Composition for improving inflammation in 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

Reference to related applications

[0001] This patent application is made subject to a priority claim based on the earlier patent application filed in Japan, Japanese Patent Application No. 2020-208555 (filing date: December 16, 2020). The entire disclosure in the earlier patent application is incorporated herein by reference. [Technical Field]

[0002] This invention relates to a composition for improving inflammation in brain tissue. [Background technology]

[0003] The brain is the central nervous system in animals and the organ that controls their vital functions. It is known that abnormalities in the brain can impair not only physical but also mental functions. Inflammation of brain tissue is one known cause of brain abnormalities, and research into the causes and treatment methods of this inflammation is ongoing.

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

[0005] On the other hand, while research and development of various therapeutic drugs are underway for these brain dysfunctions, most of them are symptomatic treatments for the causes of organic brain damage, and are not yet sufficient as methods to improve or enhance these brain dysfunctions.

[0006] Incidentally, while there is some knowledge regarding the relationship between lactic acid bacteria and the improvement of brain function (for example, Patent Documents 1-3), there have been no reports on the relationship between lactic acid bacteria and fluctuations 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 the amount of inflammatory cytokines in the brain tissue of the target population could be reduced by ingesting lactic acid bacteria, or furthermore, that brain dysfunction such as a decline in higher brain function, mental disorders, and mood disorders could be improved in the target population.

[0007] Since inflammation of brain tissue can be a factor in brain dysfunction such as a decline in higher brain function, mental disorders, and mood disorders, there is a need for methods to effectively improve inflammation of brain tissue. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2017 / 179602 [Patent Document 2] Special Publication No. 2018-531595 [Patent Document 3] Special Publication No. 2015-526085 [Non-patent literature]

[0009] [Non-Patent Document 1] Akira Monji, Special Feature: The Cutting Edge of Pathophysiological Research in Mental Illnesses - The Neuroinflammatory Hypothesis of Mental Illnesses, Journal of Psychiatry and Neurology, Vol. 114, No. 2, pp. 124-133, 2012.

[0010] One objective of this invention is to provide a composition useful for improving inflammation in a target, and in particular a composition useful for improving inflammation in the brain tissue of a target.

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

[0012] The present invention provides the following: [1] A composition for suppressing inflammation of brain tissue, containing lactic acid bacteria belonging to the genus Lactobacillus. [2] The composition according to [1], wherein the brain tissue is the hippocampus. [3] The composition according to [1] or [2], for the improvement of disorders caused by inflammation of brain tissue. [4] The composition according to [3], wherein the disorder is at least one disorder selected from the group consisting of mental disorders and mood disorders. [5] The composition according to [3], wherein the disorder is a higher brain dysfunction. [6] The composition according to [5], wherein the higher brain dysfunction is an impairment of at least one function selected from the group consisting of selective attention function, cognitive function, memory function, executive function, and learning function. [7] The composition according to [5] or [6] 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, Lewy body dementia, frontotemporal dementia, amnesia syndrome, generalized attention disorder, social behavior disorder, and memory impairment. [9] The composition according to any one of [1] to [8], wherein the lactic acid bacteria have the activity to reduce the amount of at least one selected inflammatory cytokine 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 the 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 chemoattractant protein-1, macrophage inflammatory protein-1 and tumor necrosis factor in brain tissue, comprising a lactic acid bacterium belonging to the genus Lactobacillus.

[12] The composition according to

[11] , wherein the brain tissue is the hippocampus.

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

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

[15] The composition according to

[14] , 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.

[16] The composition according to

[14] or

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

[17] The composition according to

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

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

[17] , wherein the lactic acid bacterium comprises a lactic acid bacterium 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 having 90% or more homology with the nucleotide 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 strain OLL2712 deposited under accession number FERM BP-11262.

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

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

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

[21] , wherein the lactic acid bacterium comprises heat-treated dead 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 causing the subject to ingest an effective amount of a lactic acid bacterium belonging to the genus Lactobacillus.

[26] A method for improving a disorder caused by inflammation in brain tissue of a subject, comprising causing the subject to ingest an effective amount of a lactic acid bacterium 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 protein-1, macrophage inflammatory protein-1 and tumor necrosis factor in brain tissue of a subject, comprising causing the subject to ingest an effective amount of a lactic acid bacterium belonging to the genus Lactobacillus.

[28] A method for improving at least one disorder selected from the group consisting of mental disorders, mood disorders and higher brain dysfunction in a subject, comprising causing the subject to ingest an effective amount of a lactic acid bacterium 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 function, 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 dementia, dementia with Lewy bodies, frontotemporal dementia, amnestic syndrome, generalized attention disorder, social behavior disorder and memory disorder.

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

[33] The use according to

[32] , wherein the brain tissue is the hippocampus.

[34] The use according to

[32] or

[33] , wherein the composition is a composition for improving damage 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 mental disorders and mood disorders.

[36] The use described in

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

[37] The use according to

[36] , wherein the higher brain dysfunction is an impairment 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 according to

[36] or

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

[39] The use as described in

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

[40] Use of lactic acid bacteria according to any one of

[32] to

[39] , wherein the lactic acid bacteria have the activity to reduce the amount of at least one selected inflammatory cytokine 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.

