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WO2018180728A1 - Composition favorisant l'expression d'un gène anti-inflammatoire - Google Patents

Composition favorisant l'expression d'un gène anti-inflammatoire Download PDF

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Publication number
WO2018180728A1
WO2018180728A1 PCT/JP2018/010882 JP2018010882W WO2018180728A1 WO 2018180728 A1 WO2018180728 A1 WO 2018180728A1 JP 2018010882 W JP2018010882 W JP 2018010882W WO 2018180728 A1 WO2018180728 A1 WO 2018180728A1
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WO
WIPO (PCT)
Prior art keywords
bifidobacterium
composition
inflammatory
infantis
culture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/010882
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English (en)
Japanese (ja)
Inventor
徹哉 久原
あづさ 田中
金忠 清水
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Morinaga Milk Industry Co Ltd
Original Assignee
Morinaga Milk Industry Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Morinaga Milk Industry Co Ltd filed Critical Morinaga Milk Industry Co Ltd
Priority to JP2019509361A priority Critical patent/JP6799673B2/ja
Publication of WO2018180728A1 publication Critical patent/WO2018180728A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • 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
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor

Definitions

  • the present invention relates to a composition for promoting the expression of inflammation control genes.
  • Intestinal health is important not only for one organ, the intestine, but also for general health.
  • the intestinal tract tissue has a barrier function and is responsible for preventing pathogenic microorganisms from entering the living body, such as by mobilizing about 60% of immune cells in the human body.
  • inflammatory cytokines TNF- ⁇ , IL-1 ⁇ , IL-6, etc.
  • the intestinal barrier function may be disrupted and spread to systemic chronic diseases.
  • inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are enteropathy of unknown cause and may be accompanied by complications other than the gastrointestinal tract, and are designated as designated intractable diseases.
  • a human antibody drug such as an anti-IL-23 antibody drug (Non-patent Document 1) or a steroid drug therapy is known. .
  • Non-Patent Document 1 Angiotensin converting enzyme 2 (ACE2), which is one of the enzymes that control the renin-angiotensin system, is an enzyme that converts AngII that induces vasoconstriction into Ang1-7 that antagonizes it, and suppresses inflammation. It is known to work (Non-Patent Document 2). ACE2 is known to maintain the intestinal environment by controlling amino acid absorption in the small intestine and suppress inflammatory effects (Non-patent Document 3).
  • Mucin1 (Muc-1) is known to suppress inflammatory signals via a wide range of TLR signals (Non-Patent Document 4).
  • Patent Documents 1 to 3 the use of microorganisms that are beneficial to health maintenance such as Bifidobacterium is called “probiotics”, and many studies have been conducted. It has also been reported on the preventive or ameliorating action of inflammatory diseases caused by Bifidobacterium (Patent Documents 1 to 3).
  • JP 2012-158568 A International Publication No. 2007/122885 Pamphlet JP 2011-032170 A
  • an object of the present invention is to provide a composition for promoting the expression of an inflammation regulatory gene and a composition for suppressing inflammatory cytokine production that are safe and have high effects.
  • an object of the present invention is to provide a composition for promoting the expression of an inflammation regulatory gene and a composition for suppressing the production of inflammatory cytokines, which are excellent in safety for infants and children and have a high effect.
  • the first invention for solving the above-mentioned problems is that Bifidobacterium infantis (Bifidobacterium longsp. Infantis) LMG23728 and / or Bifidobacterium breve (Bifidobacterium breve) FERM BP-11175
  • composition and “agent” have the same meaning.
  • the present invention also relates to Bifidobacterium infantis (Bifidobacterium longum subsp. Infantis) LMG23728 and / or Bifidobacterium breve (Bifidobacterium breve) FERM BP-11175 Bifidobacterium or its Bifidobacterium genus Is an inflammatory cytokine production inhibitor of TNF- ⁇ and / or IL-23 or a composition for suppressing inflammatory cytokine production.
  • the active ingredient of the composition is the culture supernatant of the Bifidobacterium.
  • the composition is a pharmaceutical composition or a food or drink composition.
