WO2021010118A1 - Composition pour l'amélioration ou la prophylaxie de troubles de l'anxiété et/ou de troubles de l'humeur - Google Patents

Composition pour l'amélioration ou la prophylaxie de troubles de l'anxiété et/ou de troubles de l'humeur Download PDF

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WO2021010118A1
WO2021010118A1 PCT/JP2020/024878 JP2020024878W WO2021010118A1 WO 2021010118 A1 WO2021010118 A1 WO 2021010118A1 JP 2020024878 W JP2020024878 W JP 2020024878W WO 2021010118 A1 WO2021010118 A1 WO 2021010118A1
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composition
enterococcus
receptor
test
expression
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PCT/JP2020/024878
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English (en)
Japanese (ja)
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謙太郎 永岡
淳 神邉
祐子 板谷
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コンビ株式会社
国立大学法人東京農工大学
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Priority to KR1020217038309A priority Critical patent/KR20220034724A/ko
Publication of WO2021010118A1 publication Critical patent/WO2021010118A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a composition for improving anxiety disorder and / or mood disorder, and more specifically, for improving or preventing anxiety disorder and / or mood disorder containing a bacterium belonging to the genus Enterococcus as an active ingredient. With respect to the composition of.
  • the present invention also relates to a composition for enhancing the expression of at least one receptor selected from the group consisting of ⁇ 3 adrenergic receptor, dopamine D5 receptor and vasopressin receptor 1A, which comprises the bacterium as an active ingredient. ..
  • the present invention relates to a composition for activating neurotransmission in the brain, which comprises the bacterium as an active ingredient.
  • Non-Patent Document 1 discloses the cerebrointestinal axis plays an important role not only in human physical health but also in mental health.
  • research results on humans and rodents have shown that the diversity and abundance of the intestinal flora is reduced in depression (Non-Patent Document 1).
  • depressive behavior such as depressive symptoms, anxiety and sexual coldness is induced, and tryptophan metabolism responsible for biosynthesis of neurotransmitters such as serotonin may be altered. It has been reported (Non-Patent Document 1).
  • Non-Patent Document 2 changes in the intestinal flora also affect the HPA axis (hypothalamic-pituitary-adrenal system axis), which is responsible for the defense response to stress, and probiotics (so-called good bacteria) involved in it are also detected.
  • Non-Patent Document 2 Furthermore, the direct association between bacterial flora and HPA reactivity has been demonstrated by Sudo et al. Specifically, the response of corticosterone and adrenocorticotropic hormone to restraint stress in sterile mice (germ-free mice) was enhanced as compared with normal SPF mice (conventionally house-specific pathogen-free mice). It has been reported by Sudo et al. (Non-Patent Document 2), and the results of this research reveal that the intestinal environment contributes not only to immunity but also to brain development and the endocrine system. ing.
  • Non-patent Document 4 discloses that probiotics may regulate stress responsiveness and stress-related behaviors. For example, in rats pretreated with probiotic Lactobacillus farciminis, it has been found to reduce intestinal permeability typically resulting from restraint stress and suppress the associated increase in HPA reactivity. Document 3). In addition, recent studies have shown that healthy male Balb / C mice are fed with Lactobacillus rhamnosus, resulting in elevated cross labyrinth test (EPM), forced swimming test (FST) and open field test (OF). It has been clarified that anxiety-like and depression-like behaviors are reduced (Non-Patent Document 4).
  • EPM cross labyrinth test
  • FST forced swimming test
  • OF open field test
  • Non-Patent Document 5 the probiotic-treated mouse population increased the number of invasions into the open arm in EPM, decreased the immobility time in FST, and increased the number of invasions and staying time in the central region in OF. I let you.
  • adult rats that had undergone mother-infant segregation during the neonatal period were found to have reduced depressive symptoms and behavioral effects seen in antidepressant treatment after treatment with probiotic Bifidobacterium infantis.
  • An object of the present invention is to find a bacterium having an anxiolytic effect and / or antidepressant effect, and to provide a composition for improving or preventing anxiety disorder and / or mood disorder containing the bacterium as an active ingredient. And.
  • the present inventors ingested a bacterium belonging to the genus Enterococcus into mice and subjected them to various behavioral tests (open field test, elevated cross maze test, forced swimming test) to analyze their behavior.
  • various behavioral tests open field test, elevated cross maze test, forced swimming test
  • enterococcus non-ingestion group control group
  • enterococcus has an anxiolytic effect. It became clear that there was.
  • Enterococcus is a type of lactic acid bacterium, which is a normal intestinal bacterium of humans and animals.