[41] Use of the lactic acid bacteria described in

[40] , wherein the brain tissue is the hippocampus.

[42] Use of Lactobacillus bacteria for the preparation of a composition for reducing the amount of at least one selected inflammatory cytokine 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.

[43] Use of the lactic acid bacteria described in

[42] , wherein the brain tissue is the 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 Lactobacillus bacteria belonging to the genus Lactobacillus for the manufacture of compositions for improving inflammation-related disorders in brain tissue.

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

[47] The use according to

[46] , wherein the higher brain dysfunction is an impairment 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 improving a disease caused by the higher brain dysfunction.

[49] The use as described in

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

[50] Lactobacillus bacteria, which are used to suppress inflammation in brain tissue.

[51] Lactobacillus bacteria for improving inflammation-related disorders in brain tissue.

[52] Lactobacillus bacteria for reducing the amount of at least one selected inflammatory cytokine 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.

[53] Lactobacillus bacteria for the improvement of at least one disorder selected from the group consisting of mental disorders, mood disorders and higher brain dysfunction.

[54] The lactic acid bacteria belonging to the genus Lactobacillus as described in

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

[55] Lactobacillus bacteria belonging to the genus Lactobacillus as described in

[53] or

[54] , for improving diseases caused by the aforementioned higher brain dysfunction.

[56] Lactobacillus bacteria belonging to the genus Lactobacillus as described in

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

[57] Use of Lactobacillus bacteria to suppress inflammation in brain tissue.

[58] Use of Lactobacillus bacteria to improve inflammation-related disorders in brain tissue.

[59] Use of Lactobacillus bacteria to reduce the amount of at least one selected inflammatory cytokine 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.

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

[61] The use of lactic acid bacteria belonging to the genus Lactobacillus as described in

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

[62] Use of lactic acid bacteria belonging to the genus Lactobacillus as described in

[60] or

[61] for improving diseases caused by the aforementioned higher brain dysfunction.

[63] The disease is selected from the group consisting of Alzheimer's disease, Lewy body dementia, frontotemporal dementia, amnesia syndrome, generalized attention disorder, social behavior disorder, and memory impairment, and the use of lactic acid bacteria belonging to the genus Lactobacillus as described in

[62] .

[0013] According to the present invention, by administering lactic acid bacteria belonging to the genus Lactobacillus to the target organism, the amount of specific cytokines suggested to be associated with inflammation can be effectively reduced in the target organism, particularly in the brain tissue of the target organism. Therefore, according to the present invention, inflammation in the target organism, particularly in the brain tissue of the target organism, can be efficiently 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 contains 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 subjects to whom the composition of the present invention is applied are not particularly limited as long as the effects of the present invention are achieved, and include mammals such as humans, monkeys, chimpanzees, cattle, horses, sheep, and goats, and are preferably humans. The subjects to whom the composition of the present invention is applied may also be subjects experiencing inflammation, particularly inflammation in brain tissue, or subjects in which the occurrence of 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 human 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 human subject is not particularly limited.

[0016] In this specification, “brain tissue” means the entire brain or a subregion of the brain to which the composition of the present invention is applied. According to a preferred embodiment of the present invention, “brain tissue” includes the hippocampus. That is, according to a preferred embodiment of the present invention, the brain tissue inflammation inhibitory composition of the present invention is a composition for improving inflammation in the hippocampus.

[0017] In this specification, the “suppression” of inflammation includes both the “treatment” and the “prevention” of inflammation. The “treatment” of inflammation includes not only stopping, alleviating, or delaying the progression or worsening of inflammation through medical procedures, but also stopping, alleviating, or delaying the progression or worsening of inflammation through non-medical procedures. Furthermore, the “prevention” of inflammation includes taking proactive measures against anticipated worsening of inflammation and preventing the onset or recurrence of inflammation through medical or non-medical procedures.

[0018] According to a preferred embodiment of the present invention, Lactobacillus bacteria contained in the composition of the present invention have activity to reduce at least one amount 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 chemotactic factor-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), and tumor necrosis factor-α (TNF-α). According to another preferred embodiment, Lactobacillus bacteria contained in the composition of the present invention have activity to reduce at least one amount of the above-mentioned inflammatory cytokines in brain tissue. According to yet another embodiment, Lactobacillus bacteria contained in the composition of the present invention have activity to reduce at least one amount of the above-mentioned inflammatory cytokines in the hippocampus.

[0019] In this specification, "having reducing activity" with respect to inflammatory cytokines means that when a subject is stimulated with Lactobacillus bacteria or a composition containing said bacteria, the amount of inflammatory cytokines in the stimulated subject, particularly in the brain tissue of said subject, tends to decrease compared to an unstimulated subject, preferably statistically significant (i.e., beyond the margin of error). The amount of inflammatory cytokines and the determination of whether or not there is reducing activity can be performed, for example, by the method shown in the examples. Furthermore, statistical analysis of the amount of inflammatory cytokines can be performed using statistical analysis methods known to those skilled in the art. Specifically, statistical analysis of the amount of inflammatory cytokines can be performed by a t-test.