  • composition of the present invention is preferably used for the prevention and / or improvement of one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • cultivation are high safety
  • the second invention for solving the above-mentioned problems is to promote the expression of one or more inflammation control genes selected from the group consisting of ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10 Bifidobacterium infantis (Bifidobacterium longum subsp. Infantis) LMG23728 and / or Bifidobacterium breve FERM BP-11175 Bifidobacterium or Bifidobacterium spp. Or it is a culture supernatant, The preferable form of the said bacteria or its culture or culture supernatant is as above-mentioned.
  • the present invention provides Bifidobacterium longum subsp. Infantis LMG 23728 and / or Bifidobacterium breve used for suppression of TNF- ⁇ and / or IL-23 inflammatory cytokine production.
  • Bifidobacterium breve It is also a Bifidobacterium bacterium of FERM BP-11175, or a culture or culture supernatant thereof, and the preferred form of the bacterium, or the culture or culture supernatant thereof is as described above.
  • the second invention has the following preferred forms.
  • the composition is a pharmaceutical composition or a food or drink composition.
  • the bacterium, or the culture or culture supernatant thereof is used for the prevention and / or improvement of one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • the inflammatory disease is an inflammatory disease of an infant or a child.
  • the third invention for solving the above-mentioned problems is to promote the expression of one or more inflammation control genes selected from the group consisting of ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10 Bifidobacterium infantis (Bifidobacterium longsp. Infantis) LMG23728 and / or Bifidobacterium breve (Bifidobacterium breve) FERM BP-11175 in the manufacture of the agent or expression promoting composition
  • the use of bacteria or a culture or culture supernatant thereof is preferred, and the preferred form of the bacteria or culture or culture supernatant is as described above.
  • the present invention also relates to Bifidobacterium longum subsp. Infantis LMG23728 and / or Bifidobacteria in the production of a composition for suppressing the production of inflammatory cytokines such as TNF- ⁇ and / or IL-23.
  • Bifidobacterium breve FERM BP-11175 Bifidobacterium genus, or a culture or culture supernatant thereof.
  • the preferred form of the bacterium, or the culture or culture supernatant is as described above. It is.
  • the third invention has the following preferable forms.
  • the composition is a pharmaceutical composition or a food or drink composition.
  • the bacterium, or the culture or culture supernatant thereof is used for the prevention and / or improvement of one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • the inflammatory disease is an inflammatory disease of an infant or a child.
  • a fourth invention for solving the above-mentioned problems is a Bifidobacterium infantis (Bifidobacterium longsp. Infantis) LMG23728 and / or Bifidobacterium breve (Bifidobacterium breve) FERM BP-1175.
  • Promoting expression of one or more inflammation control genes selected from the group consisting of ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10 A method for promoting the expression of one or more inflammation control genes selected from the group consisting of ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10, comprising administering to a subject in need thereof Yes, the details
  • the preferred form of the fungus or its culture or culture supernatant is as described above.
  • the present invention also relates to Bifidobacterium infantis (Bifidobacterium longum subsp. Infantis) LMG23728 and / or Bifidobacterium breve (FERM BP-11175 Bifidobacterium, Bifidobacterium genus, or Bifidobacterium br11
  • a method for inhibiting the production of inflammatory cytokines by TNF- ⁇ and / or IL-23 comprising administering a product or culture supernatant to a subject in need of inhibition of inflammatory cytokine production by TNF- ⁇ and / or IL-23
  • the preferred form of the bacterium or its culture or culture supernatant is as described above.
  • the fourth invention has the following preferred forms.
  • the composition is a pharmaceutical composition or a food or drink composition.
  • the bacterium, or the culture or culture supernatant thereof is used for the prevention and / or improvement of one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • one or more inflammatory diseases selected from inflammatory bowel disease, inflammatory joint disease, and inflammatory skin disease.
  • the inflammatory disease is an inflammatory disease of an infant or a child.
  • compositions for promoting the expression of an inflammation control gene or a composition for suppressing the production of inflammatory cytokines that is safe and highly effective. According to the present invention, it is possible to provide a composition for promoting the expression of an inflammation control gene or a composition for suppressing the production of inflammatory cytokines, which is excellent in safety and particularly effective for infants and children.