  • Previous studies have shown that when humans were given a heat-treated product (killed bacteria) of Enterococcus faecalis EC-12 strain, fatty acids such as fecal metabolic components and microbiota, lactic acid, and bifidobacteria changed. (Non-Patent Document 6).
  • Another study has shown that EC-12 induces interferon- ⁇ release in in situ experiments (Non-Patent Document 7).
  • EC-12 communicates with the host immune system to induce IgA production in young calves (Non-Patent Document 8).
  • the present inventors further analyzed gene expression in the frontal lobe of Enterococcus-fed mice. As a result, it was also clarified that the expression of Adrb3 ( ⁇ 3 adrenergic receptor) gene, Avpr1a (vasopressin receptor 1A) gene and Drd5 (dopamine D5 receptor) gene was enhanced. These are all genes encoding receptors involved in the activation of neurotransmission. In addition, it has been reported that Drb3 induces anxiolytic-like behavior and antidepressant-like behavior, and Drd5 promotes fear elimination and reward acquisition behavior.
  • Adrb3 ⁇ 3 adrenergic receptor
  • Avpr1a vaspressin receptor 1A
  • Drd5 dopamine D5 receptor
  • the present invention relates to a composition for improving anxiety disorder and / or mood disorder.
  • the present invention also relates to a composition for enhancing the expression of at least one receptor selected from the group consisting of ⁇ 3 adrenergic receptor, dopamine D5 receptor and vasopressin receptor 1A, which comprises the bacterium as an active ingredient. ..
  • the present invention relates to a composition for activating neurotransmission in the brain, which comprises the bacterium as an active ingredient, and more specifically, it is as follows.
  • ⁇ 1> A composition for improving or preventing anxiety disorders and / or mood disorders, which comprises a bacterium belonging to the genus Enterococcus as an active ingredient.
  • ⁇ 2> A composition for activating neurotransmission in the brain, which contains a bacterium belonging to the genus Enterococcus as an active ingredient.
  • ⁇ 3> A composition for enhancing the expression of at least one receptor selected from the group consisting of ⁇ 3 adrenergic receptor, dopamine D5 receptor and vasopressin receptor 1A, which comprises a bacterium belonging to the genus Enterococcus as an active ingredient.
  • ⁇ 4> The composition according to any one of ⁇ 1> to ⁇ 3>, wherein the bacterium belonging to the genus Enterococcus is Enterococcus faecalis.
  • ⁇ 5> The composition according to any one of ⁇ 1> to ⁇ 3>, wherein the bacterium belonging to the genus Enterococcus is Enterococcus faecalis EC-12 strain.
  • the present invention it is possible to enhance the expression of ⁇ 3 adrenergic receptor, vasopressin receptor 1A and dopamine D5 receptor. In addition, by enhancing the expression of these neurotransmitter receptors, it becomes possible to activate neurotransmission in the brain. Furthermore, according to the present invention, it is possible to improve or prevent anxiety disorders and / or mood disorders such as depression by exerting anxiolytic and / or antidepressant effects.
  • mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure) in an open field test are shown. It is a heat map. In the figure, under the color display, the area shown in blue indicates that the mouse staying time in the area is shorter, while the area shown in red indicates that the mouse staying time in the area is longer. In an open field study, the time spent in the central zone of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure) is shown. It is a graph.
  • the vertical axis in the figure indicates the percentage of time each mouse stayed in the central zone during the total test time.
  • the open field test the number of invasions into the central zone of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure) is shown.
  • the graph In the elevated cross maze test, the time spent in the closed arm of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure) was determined. It is a graph which shows.
  • the vertical axis in the figure shows the percentage (%) of the time each mouse stayed in the closed arm in the total test time.
  • the vertical axis in the figure indicates the percentage of time each mouse stayed in the central zone during the total test time.
  • a graph showing the immobility time of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure). is there.
  • the vertical axis in the figure shows the percentage (%) of the time when each mouse did not move in the total test time. It is a figure which shows the result of having compared the expression level of the neurotransmitter receptor in the frontal lobe by the PCR array between the mouse which ingested the Enterococcus faecalis EC-12 strain and the mouse which did not ingest the bacterial strain.
  • red indicates a neurotransmitter receptor that showed higher expression in mice fed with Enterococcus faecalis EC-12 strain
  • blue indicates that Enterococcus faecalis EC-12 strain was ingested.
  • the treated mice show neurotransmitter receptors that show lower expression.
  • Gene expression in the frontal lobe of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure) was analyzed by quantitative real-time PCR. It is a graph which shows the result. In the figure, the vertical axis shows a relative value when the expression level of each gene in the mouse not fed with the bacterial strain is 1.