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

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

[0022] The subjects to whom the composition for improving higher brain function disorders of the present invention is applied may be the same as those described for the composition for suppressing inflammation of brain tissue. Furthermore, the subjects to whom the composition is applied may be those who have normal higher brain function, or those who have impaired higher brain function (i.e., those with impaired higher brain function).

[0023] In this specification, "improving higher brain function" encompasses not only "enhancing higher brain function" but also "maintaining higher brain function" and "preventing decline in higher brain function." Furthermore, "enhancing higher brain function" includes promoting the recovery of higher brain function from a state where it has declined due to inflammation associated with aging or brain diseases (e.g., ischemic stroke such as cerebral infarction and transient ischemic attack, hemorrhagic stroke such as cerebral hemorrhage and subarachnoid hemorrhage, traumatic injuries such as concussion and cerebral contusion). Furthermore, "maintaining higher brain function" includes maintaining higher brain function in a healthy state. Furthermore, "preventing decline in higher brain function" includes preventing a decline in higher brain function in a healthy state and preventing further decline of already impaired higher brain function. Examples of higher brain functions include selective attention, cognitive function, memory function, executive function, learning, language, and calculation function. Furthermore, disorders resulting from a decline in higher brain function include, for example, hemisomnia, geographical impairment, agnosia, aphasia, memory impairment, mild cognitive impairment, apraxia, attention deficit, executive function disorder, and behavioral and emotional disorders.

[0024] The composition for improving higher brain function of the present invention can improve higher brain function and can therefore be used to improve diseases caused by higher brain function. Examples of diseases caused by impairment of higher brain function include dementia such as Alzheimer's disease, Lewy body dementia, and frontotemporal dementia, as well as amnesia syndrome, generalized attention deficit disorder, social behavior disorder, and memory impairment. In this specification, "improvement" of a disease or disorder includes both "treatment" and "prevention" of the disease or disorder. Furthermore, "treatment" of a disease or disorder includes not only stopping, mitigating, or delaying the progression or worsening of the disease or disorder through medical procedures, but also stopping, mitigating, or delaying the progression or worsening of the disease or disorder through non-medical procedures. Furthermore, "prevention" of a disease or disorder includes preparing in advance for anticipated worsening of the disease or disorder and preventing the occurrence or recurrence of the disease or disorder through medical or non-medical procedures.

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

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

[0027] The subjects to whom the mental disorder treatment composition of the present invention is applied may be the same as those described for the brain tissue inflammation suppression composition of the present invention. Furthermore, the subjects to whom it is applied may be those who have normal (healthy) mental functions (mental state) (i.e., those who do not have impaired mental functions), or those who have abnormal mental functions (i.e., those who have impaired mental functions).

[0028] Mental disorders, also known as "mental illnesses," do not have a unified definition, but they can be defined, for example, as psychological syndromes accompanied by distress or abnormalities. Examples of mental disorders include those classified within the F09-F99 classifications of Chapter 5, "Mental and Behavioral Disorders," of the World Health Organization's (WHO) "International Statistical Classification of Diseases and Related Health Problems, 10th Revision," specifically those excluding F30-F39, "Mood (Affective) Disorders." More specifically, these include disorders and illnesses such as schizophrenia, epilepsy, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, intellectual disability, personality disorders, eating disorders, sleep disorders, and adjustment disorders.

[0029] In this specification, "improving mental disorders" encompasses not only the meaning of "treatment of mental disorders" but also the meaning of "prevention of mental disorders." Furthermore, "treatment of mental disorders" includes promoting recovery from mental disorders caused by inflammation associated with aging or brain diseases (e.g., ischemic stroke such as cerebral infarction and transient ischemic attack, hemorrhagic stroke such as cerebral hemorrhage and subarachnoid hemorrhage, and traumatic injuries such as concussions and cerebral contusions). Furthermore, "prevention of mental disorders" includes maintaining normal mental function and preventing further impairment of mental function that is already impaired.

[0030] According to preferred embodiments of the present invention, the mental disorder improvement composition of the present invention is a composition for improving mental disorders, for treating mental disorders, for preventing mental disorders, for 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, and for 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, a composition for improving mood disorders is provided, comprising Lactobacillus lactic acid bacteria.

[0032] The subjects to whom the mood disorder-improving composition of the present invention is applied may be the same as those described for the brain tissue inflammation-suppressing composition of the present invention. Furthermore, the subjects to whom it is applied may be those who have a normal (healthy) mood state (emotional state) (i.e., those who do not have a mood disorder), or those who have an abnormal mood state (i.e., those who have a mood disorder).

[0033] Mood disorders, also known as "affective disorders," refer specifically to mental disorders related to mood. While there is no single, unified definition of a mood disorder, it can be described, for example, as a condition characterized by persistent mood (affective) disturbances over a period of time that cause distress or interfere with daily life. Examples of mood disorders include those classified under categories F30-F39 "Mood (Affective) Disorders" in Chapter 5, "Mental and Behavioral Disorders," of the WHO's "International Statistical Classification of Diseases and Related Health Problems, 10th Revision." More specifically, these include disorders and illnesses such as depression, mania, bipolar disorder, mixed episodes, and substance-induced mood disorders.