  • the culture supernatant is used as an active ingredient, a pharmaceutical composition or a food / drink composition using the composition for promoting the expression of inflammation control gene or the composition for suppressing inflammatory cytokine production
  • a pharmaceutical composition or a food / drink composition using the composition for promoting the expression of inflammation control gene or the composition for suppressing inflammatory cytokine production
  • the culture supernatant is discarded as a by-product in the industrial production of Bifidobacterium. Therefore, according to a preferred embodiment of the present invention, since the culture supernatant is used as an active ingredient, the by-product can be effectively used.
  • composition for promoting expression of inflammation control gene of the present invention is Bifidobacterium infantis LMG23728 (hereinafter referred to as B. Infantis LMG23728) and / or Bifidobacterium breve FERM BP- 11175 (hereinafter referred to as B. breve FERM BP-11175) Bifidobacterium bacterium or its culture is used as an active ingredient.
  • the culture supernatant of Breve FERM BP-11175 has an action of promoting the expression of inflammation control genes such as ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10.
  • the culture supernatant of Breve FERM BP-11175 has an inhibitory effect on the production of inflammatory cytokines such as TNF- ⁇ and IL-23.
  • the culture supernatant contains metabolites of these Bifidobacterium
  • the culture containing the metabolite is a composition for promoting expression of inflammation control genes or a composition for suppressing inflammatory cytokine production. It can be used as an active ingredient.
  • the Bifidobacterium bacterium reaches the intestine in a living state, a metabolite of the Bifidobacterium bacterium is produced in the intestine and an anti-inflammatory action is exhibited. Therefore, the Bifidobacterium can also be used as an active ingredient.
  • B. Infantis LMG23728 or B.I. Breve FERM BP-11175 is derived from various samples containing Bifidobacterium, B. Infantis LMG23728 or B.I. Breve FERM BP-11175 can be isolated and used, or commercially available Bifidobacterium and deposited strains can also be used.
  • B. Infantis LMG23728 Bifidobacterium is generally available from BELGIAN CO-ORDINATED COLLECTIONS OF MICRO-ORGANISMS (BCCM).
  • B. Infantis LMF23728 is the same strain as M-63 (manufactured by Morinaga Milk Company).
  • the culture is B. Infantis LMG23728 and B.I. Breve FERM BP-11175 can be obtained by culturing Bifidobacterium genus bacteria by a conventional method.
  • the culture conditions are preferably 25 ° C. to 42 ° C. and 12 hours to several days under anaerobic conditions.
  • a BAM medium manufactured by Nissui
  • Glucose manufactured by Nacalai Tesque
  • a culture can be obtained by inoculating Breve FERM BP-11175 and culturing at 37 ° C. for 16 hours in an anaerobic jar (CO2: 20%, N2: 80%).
  • the culture is a composition containing a metabolite of the genus Bifidobacterium obtained by culturing by the above-described method or the like. That is, as the culture, a composition containing the metabolite of the Bifidobacterium genus bacteria, a medium component and the microbial cells can be used as it is, and the metabolite of the Bifidobacterium bacterium is included from the composition. A fraction obtained by separation and purification by a method such as filtration, centrifugation, or extraction can also be used. In addition, the culture may be subjected to a concentration and drying process.
  • a culture supernatant as the active ingredient of the present invention.
  • the culture supernatant As an active ingredient, the solid content derived from the culture is reduced while sufficiently maintaining the concentration of the active ingredient when designing a pharmaceutical composition or a food / beverage product composition to be described later. It is possible to increase the degree of freedom in designing pharmaceutical compositions and food / drink composition compositions.
  • the culture supernatant is generally separated as a temporary light liquid and discarded. From the viewpoint of effective utilization of such by-products, the culture supernatant is preferably used.
  • the “culture supernatant” does not need to be completely removed of solid components including medium components and bacteria by a method such as centrifugation, but the metabolite of the Bifidobacterium genus is used. If the liquid layer is mainly contained, it can be said to be a “culture supernatant”.