  • the vertical axis represents the occupancy rate (relative abundance, Reactive abundance of taxa) of Bacteria belonging to the genus Butyricoccus.
  • Bacterial genomic DNA was extracted from the cecal contents of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure).
  • EC12 Enterococcus faecalis EC-12 strain
  • control the vertical axis represents the occupancy rate of Enterococcus bacteria (relative abundance, Reactive abundance of taxa).
  • Bacterial genomic DNA was extracted from the cecal contents of mice fed with Enterococcus faecalis EC-12 strain (“EC12” in the figure) and mice not fed with the bacterial strain (“control” in the figure). It is a box plot figure which shows the result of generation sequence analysis. In the figure, the vertical axis represents the occupancy rate (relative abundance, Reactive abundance of taxa) of bacteria belonging to the genus Lactobacillus.
  • the present inventors analyzed the behavior of mice ingesting bacteria belonging to the genus Enterococcus.
  • the open field test and the elevated cross labyrinth test which are tests for evaluating anxiety and fear, a significant difference from the enterococcus non-ingestion group (control group) was observed, and enterococcus has an anxiolytic effect. It was revealed that there was.
  • Adrb3 ⁇ 3 adrenergic receptor
  • Avpr1a vasopressin receptor 1A
  • Drd5 dopamine D5 receptor
  • the present invention is for enhancing the expression of at least one receptor selected from the group consisting of ⁇ 3 adrenergic receptor, dopamine D5 receptor and vasopressin receptor 1A, which comprises a bacterium belonging to the genus Enterococcus as an active ingredient.
  • ⁇ 3 adrenergic receptor a receptor selected from the group consisting of ⁇ 3 adrenergic receptor, dopamine D5 receptor and vasopressin receptor 1A, which comprises a bacterium belonging to the genus Enterococcus as an active ingredient.
  • composition for activating neurotransmission in the brain which contains the bacterium as an active ingredient.
  • the present invention relates to a composition for improving or preventing anxiety disorders and / or mood disorders, which comprises the bacterium as an active ingredient.
  • the "bacteria belonging to the genus Enterococcus” contained as an active ingredient in the composition of the present invention belongs to the phylum Firmicutes of lactic acid bacteria and is a bacterium contained in enterococci.
  • Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae can be mentioned.
  • Enterococcus faecalis include strains such as Enterococcus faecalis EC-12 strain, ATCC 19433, ATCC 14508, ATCC 23655, IFO 16803, and IFO 16804, or mutant strains thereof.
  • a "mutant strain” is a strain that has been mutated to a specific strain by a method well known to those skilled in the art to the extent that the person skilled in the art does not change its properties, or is confirmed by those skilled in the art to be equivalent thereto. It means to include what can be done.
  • the bacterium contained as an active ingredient in the composition of the present invention is preferably Enterococcus faecalis, and more preferably Enterococcus faecalis EC-12 strain.
  • Enterococcus faecalis EC-12 strain (Enterococcus faecalis EC-12) was released on February 25, 2005 (original deposit date) at the National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary Center ( ⁇ ). 305-5466 Deposited at 1-1-1, Central 6), East 1-1, Tsukuba City, Ibaraki Prefecture, Japan. The accession number is FERM BP-10284.
  • the patented microorganism deposit business was carried out by the National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary Center (former name: IPOD), and the National Institute of Technology and Evaluation (NITE, ⁇ 292-0818, Kisarazu City, Chiba Prefecture). It was succeeded to Kazusakamatari 2-5-8, Room 122).
  • the bacterium belonging to the genus Enterococcus is contained as a live bacterium and as a dead bacterium.
  • the killed cells are preferable as the active ingredient of the composition of the present invention in that they have excellent heat resistance, stable quality, and can be widely used as foods and pharmaceuticals because they do not contaminate the production line.
  • the "killed cells" in the composition of the present invention include heat-sterilized cells (heat-sterilized bodies).
  • the heat sterilized product can be prepared from a culture obtained by culturing a bacterium belonging to the genus Enterococcus according to a conventional method.
  • the preparation method is not particularly limited, but for example, the cells are collected by a method such as filtration or centrifugation, washed with water, suspended in water or the like (distilled water, physiological saline, etc.), and at 120 ° C. or lower ( It can be prepared by heat treatment within 30 minutes (preferably 30 minutes to 3 seconds) at 80 to 120 ° C.).
  • the "killed cells" according to the present invention can be obtained by subjecting to, for example, firing, steaming (for example, 170 ° C. or lower, within 60 minutes), gamma ray or neutron beam irradiation instead of the heat treatment.