[0034] In this specification, "improving mood disorders" encompasses not only the meaning of "treating mood disorders" but also the meaning of "preventing mood disorders." Furthermore, "treating mood disorders" includes promoting recovery from mood disorders caused by inflammation associated with aging or brain diseases (e.g., ischemic stroke such as cerebral infarction and transient ischemic attack, hemorrhagic stroke such as cerebral hemorrhage and subarachnoid hemorrhage, and traumatic injuries such as concussions and cerebral contusions). Furthermore, "preventing mood disorders" includes maintaining a normal mood state and preventing further deterioration from an already impaired mood state.

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

[0036] Composition for reducing inflammatory cytokine levels According to another aspect of the present invention, a composition for reducing the amount of inflammatory cytokines, comprising Lactobacillus bacteria, is provided. In 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. In a more 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 inflammatory cytokine levels 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. In other words, according to a preferred embodiment, the composition for reducing inflammatory cytokine levels 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 inflammatory cytokine levels of the present invention reduces the amount of IL-17.

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

[0039] The inflammatory cytokines whose production is suppressed by the composition for suppressing 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 suppressing inflammatory cytokine production of the present invention suppresses the production of at least one of the above-mentioned inflammatory cytokines. In a preferred embodiment, the composition for suppressing inflammatory cytokine production of the present invention suppresses the production of IL-17.

[0040] Specific examples of Lactobacillus lactic acid bacteria included 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. Examples include Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus fermentum, Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus pentosus, Lactobacillus paraplantarum, Lactobacillus paracollinoides, and Lactobacillus hammesii. Of these Lactobacillus species, Lactobacillus plantarum is preferred, and Lactobacillus plantarum strain OLL2712 is preferred. 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" in the INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY, Volume 70, Issue 4, published on April 15, 2020, is titled "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 The reorganization of lactic acid bacteria announced in "Leuconostocaceae" has newly established 25 genera, namely Lactobacillus, Paralactobacillus, Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, and Loigolactobacillus. acilus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, Lactiplantibacillus, Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, AcetilactobacillusThis refers to lactic acid bacteria belonging to one of the genera Apilactobacillus, Levilactobacillus, Secundilactobacillus, and Lentilactobacillus. Among the lactic acid bacteria belonging to the genera after the above reorganization, in this invention, lactic acid bacteria belonging to one of the genera Lactobacillus, Lacticaseibacillus, Lactiprantibacillus, Liquorylactobacillus, Limosiractobacillus, and Leviractobacillus are preferably used. Note that, according to the above reorganized classification, the conventional Lactobacillus plantarum is classified under the genus Lactiprantibacillus and is referred to as Lactiprantibacillus plantarum.

[0041] Lactobacillus plantarum strain OLL2712 was deposited on July 2, 2010, at the Patent Organism Depositary Center of the National Institute of Advanced Industrial Science and Technology (Central No. 6, 1-1-1 Higashi, Tsukuba City, Ibaraki Prefecture, Japan), and subsequently transferred to international depositary status, where it was assigned accession number FERM BP-11262. As stated 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 microbial deposit business from the Patent Organism Depository Center of the National Institute of Advanced Industrial Science and Technology (IPOD, AIST). Therefore, 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 accession number FERM BP-11262.

[0042] As the Lactobacillus lactic acid bacteria included in the composition of the present invention, strains substantially equivalent to the deposited strain described above may also be used. It is a surprising fact to those skilled in the art that the deposited strain and substantially equivalent strains can reduce the amount of inflammatory cytokines in brain tissue, particularly in the hippocampus. A substantially equivalent strain refers to, for example, the Lactobacillus lactic acid bacteria strain described above, in which the base sequence of its 16S rRNA gene has 90% or more, preferably 95% or more, more preferably 98% or more, and even more preferably 99% or more homology to the base sequence of the 16S rRNA gene of the deposited strain (SEQ ID NO: 1), and preferably has the same mycological properties as the above strain. A strain having the same mycological properties is preferably a strain that has activity comparable to the deposited strain in terms of reducing the amount of inflammatory cytokines in the brain tissue, particularly in the hippocampus, of a target (e.g., human). Furthermore, the Lactobacillus lactic acid bacteria included in the composition of the present invention may be strains bred from deposited strains or substantially equivalent strains through mutation treatment, genetic modification, selection of naturally occurring mutants, etc., as long as the effects of the present invention are achieved.

[0043] The Lactobacillus lactic acid bacteria included in the composition of the present invention include not only the Lactobacillus lactic acid bacteria cells themselves, but also, for example, cultures containing Lactobacillus lactic acid bacteria cells. Both live and dead Lactobacillus lactic acid bacteria cells can be used, but dead cells are preferred, and more preferably dead cells obtained by heat treatment of live cells (heat-treated dead cells). That is, the Lactobacillus lactic acid bacteria included in the composition of the present invention preferably include dead cells, and more preferably heat-treated dead cells. Furthermore, 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 for example, it is 1 to 30, preferably 5 to 15, and more preferably 11 to 13.