  • B. Infantis LMG23728 and / or B.I. Any single Bifidobacterium bacterium of Breve FERM BP-11175 or a culture thereof may be used, or both Bifidobacterium bacteria or a culture thereof may be used in combination.
  • composition for promoting the expression of an inflammation control gene or the composition for suppressing the production of inflammatory cytokine of the present invention can be administered to mammals including humans.
  • dosage form either oral administration or parenteral administration may be selected according to the patient's symptoms and the like.
  • the dosage of the culture depends on the dosage form and food form of the composition for promoting the expression of inflammation control genes or the composition for suppressing the production of inflammatory cytokines, patient symptoms, age, etc.
  • 0.001 g / kg body weight or more preferably 0.01 to 0.1 g / kg body weight can be used as a guide.
  • the administration can be performed once or several times a day, and the administration period is preferably continued for several days or more.
  • the dose of the microbial cell is an agent of the composition for promoting expression of inflammation control gene or the composition for suppressing inflammatory cytokine production.
  • the patient's symptoms, age, etc. 1 ⁇ 10 6 CFU / kg body weight or more per day, preferably 1 ⁇ 10 7 to 1 ⁇ 10 12 CFU / kg body weight can be used as a guide.
  • CFU means a colony forming unit. When the Bifidobacterium is dead, CFU can be replaced with individual cells.
  • administration can be performed once or several times a day, and the administration period is preferably continued for several days or more.
  • composition for promoting expression of an inflammation control gene of the present invention is capable of expressing one or more inflammation control genes selected from the group consisting of ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10. Has the effect of promoting.
  • ACE2 converts Ang II (Angiotensin II) to Ang 1-7 in the renin-angiotensin system involved in inflammation control of intestinal tissue (Non-patent Document 1).
  • Ang II strongly induces vasoconstriction via AT1R, and also induces active oxygen to cause oxidative stress in tissues and increase inflammatory response.
  • Ang1-7 is known to exert antioxidant stress and anti-inflammatory ability via AgtR2 and Mas-1 (Non-patent Document 1).
  • the composition for promoting the expression of an inflammation regulatory gene selected from ACE2, AgtR2 and Mas-1 of the present invention can be used as an antioxidant, an anti-inflammatory agent and the like.
  • the composition for promoting the expression of an inflammation control gene selected from ACE2, AgtR2, and Mas-1 can be used as a composition for preventing or ameliorating inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
  • MKP-1 mitogen-activated protein kinase phosphatase 1
  • Muc-1 suppresses inflammation caused by TLR activation by selectively dephosphorylating p38MAPK and c-JUN terminal kinase.
  • Muc-1 also suppresses inflammation caused by TLR activation (Non-patent Document 4). Therefore, by increasing the gene expression levels of MKP-1 and Muc-1, the effect of preventing or improving inflammation due to TLR activation is exhibited. Therefore, the composition for promoting the expression of an inflammation control gene selected from MKP-1 and Muc-1 of the present invention can be used as a composition for preventing or improving inflammation due to activation of TLR.
  • IL-10 acts on T cells and macrophages to induce cell activation suppression and antigen presentation ability decrease, and soothes inflammation due to activation of T cells and macrophage cells. Therefore, by increasing the gene expression level of IL-10, the cell activation suppressing effect and the antigen presenting ability reducing effect are exhibited.
  • the IL-10 gene expression promoting composition of the present invention can be used as a composition for preventing or improving inflammation caused by activation of T cells and macrophage cells including autoimmune diseases. More specifically, the IL-10 gene expression promoting composition of the present invention is used as a composition for preventing or ameliorating diseases such as autoimmune hemolytic anemia, multi-gland autoimmune syndrome, and Alzheimer's disease. Can do.
  • composition for suppressing inflammatory cytokine production of the present invention has an action of suppressing the production of inflammatory cytokines such as TNF- ⁇ and IL-23.
  • TNF- ⁇ is a kind of inflammatory cytokine, induces apoptosis through TNF receptor 1, and induces activation of transcription factors such as NF- ⁇ B or AP-1 to produce various inflammatory mediators • Increase release. Therefore, by suppressing the production of TNF- ⁇ , the effect of preventing or improving inflammation due to the production / release of inflammatory mediators is exhibited.