  • firing for example, firing, steaming (for example, 170 ° C. or lower, within 60 minutes), gamma ray or neutron beam irradiation instead of the heat treatment.
  • steaming for example, 170 ° C. or lower, within 60 minutes
  • gamma ray or neutron beam irradiation instead of the heat treatment.
  • a fire sterilizer, a steam sterilizer, an irradiation sterilizer may be used.
  • these killed cells may be in the form of a suspension with water or the like, or may be in the form of a dried product thereof.
  • the method of drying from the suspension is not particularly limited, and examples thereof include spray drying and freeze drying.
  • enzyme treatment, surfactant treatment, and grinding / crushing treatment can be performed before and after the sterilization treatment by heating or the like, or before and after the drying treatment, and those obtained by these treatments are also available. It is included in the killed cells of the present invention.
  • the heat-sterilized cells of Enterococcus faecalis EC-12 strain are commercially available under the product name "EC-12" (manufactured by Combi Corporation Life Science Division).
  • the bacterium belonging to the genus Enterococcus contained as an active ingredient in the composition of the present invention may be a bacterial cell as described above, and may be a substance contained in the bacterium, a secretory product of the bacterium, or a metabolite of the bacterium. There may be.
  • ⁇ 3 adrenaline receptor (Adrb3), whose expression is enhanced by bacteria belonging to the genus Enterococcus, is one of the G protein-conjugated receptors activated by catecholamines such as adrenaline and noradrenaline, and is human. If it is derived, it is typically a protein consisting of the amino acid sequence specified by GenBank accession number: NP_0000016 (protein encoded by the nucleotide sequence specified by GenBank accession number: NM_0000025), and is a mouse. If it is derived, it is typically a protein consisting of the amino acid sequence specified by GenBank accession number: NP_038490 (protein encoded by the nucleotide sequence specified by GenBank accession number: NM_013462).
  • the dopamine D5 receptor (Drd5) whose expression is enhanced by a bacterium belonging to the genus Enterococcus is a G protein-conjugated receptor activated by dopamine (dopamine) and is of human origin.
  • a protein consisting of an amino acid sequence specified by GenBank accession number: NP_000789 protein encoded by a nucleotide sequence specified by GenBank accession number: NM_000798
  • NP_038531 protein encoded by the nucleotide sequence specified by GenBank accession number: NM_013503
  • the vasopressin receptor 1A (Avpr1a) whose expression is enhanced by bacteria belonging to the genus Enterococcus is a G protein-conjugated receptor activated by arginine vasopressin (AVP) and may be of human origin.
  • AVP arginine vasopressin
  • it is typically a protein consisting of an amino acid sequence specified by GenBank accession number: NP_000697 (a protein encoded by a nucleotide sequence specified by GenBank accession number: NM_000706), and may be derived from a mouse.
  • GenBank accession number: NP_058543 protein encoded by a nucleotide sequence specified by GenBank accession number: NM_016847).
  • the neurotransmitter receptors described above also include such naturally occurring variants without being specified in the sequences cited as typical examples.
  • expression includes not only expression at the transcription level (expression as mRNA) but also expression at the translation level (expression as a protein).
  • the site where the expression of the neurotransmitter receptor is enhanced is not particularly limited, but is, for example, the central nervous system, preferably the brain, and more preferably the frontal lobe.
  • the neurotransmission of the brain activated by bacteria belonging to the genus Enterococcus is not particularly limited, and examples thereof include neurotransmission involving catecholaminergic nerves, dopaminergic nerves or vasopressin nerves.
  • the site where the neurotransmission is activated is not particularly limited as long as it is in the brain, but is preferably the frontal lobe.
  • the "anxiety disorder” that is improved by bacteria belonging to the genus Enterococcus means a state in which anxiety is excessive.
  • “anxiety” means an emotional response to an unpleasant stimulus, and includes not only the case where a clear object does not exist but also the case where it exists (so-called fear).
  • anxiety disorder includes, for example, generalized anxiety disorder (GAD), social anxiety disorder, substance-induced anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and acute stress.
  • GAD generalized anxiety disorder
  • OCD obsessive-compulsive disorder
  • PTSD post-traumatic stress disorder
  • ASD anti-spasmodic disorder
  • segregation anxiety disorder panic disorder (fear: social phobia, height phobia, generalized anxiety disorder, advanced phobia, animal phobia, etc.), obsessive-compulsive intestinal syndrome, fibromyalgia Can be mentioned.
  • the "mood disorder” that is improved by bacteria belonging to the genus Enterococcus means a state in which the person goes too far and feels depressed (so-called depression, depression).