[0044] The culture conditions for Lactobacillus lactic acid bacteria are not particularly limited as long as the effects of the present invention are achieved, and may be conditions commonly used for culturing lactic acid bacteria. For example, as a medium, one obtained by dissolving whey powder and whey protein concentrate in sterile water, digesting with protease A, adding yeast extract, fish extract and MnSO₄, further adding various nutrients (vitamins, minerals, fatty acid esters), adjusting the pH to 6.7 with NaOH, and then sterilizing by autoclaving can be used. Further, the pH during culture can be 4.8 to 6.8. K₂CO₃ can be used for pH adjustment. The temperature during culture can be 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 is performed under conditions commonly used for sterilizing lactic acid bacteria.

[0046] As the Lactobacillus lactic acid bacteria, those subjected to treatments such as concentration, dilution, freezing, drying, and powderization in addition to the above heat treatment can also be used.

[0047] As the Lactobacillus lactic acid bacteria contained in the composition of the present invention, those prepared by the above-described culture and various treatments may be used, 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 achieved, but is preferably 10 6 to 10 13 cells / g, more preferably 10 6 to 1×10 12 cells / g, still more preferably 10 7 to 10 11 cells / g, even more preferably 10 8 to 10 11 cells / g, particularly preferably 10 8 to 10 10The value is 100 cells / g. Furthermore, in the composition of the present invention, the dry mass of bacterial cells per unit mass of solid content 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 bacteria, as long as they do not interfere with the effects of the present invention. Examples of components other than Lactobacillus bacteria include culture medium components, additives suitable for oral or tube administration, solvents such as water, carbohydrates, proteins, lipids, vitamins, minerals, essential trace metals (manganese sulfate, zinc sulfate, magnesium chloride, potassium carbonate, etc.), flavorings, food hygiene or pharmaceutically acceptable carriers, food additives, and the like.

[0050] Examples of carbohydrates include sugars, modified starches (dextrin, soluble starch, British starch, oxidized starch, starch esters, starch ethers, etc.), and dietary fiber.

[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, chicken egg protein, meat protein, and other animal and plant proteins, their hydrolysates, butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipids, lactose, and various other milk-derived components.

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

[0053] Examples of vitamins include vitamin A, carotenes, B vitamins, vitamin C, vitamin D, vitamin E, vitamin K, 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 compositions of the present invention can be produced by combining Lactobacillus lactic acid bacteria with pharmaceutically acceptable carriers and / or additives, food hygiene acceptable carriers and / or additives, etc., as described above. Accordingly, according to one aspect of the present invention, a method for producing a composition for suppressing inflammation of brain tissue is provided, comprising the step of incorporating Lactobacillus lactic acid bacteria. Furthermore, according to another aspect of the present invention, a method for producing a composition for improving higher brain dysfunction, a composition for improving mental disorders, or a composition for improving mood disorders is provided, comprising the same steps as described 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 together is particularly advantageous in reducing the amount of cytokines, which have been suggested to be associated with the suppression of inflammation, in brain tissue, including the hippocampus. Such fermented milk is not particularly limited as long as the effects of the present invention are achieved, but examples include set-type yogurt (hard yogurt, solid fermented milk), soft yogurt (paste-like fermented milk), drinkable yogurt (liquid fermented milk), frozen yogurt, etc.

[0057] According to one aspect 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 is a food that can contain lactic acid bacteria, and may be in any form that can be taken orally or via tube, such as a solution, suspension, emulsion, powder, paste, semi-solid molded product, solid molded product, etc. Specific food products include, for example, solid or semi-solid foods (bread, crackers, pizza crusts, yogurt, cheese, powdered milk, etc.), beverages (dairy beverages (milk, lactic acid bacteria beverages, dairy beverages, etc.)), liquid foods, foods for the sick, nutritional foods, frozen foods, processed foods, confectionery (chocolate, tablets, gummies, jelly, candy, biscuits, ice cream, frozen desserts, etc.), seasonings, and other commercially available foods, but it is preferable that it be a dairy product containing lactic acid bacteria (dairy beverages, yogurt, etc.).

[0058] The food composition of the present invention can be a food or beverage labeled with uses such as suppressing inflammation occurring in brain tissue, improving inflammation occurring in brain tissue, suppressing the occurrence of inflammation in brain tissue, suppressing the production of inflammatory cytokines in brain tissue, suppressing inflammation occurring in the hippocampus, improving inflammation occurring 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, improving diseases or disorders caused by a decline in higher brain function, improving mental disorders, preventing mental disorders, improving mood disorders, and preventing mood disorders. Specifically, foods and beverages include those for: "suppressing inflammation in brain tissue," "improving inflammation in brain tissue," "suppressing the occurrence of inflammation in brain tissue," "suppressing the production of inflammatory cytokines in brain tissue," "suppressing inflammation in the hippocampus," "improving inflammation 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," "improving diseases or disorders caused by a decline in higher brain function," "improving mental disorders," "preventing mental disorders," "improving mood disorders," and "cognition." The following can be used to indicate the product's function: "For improving function," "For suppressing 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 suppressing the decline (or deterioration) 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," and "For maintaining a positive mood (such as being mentally sharp, lively, positive, energetic, etc.)." In addition, other indications can be used if they describe the effects resulting from suppressing inflammation in brain tissue (for example, suppressing inflammation in the hippocampus), reducing the amount of inflammatory cytokines in brain tissue (suppression of production), or reducing the amount of inflammatory cytokines in the hippocampus (suppression of production).With respect to each of the above-mentioned uses, "memory" includes the ability to encode (encode), store (retain), retrieve (recall), and use (process) information. Furthermore, "memory function" or "memory capacity" includes, for example, the ability to remember language (verbal memory), the ability to remember numbers (digital memory), and the ability to remember space (spatial cognitive ability, spatial awareness; for example, the ability to grasp two-dimensional or three-dimensional locations). In addition, "memory function" or "memory capacity" includes both long-term and short-term memory function or memory capacity, but the compositions of the present invention can contribute particularly significantly to short-term memory function or memory capacity.