  • IL-23 is a kind of inflammatory cytokine and induces the expression of inflammatory cytokines such as IL-17 and TNF- ⁇ .
  • IL-23 is known to be deeply involved in inflammatory colitis, colitis, Crohn's disease, psoriasis, septic shock, etc. (Non-patent Document 3). Therefore, by suppressing the production of IL-23, an effect of preventing or improving inflammatory bowel disease, colitis, Crohn's disease, psoriasis, septic shock, etc. is exhibited.
  • AngII promotes the expression of inflammatory regulatory genes such as ACE2, AgtR2, Mas-1, MKP-1, Muc-1, and IL-10 and suppresses the production of inflammatory cytokines such as TNF- ⁇ and IL-23.
  • Inflammation caused by AT1R, inflammation caused by TLR activation, inflammation caused by T cell and macrophage cell activation, inflammation caused by production and release of various inflammatory mediators caused by TNF- ⁇ , and inflammation caused by IL-23 production The preventive or ameliorating action of a wide range of inflammatory diseases caused by the disease is exhibited.
  • the composition for promoting expression of inflammatory regulatory genes or the composition for suppressing inflammatory cytokine production of the present invention is an inflammatory bowel disease, inflammatory skin disease, inflammatory joint disease, wound, arteriosclerotic disease, neurodegenerative disease, It can be widely used as a composition for preventing and / or improving inflammatory diseases including autoimmune diseases and tumor diseases.
  • Specific diseases include rheumatism, juvenile idiopathic arthritis, rheumatoid systemic lupus erythematosus, scleroderma, antiglomerular basement membrane disease, systemic lupus erythematosus, Addison's disease, antiphospholipid antibody syndrome, IgA thread Globe nephritis, Goodpasture syndrome, Lambert Eaton myasthenia syndrome, idiopathic purpura, autoimmune thyroiditis, pemphigus, autoimmune hemolytic anemia, herpes zoster dermatitis, membranous glomerulonephritis, Graves' disease , Sympathetic ophthalmitis, multigland autoimmune syndrome, multiple sclerosis, Reiter's disease, acute lung injury (ALI), Crohn's disease, myocardial infarction / cerebrovascular disorder, Alzheimer, ulcerative colitis, psoriasis, nonalcoholic Examples include fatty liver disease (NAFLD) and nonalcoholic
  • prevention includes reduction of the risk of developing a disease.
  • improvement includes both treatment and symptom relief.
  • the active ingredient of the present invention is also excellent in the action of suppressing weight loss associated with inflammatory diseases. Therefore, the composition for promoting expression of the inflammation control gene or the composition for suppressing inflammatory cytokine production of the present invention can also be used as a composition for suppressing weight loss associated with inflammatory disease.
  • the active ingredient of the present invention is a Bifidobacterium genus bacteria or a culture thereof that is present in large numbers in infants, it can be suitably used for inflammatory diseases in infants and children.
  • Specific examples include inflammatory skin diseases such as psoriasis and inflammatory joint diseases such as juvenile idiopathic arthritis.
  • composition for promoting the expression of an inflammation control gene or the composition for suppressing the production of inflammatory cytokines of the present invention can be in the form of a pharmaceutical composition or a food or drink composition.
  • the pharmaceutical composition of the present invention is an active ingredient of the above-mentioned composition for promoting expression of an inflammation control gene or composition for suppressing inflammatory cytokine production according to the present invention.
  • Infantis LMG23728 and / or B.I. Breve FERM BP-11175, or a culture thereof can be prepared by formulating with any additive such as a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention can be in the form of solid preparations such as powders, granules, tablets and capsules, and liquids such as solutions, syrups, suspensions and emulsions.
  • the pharmaceutical composition of the present invention can be in the form of enteral administration or parenteral administration. For example, in the case of parenteral administration, suppositories, sprays and the like can be mentioned.
  • preparation carrier and additives various conventional organic or inorganic carriers can be used depending on the dosage form.
  • examples include excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.
  • Excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch; crystalline cellulose, hydroxypropylcellulose, hydroxypropyl Cellulose derivatives such as methylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate; phosphate derivatives such as calcium phosphate; And carbonate derivatives thereof; and sulfate derivatives such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit
  • starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch
  • crystalline cellulose hydroxypropylcellulose, hydroxypropyl
  • binder examples include gelatin, polyvinyl pyrrolidone, and Magrogol in addition to the above excipients.
  • disintegrant examples include, in addition to the above excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • Lubricants include: talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as bee gum and gallow; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; Carboxylic acid sodium salts such as sodium sulfate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; starch derivatives and the like .
  • the stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
  • flavoring agents examples include sweeteners, acidulants, and fragrances.
  • a solvent such as water, a flavoring agent and the like can be mentioned.
  • the culture when used as a pharmaceutical composition using the active ingredient, B. Infantis LMG23728 and / or B.I.
  • the content of the culture of Breve FERM BP-11175 is 0.001 to 10% by mass, preferably 0.01 to 10% by mass, corresponding to the solid content in the culture supernatant.
  • the content of the cells of the brebe FERM BP-11175 can be 1 ⁇ 10 6 CFU / kg or more, preferably 1 ⁇ 10 7 to 1 ⁇ 10 12 CFU / kg per day.
  • the food and beverage composition of the present invention is, for example, B.I. Infantis LMG23728 and / or B.I. Manufactured by appropriately blending and processing Brave FERM BP-11175 or its culture with known ingredients and materials used as food hygiene acceptable bases, carriers, additives and other food additives can do.
  • the “food / beverage product composition” includes foods / foods consumed by humans and feeds consumed by animals other than humans.
  • the food and beverage composition of the present invention includes dairy products such as processed milk and fermented milk; beverages such as lactic acid bacteria beverages, soft drinks, carbonated beverages, nutritional beverages, fruit beverages (including concentrated concentrates and powders for preparation of these beverages). Ice cream, ice sherbet, shaved ice and other frozen desserts; candy, chewing gum, candy, gum, chocolate, tablet confectionery, snacks, biscuits, jelly, jam, cream, baked confectionery, etc .; enteral nutrition; functional food Or the like.
  • fermented milk, lactic acid bacteria beverages and the like can be produced as containing a culture of Bifidobacterium, and can also be provided in a form containing bacterial cells, so that the viewpoint of production efficiency To a preferable form.
  • beverages such as soft drinks, carbonated beverages, nutritional beverages, fruit juice beverages, and lactic acid bacteria beverages are particularly preferred from the viewpoint of efficiently ingesting the active ingredients.
  • it is also preferable that it is a granular form, a tablet form, or a liquid supplement as a form of a functional food at the point that an ingestor is easy to grasp
  • additives such as carriers, excipients, binders, disintegrants, lubricants, colorants and the like that are widely used in ordinary foods can be used in the food and drink composition of the present invention.
  • the Bifidobacterium genus bacteria or a culture thereof which is an active ingredient, for example, lactulose, maltitol, Sugars such as lactitol, and other sugars such as dextrin and starch; proteins such as gelatin, soy protein and corn protein; amino acids such as alanine, glutamine and isoleucine; polysaccharides such as cellulose and gum arabic; It is also preferable to formulate with oils and fats such as medium chain fatty acid triglycerides.
  • the content of the culture of Breve FERM BP-11175 is 0.001 to 10% by mass, preferably 0.01 to 10% by mass, corresponding to the solid content in the culture supernatant.
  • the content of the microbial cells (viable bacteria) of breve FERM BP-11175 is usually 1 ⁇ 10 6 CFU / kg or more, preferably 1 ⁇ 10 7 to 1 ⁇ 10 12 CFU / kg per day. it can. If the bacterium is dead, the CFU can be replaced with cells.
  • the food / beverage composition of the present invention is preferably a functional food.
  • the “functional food” means a food on which a disease prevention effect or a disease occurrence risk reduction effect is directly or indirectly indicated.