  • “mood disorders” include, for example, major depressive disorder (MDD), bipolar disorder (BD), atypical depression, depressive depression, psychotic major depression, tension depression, and postpartum. Depression, seasonal emotional disorders, dysthymia, unspecified depressive disorder (DD-NOS), substance-induced mood disorders, postmenopausal depression, and adolescent depression.
  • MDD major depressive disorder
  • BD bipolar disorder
  • atypical depression depression
  • depressive depression depression
  • psychotic major depression atypical depression
  • tension depression atypical depression
  • DD-NOS unspecified depressive disorder
  • substance-induced mood disorders substance-induced mood disorders
  • postmenopausal depression postmenopausal depression
  • adolescent depression adolescent depression.
  • “improvement” includes not only complete recovery (treatment) from the above disorder, but also alleviation of the symptoms of the above disorder and suppression of its progression. “Prevention” includes suppressing or delaying the onset of the disorder and suppressing its recurrence.
  • composition of the present invention may be in the form of a pharmaceutical composition, food or drink (including animal feed), or a reagent used in a model animal experiment or the like.
  • composition in the present invention can be formulated by a known pharmaceutical method.
  • a known pharmaceutical method for example, capsules, tablets, pills, liquids, powders, granules, fine granules, film coatings, pellets, lozenges, sublinguals, chews, buccal agents, pastes, syrups, suspensions, Orally or parenterally as an elixir, emulsion, coating, ointment, ointment, pap, transdermal absorption type preparation, lotion, inhalant, aerosol, injection, suppository, etc.
  • the present invention can be orally ingested non-invasively and easily, as shown in Examples described later. That is, the preferred method of ingesting the composition of the present invention is oral ingestion.
  • pharmacologically or food and drink acceptable carriers specifically saline, sterile water, vegetable oils, solvents, excipients, bases, emulsifiers, suspending agents, surfactants , Stabilizers, flavoring agents, fragrances, vehicles, preservatives, binders, diluents, isotonic agents, soothing agents, bulking agents, disintegrants, buffers, coating agents, lubricants, colorants, sweetness It can be appropriately combined with an agent, a thickener, a flavoring agent, a solubilizing agent, or other additives.
  • composition of the present invention When used as a pharmaceutical composition, it may be used in combination with a known substance used for improving or preventing the above-mentioned disorders.
  • known substances include antidepressants (benzodiazepine antidepressants, etc.), antidepressants (selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrin (noradrenaline) reuptake inhibitor (SNRI), etc.
  • Tricyclic antidepressants TCA
  • tetracyclic antidepressants TAA
  • triazolopyridine antidepressants SARI
  • monoamine oxidase inhibitors MAO inhibitors
  • noradrenergic and specific serotoninergic antidepressants Drugs (NaSSA), norepinephrine / dopamine reuptake inhibitors (NDRI)).
  • the food or drink may be, for example, a health food, a functional food, a food for specified health use, a food with a nutritional function, a food with a functional claim, a nutritional supplement, a food for the sick, or It can be an animal feed.
  • Functional foods are usually classified into three categories, probiotics, biogenics, and prebiotics, based on the mechanism of action thereof, and in the present invention, the modes of probiotics and biogenics can be taken. ..
  • the food and drink of the present invention can be ingested as the composition as described above, and can also be ingested as various foods and drinks.
  • Specific examples of foods and drinks include fermented foods such as yogurt and drink yogurt, fermented beverages; products containing oils such as cooking oil, dressings, mayonnaise and margarine; soups, dairy beverages, soft drinks, tea beverages and alcoholic beverages.
  • Liquid foods such as drinks, jelly-like beverages and functional beverages; carbohydrate-containing foods such as rice, noodles and bread; processed livestock foods such as ham and sausage; processed marine foods such as kamaboko, dried food and salty foods; Processed vegetable foods such as; Semi-solid foods such as jelly; Fermented foods such as miso; Western confectionery, Japanese confectionery, candy, gums, gummy, chilled confectionery, ice confectionery, etc.; curry, ankake, Chinese soup, etc. Retort products; instant foods such as instant soup and instant miso soup, and microwave-compatible foods. Further, healthy foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly can be mentioned.
  • the food and drink according to the present invention can be produced by a production technique known in the art.
  • one or more components effective for improving or preventing the above-mentioned disorders for example, other lactic acid bacteria (for example, Lactobacillus farciminis, Lactobacillus rhamnosus, Bifidobacterium infantis, etc.), enterococcus bacteria in the intestinal tract, etc.
  • One or more components eg, prebiotic components such as oligosaccharides and dietary fibers
  • it may be a multifunctional food or drink by combining it with other ingredients or other functional foods that exhibit functions other than the improvement.