[0059] In this specification, "display" means all actions taken to inform consumers of the above-mentioned uses, and any display that can evoke or infer the above-mentioned uses falls under the definition of "display" in this invention, regardless of the purpose of the display, the content of the display, the object and medium on which it is displayed, etc. However, it is preferable to display the above-mentioned uses in a way that consumers can directly recognize them.

[0060] Preferably, the labeling is permitted by the government or other administrative body (for example, labeling approved under various systems established by the government and carried out in accordance with such approval). Examples include labeling as health food, functional food, functional food, enteral nutrition food, special dietary food, food for the sick, nutritional functional food, quasi-drug, etc., as well as other labeling approved by the Ministry of Health, Labour and Welfare, such as Foods for Specified Health Uses (FOSHU) and labeling approved under similar systems. Examples of the latter include labeling as Foods for Specified Health Uses, labeling as conditionally approved FOSHU, labeling that it affects the structure or function of the body, labeling that it reduces the risk of disease, etc. More specifically, examples include labeling as Foods for Specified Health Uses (especially labeling for health purposes) as defined in the Enforcement Regulations of the Health Promotion Act (Ministry of Health, Labour and Welfare Ordinance No. 86 of April 30, 2003), and similar labeling.

[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 manufactured according to the normal manufacturing procedure of the food, except for the inclusion of lactic acid bacteria. Here, a pharmaceutical composition is a composition of the present invention prepared as an oral or parenteral preparation according to a conventional method. For formulation, additives acceptable for formulation may be used in combination. Examples of additives acceptable for formulation include excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavorings, buffers, antioxidants, pH adjusters, etc. When the pharmaceutical composition is an oral preparation, it can take the form of a solid preparation such as a tablet, powder, granules, capsule, pill, or sustained-release preparation, or a liquid preparation such as a solution, suspension, or emulsion. When the pharmaceutical composition is a parenteral preparation, it can take the form of an injection or suppository. However, from the viewpoint of ease of administration to the target, the pharmaceutical composition is preferably an oral preparation.

[0062] The amount of the composition of the present invention to be taken is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately adjusted according to the age, health condition, 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. In addition, the dry mass of 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. In addition, the number of lactic acid bacteria is preferably 10 4 ~10 12 pieces / kg body weight, comfortable10 5 ~10 11 pieces / kg body weight, more preferably 10 6 ~10 10 pieces / kg body weight, particularly preferably 10 6 ~10 8 The unit is weight per kilogram.

[0063] To better exert its effects, the composition of the present invention is preferably ingested (administered) continuously over a long period of time. Specifically, it is preferably ingested (administered) continuously for 3 days or more, and more preferably for 1 week or more. Examples of ingestion (administration) periods include 1 to 6 weeks, 1 to 12 weeks, 2 to 10 weeks, 4 to 10 weeks, 4 to 12 weeks, etc. In this specification, "continuous" means ingesting a predetermined amount of the composition of the present invention every day.

[0064] Another aspect of the present invention provides a method for suppressing inflammation in the brain tissue of a target, comprising administering an effective amount of Lactobacillus bacteria to the target. A preferred embodiment provides a method for suppressing inflammation in the hippocampus of a target, comprising administering an effective amount of Lactobacillus bacteria to the target. The above method may be non-therapeutic or therapeutic.

[0065] Furthermore, the target population for lactic acid bacteria intake is not particularly limited to those who need to suppress inflammation in brain tissue; healthy individuals may also be eligible, as well as those who have inflammation in their brain tissue or those who should be prevented from developing inflammation in their brain tissue.

[0066] In the method for suppressing inflammation in brain tissue, the dosage and duration of intake 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 according to the age, health condition, weight, etc. of the person receiving the intake. Typically, in the method of the present invention, the dosage and duration of intake of the lactic acid bacteria are the same as those of the lactic acid bacteria in the composition of the present invention.