  • foods sold in the form of foods for specified health use, functional display foods, and health supplements at present in Japan are examples of foods sold in the form of foods for specified health use, functional display foods, and health supplements at present in Japan.
  • Such a functional food is in a form with a label indicating “use for prevention or improvement of inflammatory diseases”.
  • the “display” includes all displays having a function of informing the consumer of the use. In other words, any display capable of recalling / analyzing the use corresponds to the “display” regardless of the purpose of display, the content of display, the target object / medium to be displayed, and the like.
  • the “labeled” means that there is a display act of associating and recognizing the display and the food composition (product). It is preferable that the display act is one in which the consumer can directly recognize the application.
  • the displayed content is a display approved by the government or the like (for example, a display that is approved based on various systems determined by the government and is performed in a mode based on such approval).
  • the display approved by the Consumer Affairs Agency for example, the display approved by the food system for specific health use, the functional display food, and the similar system can be exemplified.
  • Example 1 B. The effect of administration of the culture supernatant of Infantis LMG23728 on colitis model mice was examined. The test was conducted by the following method.
  • Test (1-1) Preparation of culture supernatant 11% reduced skim milk powder and 0.6% yeast extract were dissolved in ion exchange water and autoclaved at 90 ° C. for 30 minutes to prepare a culture medium.
  • Bifidobacterium longum ATCC BAA-999 (hereinafter referred to as B. longum ATCC BAA-), which is known to have an inhibitory effect on interleukin (IL) -17 production. 999) and Bifidobacterium breve LMG23729 (hereinafter referred to as B. breve LMG23729) (see Patent Document 3).
  • Bifidobacterium of the comparative example a culture supernatant was similarly prepared and used for the test.
  • DSS extran sulfate sodium, manufactured by MP Biomedicals
  • Example 2 Method for evaluating inflammation improving effect and method for measuring expression level of inflammation control gene
  • Example 1 Method for evaluating inflammation
  • the effect of improving inflammation was expressed by (i) body weight, (ii) colon length. , (Iii) DAI, expression levels of inflammation control genes ((iv) ACE2, (v) AgtR2, (vi) Mas-1), and expression levels of inflammatory cytokines ((vii) TNF- ⁇ , (viii) IL -23).
  • ACE2 primer set (SEQ ID NO: 1 (forward primer), SEQ ID NO: 2 (reverse primer)), AgTR2 (AgtR2) primer set (TAKARA BIO INC., SEQ ID NO: 3 (forward primer) using the prepared cDNA as a template ), SEQ ID NO: 4 (reverse primer)), Mas-1 (MASR) primer set (manufactured by Takara Bio Inc., SEQ ID NO: 5 (forward primer), SEQ ID NO: 6 (reverse primer)), TNF- ⁇ primer set (Takara) Bio: SEQ ID NO: 7 (forward primer), SEQ ID NO: 8 (reverse primer)), or IL-23 primer set (TAKARA BIO INC., SEQ ID NO: 9 (forward primer), SEQ ID NO: 10 (reverse primer)), and S Using BR Premix ExTaq II reagent performs quantitative PCR in real time PCR Thermal cycler (iCycler, BioRad Co.) to measure the gene expression level. Evaluation was performed by converting the
  • DAI Disease Activity Index
  • the DAI is represented by the sum of scores (see Table 2) for the three items of weight loss rate, fecal properties, and occult blood / bleeding. It can be evaluated that the lower the DAI, the less likely the presence of tissue crypts or inflammation.
  • mice administered with the culture supernatant of Infantis LMG23728 were significantly reduced in weight loss as compared to the group not administered with the bacteria.
  • mice administered with the culture supernatant of Infantis LMG23728 were significantly suppressed in weight loss most significantly as compared with mice administered with culture supernatants of other Bifidobacterium bacteria.
  • mice administered with the culture supernatant of Infantis LMG23728 were longer than mice administered with the fungus-free group and other culture supernatants of Bifidobacterium, and colonic contraction was significantly suppressed. It was.
  • B. Mice administered with the culture supernatant of Infantis LMG23728 had low DAI. That is, B.I. Mice administered with the culture supernatant of Infantis LMG23728 may be less likely to be inflamed than mice administered with the fungus-free group or mice administered with the culture supernatant of other Bifidobacterium bacteria. Indicated.