  • composition of the present invention can be used for animals including humans, but there are no particular restrictions on animals other than humans, and various domestic animals, poultry, pets, laboratory animals and the like can be targeted. it can. Specific examples include, but are not limited to, pigs, cows, horses, sheep, goats, chickens, ducks, ostriches, ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys and the like.
  • the target of the composition of the present invention includes animals suffering from the above-mentioned disorder regardless of the onset thereof, and from the viewpoint of prevention, the above-mentioned disorder is not developed or the above-mentioned disorder is defined. Animals suspected of being affected may be administered or ingested the compositions of the invention. Furthermore, from the viewpoint of preventing recurrence, the composition of the present invention can be suitably used even for animals that do not have the symptoms.
  • the dose or ingestion thereof depends on the age, body weight, symptoms of the above disorders, health condition, type of composition (pharmaceutical products, foods and drinks, etc.), etc. It is selected as appropriate.
  • the daily dose or intake of bacteria belonging to the genus Enterococcus is generally 0.5 ⁇ 10 9 / kg body weight to 50 ⁇ 10 9 / kg body weight, preferably 2 ⁇ 10 9 / kg body weight.
  • the body weight is from kg to 50 ⁇ 10 9 pieces / kg.
  • the daily dose or intake of bacteria belonging to the genus Enterococcus is preferably 10 mg / kg body weight to 1 g / kg body weight, more preferably 20 mg / kg body weight to 500 mg / kg body weight, and further preferably 50 mg / kg body weight. It can also be exemplified by a body weight of ⁇ 200 mg / kg.
  • the present invention also improves anxiety disorders and / or mood disorders in a subject, which is characterized in that a bacterium belonging to the genus Enterococcus or a composition containing the same as an active ingredient is administered or ingested to the subject. Alternatively, it also provides a method for prevention.
  • the administration or ingestion of a bacterium belonging to the genus Enterococcus or a composition containing it as an active ingredient is as described above, but the administration or ingestion is divided into once or a plurality of times (for example, twice) per day. You may.
  • the period of administration or ingestion may be discontinued depending on the degree of improvement of the above-mentioned disorder, but from the viewpoint of preventing recurrence, administration or ingestion may be continued without discontinuation.
  • Continuous it may be continued every day or at intervals, but in terms of effect, bacteria belonging to the genus Enterococcus or a composition containing it as an active ingredient is administered or ingested continuously every day. Is preferable.
  • the products (pharmaceuticals, foods and drinks, reagents) or instructions thereof of the compositions of the present invention improve or prevent anxiety disorders and / or mood disorders, activate neurotransmission in the brain, or the neurotransmitter receptors described above. It may be labeled as being used to enhance the expression of.
  • the labeling of health functions as health functional foods can be distinguished from general foods in terms of form and subject, etc. It may be attached to a product of the composition or the like.
  • "marked on a product or instruction manual” means that a label is attached to the main body, container, packaging, etc. of the product, or a manual, package insert, promotional material, or other printed matter that discloses product information. It means that the display is attached to.
  • AIN93-M manufactured by Oriental Yeast Co., Ltd.
  • the amount of 0.125 mass% EC-12 compounded AIN93-M is an amount set by predicting that 100 mg of EC-12 is ingested per 1 kg of body weight per day.
  • a behavioral test was conducted after 4 weeks (during an appropriate period of 12 weeks of age). The behavioral test was recorded by a video system and analyzed using video tracking software (manufactured by Muromachi Machinery Co., Ltd., product name: ANY-maze). After each test was completed, the instruments were washed with 70% ethanol to ensure that no irritating substances (cues) such as odors or hair remained and that unintended bias was not applied to the experimental results.
  • mice were anesthetized with isoflurane (manufactured by Wako Pure Chemical Industries, Ltd.), and the frontal lobe and cecal contents were collected. All samples were then stored at ⁇ 80 ° C.
  • the cDNA synthesized using the total RNA extracted from the frontal lobe as a template was subjected to a PCR array of neurotransmitter receptors and also to real-time PCR. Genomic DNA was extracted from the contents of the cecum and used for next-generation sequence analysis.
  • Behavioral test Open Field Test In the open field test, mouse movement, behavioral activity level, and anxiety-like behavior were comprehensively evaluated. Behavioral activities show emotional reactions such as depression and anxiety. In this test, a square cage (40 x 40 x 30 cm) was used as the device.
  • Elevated cross maze test An elevated cross maze test was performed to measure anxiety-like behavior.