[0067] As described above, inflammation in brain tissue, particularly the hippocampus, can be suppressed by administering an effective amount of Lactobacillus lactic acid bacteria to a subject. Therefore, in another aspect of the present invention, a method is provided for improving disorders and diseases caused by inflammation in the brain tissue of a subject, which includes administering an effective amount of Lactobacillus lactic acid bacteria to the subject. Examples of disorders caused by inflammation in brain tissue include a decline in higher brain functions, mental disorders, and mood disorders. Accordingly, in yet another aspect of the present invention, a method is provided for improving higher brain dysfunction, a mental disorder, or a mood disorder, which includes steps similar to those for suppressing inflammation in brain tissue described above. In a preferred embodiment, a method is provided for improving higher brain dysfunction, a mental disorder, or a mood disorder, which includes steps similar to those for suppressing inflammation in the hippocampus described above.

[0068] According to another aspect of the present invention, a method is provided for reducing the amount of at least one selected inflammatory cytokine 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 the brain tissue of a target, particularly the hippocampus, by administering an effective amount of Lactobacillus lactic acid bacteria to the target.

[0069] According to another aspect of the present invention, the use of Lactobacillus lactic acid bacteria for suppressing inflammation in brain tissue is provided. According to a preferred embodiment, the use of Lactobacillus lactic acid bacteria for suppressing inflammation in the hippocampus is provided. Furthermore, as described above, Lactobacillus lactic acid bacteria can suppress inflammation in brain tissue, particularly in the hippocampus, so another aspect of the present invention provides the use of Lactobacillus lactic acid bacteria for improving inflammation-related disorders 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 non-therapeutic method.

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

[0071] According to another aspect of the present invention, the use of Lactobacillus bacteria is provided for reducing the amount of at least one selected inflammatory cytokine 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, particularly the hippocampus.

[0072] According to another aspect of the present invention, the use of Lactobacillus lactic acid bacteria is provided for the production of a composition for suppressing inflammation in brain tissue. According to a preferred embodiment, the use of Lactobacillus lactic acid bacteria is provided for the production of a composition for suppressing inflammation in the hippocampus. According to yet another aspect, the use of Lactobacillus lactic acid bacteria is provided for the production of a composition for improving inflammation-related disorders in brain tissue. According to a further preferred embodiment, the lactic acid bacteria are used for the production of a food composition, a pharmaceutical composition. Furthermore, as described above, an inflammation-suppressing composition can also be provided as a pharmaceutical composition, so another aspect of the present invention provides the use of Lactobacillus lactic acid bacteria for the production of a pharmaceutical for suppressing inflammation in brain tissue, particularly in the hippocampus. Furthermore, yet another aspect provides the use of Lactobacillus lactic acid bacteria for the production of a pharmaceutical for improving inflammation-related disorders in brain tissue. According to yet another preferred embodiment, the lactic acid bacteria are ingested by a non-therapeutic method.

[0073] According to yet another aspect of the present invention, the use of Lactobacillus lactic acid bacteria is provided for the production 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 are used for the production of a food composition, a pharmaceutical composition. As described above, each of these compositions may also be provided as a pharmaceutical composition, so another aspect of the present invention provides the use of Lactobacillus lactic acid bacteria for the production of a medicament for improving higher brain dysfunction, a mental disorder, or a mood disorder.

[0074] According to another aspect of the present invention, the use of Lactobacillus bacteria is provided for the production of a composition for reducing the amount of at least one selected inflammatory cytokine 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, particularly the hippocampus. In a preferred embodiment, the lactic acid bacteria are used for the production of a food composition, a pharmaceutical composition. As described above, the composition for reducing the amount of inflammatory cytokines in brain tissue, particularly the hippocampus, according to this aspect may also be provided as a pharmaceutical composition; therefore, another aspect of the present invention provides the use of Lactobacillus bacteria for the production of a pharmacopoeia for reducing the amount of inflammatory cytokines in brain tissue, particularly the hippocampus.

[0075] Another aspect of the present invention provides a method for suppressing inflammation in the brain tissue of a subject and reducing the risk of inflammation, comprising administering Lactobacillus lactic acid bacteria to the subject. A preferred embodiment provides a method for suppressing inflammation in the hippocampus of a subject and reducing the risk of inflammation, comprising administering Lactobacillus lactic acid bacteria to the subject. A further preferred embodiment provides that the lactic acid bacteria are ingested by a non-therapeutic method.

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

[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 embodiments conform to JIS (Japanese Industrial Standards).

[0078] Example 1: Confirmation of the anti-inflammatory effect of a composition containing Lactobacillus lactic acid bacteria. (1) Preparation of composition Yogurt was prepared by adding a lactic acid bacteria starter consisting of Lactobacillus delbrueckii subspecies bulgaricus and Streptococcus thermophilus to raw milk (a mixture containing raw milk, skim milk powder, cream, sugar, and stevia) and fermenting the raw milk at 43°C for 4 to 6 hours. To the prepared yogurt, heat-treated Lactobacillus plantarum OLL2712 strain (accession number: FERM BP-11262) was added to prepare the composition of the present invention (test composition). The heat treatment of 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 × 10⁶ 9 The result was more than one gram per 112g. On the other hand, the same yogurt used in the test composition (yogurt that does not contain heat-treated Lactobacillus plantarum OLL2712 strain) was used as the control composition.

