. Therefore, as another aspect of the present invention, there is provided use of Lactobacillus lactic acid bacteria for the production of a medicament for reducing the level of inflammatory cytokines in brain tissue, particularly the hippocampus.

[0075] According to another aspect of the present invention, there is provided a method for suppressing inflammation in the brain tissue of a subject, and a method for reducing the risk of inflammation, comprising administering Lactobacillus lactic acid bacteria to the subject. According to a preferred embodiment, there is provided a method for suppressing inflammation in the hippocampus of a subject, and a method for reducing the risk of inflammation, comprising administering Lactobacillus lactic acid bacteria to the subject. According to a further preferred embodiment, the lactic acid bacteria is administered to the subject by a non-therapeutic method.

[0076] According to yet another aspect of the present invention, there is provided a method for improving higher brain dysfunction, a method for improving mental disorders, or a method for improving mood disorders in a subject, comprising administering Lactobacillus lactic acid bacteria to the subject.

[0077] The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples. Unless otherwise specified, the units and measurement methods in these examples are in accordance with JIS (Japanese Industrial Standards).

[0078] Example 1: Confirmation of the anti-inflammatory effect of a composition containing Lactobacillus genus lactic acid bacteria (1) Preparation of composition A lactic acid bacteria starter consisting of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus was added to raw milk (a mixture containing raw milk, skim milk powder, cream, sugar, and stevia), and the raw milk was fermented by maintaining at 43°C for 4 to 6 hours to prepare yogurt. Heat-treated lactic acid bacteria Lactobacillus plantarum OLL2712 strain (accession number: FERM BP-11262) was added to the prepared yogurt to prepare a composition of the present invention (test composition). The heat treatment of the lactic acid bacteria Lactobacillus plantarum OLL2712 strain was performed by concentrating the bacterial cells and then heating at 60°C for 10 minutes. The amount of lactic acid bacteria contained in the test composition was 5 x 10 ９ On the other hand, the same yogurt as that used in the test composition (yogurt not containing the heat-treated lactic acid bacteria Lactobacillus plantarum OLL2712 strain) was used as a control composition.

[0079] (2) Administration of Composition to KK-Ay Mice Eighteen 5-week-old male KK-Ay mice (manufactured by CLEA Japan) were acclimated for one week and then divided into groups 1 to 3 (six mice per group) based on body weight, fasting blood glucose levels, and blood triglyceride levels. The mice were divided so that there was no significant bias in the mean ± standard deviation of body weight, fasting blood glucose levels, and blood triglyceride levels of the mice in each group. Each mouse in each group was housed in an individual cage. Distilled water was administered orally to Group 1, a control composition to Group 2, and a test composition to Group 3 daily for three weeks at a dose of 0.5 ml / g body weight.

[0080] (3) Measurement of Inflammatory Cytokine Levels in Brain Tissue After the 3-week oral administration described in (2) above, hippocampi were excised from all mice in each group and bead-disrupted in RIPA buffer (Sigma) containing 1% each of protease inhibitor cocktail (Sigma) and phosphatase inhibitor cocktail (Sigma). The excised hippocampi were centrifuged at 14,000 × g for 20 minutes at 4°C. The supernatant was stored at -80°C, and the levels of various inflammatory cytokines were measured using Bio-Plex Pro Mouse Cytokine GI23-Plex (Bio-Rad). The measured values ​​were divided by the total protein concentration in the disrupted solution, as determined by the BCA method, to calculate the content per unit protein mass.

[0081] The amounts of various inflammatory cytokines in the hippocampus isolated from mice of each group are shown in Table 1 below. Note that for IL-12, the amounts shown are for IL-12 (p40), which is a homodimer of the p40 subunit, and IL-12 (p70), which is a mixture of the p40 subunit and the p35 subunit. In the table, the amounts of various inflammatory cytokines are all expressed in pg / mg.

[0082] The results in Table 1 show that Group 2, which received the control composition, showed no significant changes in the levels of various inflammatory cytokines in the hippocampus compared to Group 1. On the other hand, Group 3, which received the test composition, showed a significant decrease (p<0.05) or a tendency toward a decrease (p<0.1) in the levels of IL-1, IL-6, IL-9, IL-12, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1, and TNF-α in the hippocampus compared to Group 1. These results demonstrate that the composition of the present invention reduces the levels of various inflammatory cytokines in the hippocampus.