  • the device used in this test has two open arms (25 x 5 cm, with a 3 cm high wall (ledge)) and two closed arms (25 x 5 cm, with a 30 cm high transparent wall). Crosses in a cross shape on the central platform (5 x 5 cm). The arm and central platform were made of white plastic plate. The entire device was installed 55 cm from the floor.
  • the forced swimming test is one of the experimental methods for causing depressive symptoms in rodents, and is used to evaluate the antidepressant effect of antidepressants and novel compounds.
  • a cylindrical beaker made of glass (height 28 cm, diameter 16 cm) was used as the aquarium.
  • the water level was 10 cm from the bottom.
  • the temperature of the water was measured with a thermometer and set to 23-25 ° C.
  • RNA solution prepared from the frontal lobe of each mouse was collected and mixed in each group. Then 4 ⁇ L of total RNA cocktail was used.
  • the cDNA was synthesized using the RT2 First Strand cDNA Synthesis Kit Mouse Neurotransmitter Receptor (manufactured by Qiagen).
  • Quantitative real-time PCR was performed using a power-up SYBR Green Master Mix (manufactured by Applied Bio Biosystem) and 7500 high-speed real-time PCR (manufactured by Applied Bio Biosystem) in a volume of 25 ⁇ L according to the instruction manual.
  • the conditions of the PCR cycle are as follows. Repeat 40 cycles of 95 ° C. for 10 minutes, then 95 ° C. for 15 seconds and 60 ° C. for 1 minute. The results were analyzed at the GeneGlobal Data Analysis Center (Qiagen). The obtained results are shown in FIGS. 3A to 3C.
  • next-generation sequence analysis Bacterial genomic DNA was extracted from the cecal contents and used for next-generation sequence analysis. Genomic DNA extraction and next-generation sequence analysis can be performed by Watcharin N. et al. Sovigit et al., Neurosci Res. , April 22, 2019, pii: S0168-0102 (19) 30142-7 ("2.4. Execution of DNA from DNA sequencing” and "2.5. Library preparation and DNA sequencing”). It was done along.
  • Example 2 Gene expression in the frontal lobe
  • the expression of the neurotransmitter receptor gene in the frontal lobe was comprehensively analyzed by PCR array analysis.
  • the expression of neurotransmitter receptor genes in the frontal lobe was analyzed by quantitative real-time PCR.
  • Adrb3 ( ⁇ 3 adrenergic receptor), Avpr1a (vasopressin receptor 1A) and Drd5 (dopamine D5 receptor), whose gene expression was enhanced by ingestion of EC-12, are all receptors involved in the activation of neurotransmission.
  • the body Therefore, it is suggested that neurotransmission is activated in the brain such as the frontal lobe with the increase of these neurotransmitter receptors due to the ingestion of bacteria belonging to the genus Enterococcus.
  • Adrb3 it has been clarified from the results of research using its selective agonist amibegron that it induces anxiolytic-like behavior and antidepressant-like behavior (Tanyeri, Pelin et al., Pharmacol Biochem Behav., See September 2013, Volume 110, pp. 27-32).
  • Drd5 along with its family, Drd1, has been reported to promote fear-eliminating and reward-earning behaviors (Perreal, Melissa L. et al., Eur J Neurosci., August 2017, Vol. 46, No. 4). , See pages 2015-2025).
  • Example 3 Analysis of cecal stool cecal stool The cecal stool of EC-12-fed mice was comprehensively analyzed by a next-generation sequencer. As a result, as shown in FIGS. 4A and 4B, the occupancy rates of each of the bacteria of the genus Butyricococcus and the bacterium of the genus Enterococcus were higher in the EC-12 intake group than in the control group. On the other hand, the occupancy rate of Lactobacillus bacteria was lower in the EC-12 intake group.
  • butyric acid Bacteria of the genus Butyricoccus have been shown to produce butyric acid. Therefore, it is presumed that a large amount of butyric acid is produced as the number of utyricoccus bacteria increases due to ingestion of bacteria belonging to the genus Enterococcus, which is involved in the regulation of expression of genes in the brain such as the neurotransmitter receptor gene. To.
  • the composition of the present invention is useful in improving, treating or preventing mood disorders such as anxiety disorders and depression.

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Abstract

Il a été découvert que l'expression du récepteur adrénergique β3, du récepteur de la dopamine D5 et du récepteur 1A de la vasopressine est améliorée par l'ingestion d'une bactérie appartenant au genre Enterococcus. Il a également été découvert que l'expression améliorée de ces récepteurs de neurotransmetteurs est accompagnée de l'activation de la neurotransmission dans le cerveau et de la présentation d'un effet anxiolytique et d'un effet antidépression. L'invention concerne une composition qui est destinée à l'amélioration ou à la prophylaxie de troubles de l'anxiété et/ou de troubles de l'humeur tels que la dépression et qui contient ladite bactérie en tant que principe actif.