[0079] (2) Administration of the composition to KK-Ay mice Eighteen five-week-old male KK-Ay mice (manufactured by CREA Japan) were acclimatized for one week and then divided into 1 to 3 groups (6 mice per group) based on body weight, fasting blood glucose, and blood triglyceride levels. The mice were divided into groups so that there was no significant bias in the mean ± standard deviation of body weight, fasting blood glucose, and blood triglyceride levels. Each group of mice was housed in an individual cage. Group 1 received distilled water, Group 2 received the control composition, and Group 3 received the test composition, each administered orally daily for three weeks at a dose of 0.5 ml / g body weight.

[0080] (3) Measurement of the amount of inflammatory cytokines in brain tissue After three weeks of oral administration as described in (2) above, the hippocampi were extracted from all mice in each group. The extracted hippocampi were then bead-lysed in RIPA buffer (Sigma) containing 1% each of protease inhibitor cocktail (Sigma) and phosphatase inhibitor cocktail (Sigma). The mixture was centrifuged at 14,000 × g for 20 minutes at 4°C, and the supernatant was stored at -80°C. The amounts of various inflammatory cytokines were measured using Bio-Plex Pro mouse cytokine GI23-Plex (Bio-Rad). The obtained measurements were divided by the total protein concentration in the lysate, which was quantified by the BCA method, to calculate the content per unit protein mass.

[0081] Table 1 below shows the amounts of various inflammatory cytokines extracted from the hippocampus of mice from each group. For IL-12, the amounts shown are for IL-12(p40), which consists of a homodimer of subunit p40, and IL-12(p70), which consists of subunits p40 and p35. In the table, all amounts of inflammatory cytokines are expressed in pg / mg. [Table 1]

[0082] As shown in Table 1, in Group 2, which was administered the control composition, no significant changes were observed in the levels of various inflammatory cytokines in the hippocampus compared to Group 1. On the other hand, in Group 3, which was administered the test composition, 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 were significantly reduced (p<0.05) or showed a tendency to decrease (p<0.1) compared to Group 1. These results indicate that the composition of the present invention reduces the levels of various inflammatory cytokines in the hippocampus.

[0083] The above results indicate that a composition containing Lactobacillus lactic acid bacteria can effectively suppress inflammation in brain tissue, particularly inflammation in the hippocampus. Furthermore, since it has been conventionally suggested that inflammation in brain tissue, particularly inflammation in the hippocampus, is involved in the onset and progression of brain diseases such as Alzheimer's disease, the above results indicate that a composition containing Lactobacillus lactic acid bacteria can treat and / or prevent various brain diseases that develop and progress due to inflammation in brain tissue. Moreover, since it has been suggested that inflammatory cytokines cause mental and mood disorders by damaging nerve cells in brain tissue or inhibiting the formation of normal nerve cells, the above results also indicate that a composition containing Lactobacillus lactic acid bacteria can reduce the amount of inflammatory cytokines in brain tissue and treat and / or prevent mental and mood disorders. In other words, the above results indicate that the composition of the present invention can effectively suppress inflammation in brain tissue, particularly inflammation in the hippocampus. Furthermore, the above results suggest that this approach can be used to improve disorders and diseases caused by inflammation of brain tissue, particularly those caused by inflammation of the hippocampus, such as impaired higher brain function, mental disorders, and mood disorders. [Industrial applicability]

[0084] According to the present invention, the amount of inflammatory cytokines in the target brain tissue can be effectively reduced, thereby suppressing inflammation in the target brain tissue. Furthermore, according to the present invention, by suppressing inflammation in the target brain tissue, disorders and diseases caused by inflammation in the brain tissue can be improved.

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 genus Lactobacillus, The aforementioned improvement composition is intended to reduce the amounts of interleukin-12 and interleukin-17 in the hippocampus. The lactic acid bacteria have the activity to reduce the amount of interleukin-12 and interleukin-17 in the hippocampus. The aforementioned lactic acid bacteria include Lactobacillus plantarum OLL2712 strain deposited under accession number FERM BP-11262, The aforementioned higher brain dysfunction is an impairment of at least one function selected from the group consisting of selective attention, cognitive function, memory function, executive function, and learning function. Composition for improvement.

2. The composition according to claim 1, wherein the aforementioned disorder is a higher brain dysfunction.

3. The composition according to claim 1 for at least one selected from for improving cognitive function, enhancing cognitive function, suppressing cognitive decline, suppressing the increase in the risk of dementia, reducing the risk of dementia, improving memory function, maintaining memory function, and suppressing the decline of memory function.

4. The composition according to claim 2 or 3 for improving a disease caused by the aforementioned higher brain dysfunction.

5. The composition according to claim 4, wherein the improvement is the treatment or prevention of the disease by a non-medical act.

6. The composition according to claim 4 or 5, wherein the disease is selected from the group consisting of Alzheimer's disease, Lewy body dementia, frontotemporal dementia, amnesia syndrome, generalized attention disorder, social behavior disorder, and memory impairment.

7. The composition according to any one of claims 1 to 6, wherein the lactic acid bacteria include dead cells of the lactic acid bacteria.

8. The composition according to any one of claims 1 to 7, wherein the lactic acid bacteria include heat-treated dead cells.

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