[0083] The above results show that a composition containing Lactobacillus lactic acid bacteria can effectively suppress inflammation in brain tissue, especially hippocampal inflammation.In addition, it has been suggested that inflammation in brain tissue, especially hippocampal inflammation, is involved in the onset / progression of brain diseases such as Alzheimer's disease.Therefore, the above results show that a composition containing Lactobacillus lactic acid bacteria can treat and / or prevent various brain diseases caused by inflammation in brain tissue.Furthermore, it has been suggested that inflammatory cytokines damage neurons in brain tissue or inhibit the formation of normal neurons, thereby causing mental disorders and mood disorders.The above results also show that a composition containing Lactobacillus lactic acid bacteria can reduce the amount of inflammatory cytokines in brain tissue, and treat and / or prevent mental disorders and mood disorders.In other words, the above results show that the composition of the present invention can effectively suppress inflammation in brain tissue, especially hippocampal inflammation. Furthermore, the above results indicate that the compound can be used to improve disorders and diseases caused by inflammation of brain tissue, particularly disorders and diseases caused by inflammation of the hippocampus, such as decreased higher brain function, mental disorders, and mood disorders.

[0084] According to the present invention, it is possible to effectively reduce the amount of inflammatory cytokines in the brain tissue of a subject, thereby suppressing inflammation in the brain tissue of a subject. Furthermore, according to the present invention, by suppressing inflammation in the brain tissue of a subject, it is possible to improve disorders and diseases caused by inflammation in the brain tissue.

Claims

1. A composition for improving at least one disorder selected from the group consisting of mental disorders, mood disorders, and higher brain dysfunction, comprising lactic acid bacteria belonging to the Lactobacillus genus.

2. A composition for suppressing inflammation in brain tissue, comprising lactic acid bacteria belonging to the genus Lactobacillus.

3. The composition of claim 2 , wherein the brain tissue is the hippocampus.

4. The composition according to claim 2 or 3, which is for improving disorders caused by inflammation of brain tissue.

5. The composition of claim 4, wherein the disorder is at least one disorder selected from the group consisting of psychiatric disorders and mood disorders.

6. The composition according to claim 1 or 4, wherein the disorder is a higher brain dysfunction disorder.

7. The composition according to claim 6, wherein the higher brain dysfunction is a dysfunction of at least one function selected from the group consisting of selective attention function, cognitive function, memory function, executive function, and learning function.

8. The composition described in claim 1 for at least one selected from the following: improving cognitive function, improving cognitive function, suppressing decline in cognitive function, suppressing an increase in the risk of dementia, reducing the risk of dementia, improving memory function, maintaining memory function, and suppressing decline in memory function.

9. The composition according to any one of claims 6 to 8, for improving a disease caused by a higher brain dysfunction.

10. The composition described in claim 9, wherein the improvement is treatment or prevention of the disease by non-medical treatment.

11. 11. The composition of claim 9 or 10, wherein the disease is selected from the group consisting of Alzheimer's dementia, Lewy body dementia, frontotemporal dementia, amnesic syndrome, generalized attention disorder, social behavior disorder and memory disorder.

12. The composition according to any one of claims 2 to 7 and 9 to 11, wherein the lactic acid bacteria have activity for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, interferon-γ, monocyte chemotactic factor-1, macrophage inflammatory protein-1 and tumor necrosis factor in brain tissue.

13. The composition of claim 12, wherein the brain tissue is the hippocampus.

14. A composition for reducing the amount of at least one inflammatory cytokine selected from the group consisting of interleukin-1, interleukin-6, interleukin-9, interleukin-12, interleukin-17, granulocyte-colony stimulating factor, granulocyte-monocyte-colony stimulating factor, interferon-γ, monocyte chemotactic factor-1, macrophage inflammatory protein-1 and tumor necrosis factor in brain tissue, comprising lactic acid bacteria belonging to the genus Lactobacillus.

15. The composition of claim 14, wherein the brain tissue is the hippocampus.

16. A composition for reducing the amount of interleukin-17, comprising lactic acid bacteria belonging to the genus Lactobacillus.

17. The composition according to any one of claims 1 to 16, wherein the lactic acid bacteria comprises lactic acid bacteria belonging to Lactobacillus plantarum.

18. The composition according to any one of claims 1 to 17, wherein the lactic acid bacterium has a 16S rRNA gene having 90% or more homology with the base sequence represented by SEQ ID NO:

1.

19. The composition according to any one of claims 1 to 18, wherein the lactic acid bacterium is Lactobacillus plantarum strain OLL2712 deposited under the accession number FERM BP-11262.

20. The composition according to any one of claims 1 to 19, wherein the lactic acid bacteria comprises killed cells of the lactic acid bacteria.

21. The composition according to any one of claims 1 to 20, wherein the lactic acid bacteria comprises heat-killed bacteria.