PCT/JP2020/024878 2019-07-12 2020-06-24 Composition pour l'amélioration ou la prophylaxie de troubles de l'anxiété et/ou de troubles de l'humeur WO2021010118A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022182908A1 (fr) * 2021-02-26 2022-09-01 California Institute Of Technology Thérapies probiotiques pour le déficit social et la réponse au stress

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018215759A1 (fr) * 2017-05-22 2018-11-29 4D Pharma Research Limited Compositions comprenant des souches bactériennes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5931884B2 (ja) * 2010-10-07 2016-06-08 カリフォルニア インスティチュート オブ テクノロジー 自閉症の生菌療法
US20160177424A1 (en) * 2014-10-16 2016-06-23 Korea Institute Of Machinery & Materials Ni-base superalloy and manufacturing method thereof
KR20170086027A (ko) * 2014-10-30 2017-07-25 캘리포니아 인스티튜트 오브 테크놀로지 신경발달 장애에서의 행동을 개선시키기 위한 박테리아를 포함하는 조성물 및 방법
CA2966363A1 (fr) * 2014-10-30 2016-05-06 California Institute Of Technology Compositions et procedes comprenant des bacteries pour ameliorer le comportement dans les troubles neurodeveloppementaux
CN108244655A (zh) * 2018-02-02 2018-07-06 云南中京国建投资有限公司 一种安神、抗抑郁的合生元组合物及其制剂与应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018215759A1 (fr) * 2017-05-22 2018-11-29 4D Pharma Research Limited Compositions comprenant des souches bactériennes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ENCK P., ZIMMERMANN K., MENKE G., MÜLLER-LISSNER S., MARTENS U., KLOSTERHALFEN S.: "A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome - A randomized controlled trial with primary care physicians", NEUROGASTROENTEROLOGY AND MOTILITY, BLACKWELL SCIENTIFIC PUBLICATIONS, OXFORD, GB, vol. 20, no. 10, 1 October 2008 (2008-10-01), GB, pages 1103 - 1109, XP055789981, ISSN: 1350-1925, DOI: 10.1111/j.1365-2982.2008.01156.x *
KAMBE, J. ET AL.: "Heat-killed Enterococcus fecalis ( EC -12) supplement alters the expression of neurotransmitter receptor genes in the prefrontal cortex and alleviates anxiety-like behavior in mice.", NEUROSCIENCE LETTERS, vol. 720, no. 134753, 10 January 2020 (2020-01-10), pages 1 - 7, XP085991394, DOI: 10.1016/j.neulet.2020.134753 *
SHIMAKAWA, MASAKI ET AL.: "Effect of Streptococcus faecalis 129 BIO 3B on visceral hypersensitivity in an experimental model of irritable bowel syndrome", JOURNAL OF INTESTINAL MICROBIOLOGY, vol. 27, no. 2, 2013, pages 120 *
TAKAHASHI, K. ET AL.: "Effect of Enterococcus faecalis 2001 on colitis and depressive-like behavior in dextran sulfate sodium-treated mice: involvement of the brain-gut axis", JOURNAL OF NEUROINFLAMMATION, vol. 16, no. 201, 1 October 2019 (2019-10-01), pages 1 - 16, XP055789990 *
TSUKAHARA TAKAMITSU, INOUE RYO, NAKANISHI NOBUO, NAKAYAMA KEIZO, MATSUBARA NORITAKA, USHIDA KAZUNARI: "Evaluation of the Low Dose Level of a Heat-Killed and Dried Cell Preparation of Enterococcus faecalis to Prevent Porcine Edema Disease Using Experimental Infection Model with Enterotoxcemic Escherichia coli in Weaning Pigs", J. VET. MED. SCI, vol. 69, 1 January 2007 (2007-01-01), pages 103 - 109, XP055789988 *
TSUKAHARA, T. ET AL.: "Effect of a cell preparation of Enterococcus faecalis strain EC -12 on digesta flow and recovery from constipation in a pig model and human subjects", MICROBIAL ECOLOGY IN HEALTH AND DISEASE, vol. 17, 2005, pages 107 - 113, XP008167676, DOI: 10.1080/08910600510044507 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022182908A1 (fr) * 2021-02-26 2022-09-01 California Institute Of Technology Thérapies probiotiques pour le déficit social et la réponse au stress
US20220273732A1 (en) * 2021-02-26 2022-09-01 California Institute Of Technology Probiotic therapies for social deficit and stress response

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