  • ACE2 angiotensin converting enzyme 2
  • ACE2 angiotensin converting enzyme 2
  • ACE2 then converts AngII (Angiotensin II) to Ang1-7 in the renin-angiotensin system (Nature, 487: 477-481, 1212).
  • Ang II strongly induces vasoconstriction via AT1R, and also induces active oxygen to cause oxidative stress in tissues and increase inflammatory response.
  • Ang1-7 has an action of antagonizing AngII.
  • AgtR2 and Mas-1 Nature, 487: 477-481, 2012. That is, it can be evaluated that the higher the gene expression level of AgtR2 and Mas-1, the higher the anti-inflammatory ability is exhibited.
  • TNF- ⁇ is a kind of inflammatory cytokine, induces apoptosis through TNF receptor 1, and also exhibits NF- ⁇ B or Induction of activation of transcription factors such as AP-1 enhances production and release of various inflammatory mediators. Therefore, it can be evaluated that inflammation is less likely to occur as the gene expression level of TNF- ⁇ is lower.
  • IL-23 is a kind of inflammatory cytokine, and induces the expression of inflammatory cytokines such as IL-17 and TNF- ⁇ . Therefore, it can be evaluated that inflammation is less likely to occur as the gene expression level of IL-23 decreases.
  • IL-23 is deeply related to inflammatory colitis, colitis, Crohn's disease, psoriasis, septic shock, etc.
  • anti-IL-23 antibody drugs exert a marked improvement effect on inflammatory bowel disease Since it is also known (Immunity, 43: 739-750, 2015), in addition to inflammatory bowel disease by suppressing the expression of IL-23, it also against autoimmune diseases, particularly inflammatory skin diseases such as psoriasis Preventive and improvement effects can be expected.
  • the gene expression levels of TNF- ⁇ and IL-23 were significantly lower than those of mice administered with the culture supernatant of Breve LMG23729.
  • Example 2 B. Infantis LMG23728, and B.I. The effect of administration of the culture supernatant of Breve FERM BP-11175 on colitis model mice was examined. The test was conducted by the following method.
  • Example 2 Evaluation Method for Inflammation Improvement Effect and Method for Measuring Expression Level of Inflammation Control Gene
  • the improvement effect on inflammation was expressed by (i) change in body weight, (ii) length of large intestine.
  • DAI and the expression level of inflammation control genes ((ix) MKP-1, (x) Muc-1, (xi) IL-10) were evaluated.
  • mice to which the culture supernatant of Infantis LMG23728 was administered were not treated with bacteria or B. Compared with mice administered with the culture supernatant of Longum ATCC BAA-999, the contraction of the large intestine was significantly suppressed.
  • MKP-1 mitogen-activated protein kinase phosphatase 1
  • TLR tumor-activated protein kinase phosphatase 1
  • Muc-1 (Mucin 1) is one of mucin proteins, O-glycosylated glycoprotein that constitutes a protective mucosal barrier of the epithelial surface layer in the intestinal epithelial tissue. Muc-1 protein has a function as an intracellular signal transduction molecule and is known to suppress inflammatory signals via a wide range of TLR signals (TLR2, 3, 4, 5, 7, 9). (Am J Respir Cell Mol Biol, 38: 263-268, 2008). Therefore, the increased expression of Muc-1 can be expected to have sepsis, inflammatory joint disease (rheumatic, juvenile idiopathic arthritis), and allergy suppressing effect.
  • Muc-1 is also expressed in dendritic cells and regulates or suppresses the production of inflammatory cytokines via TLR4 and TLR5 signals. That is, it can be evaluated that the higher the Muc-1 gene expression level, the higher the prevention or improvement effect of inflammatory diseases.
  • B.I. Infantis LMG23728 and B.I. It is observed that the culture supernatant of Breve FERM BP-11175 has a high anti-inflammatory effect. From this, B.I. Infantis LMG23728 and B.I. It has been found that there is a high anti-inflammatory effect on the metabolite of Breve FERM BP-11175. Therefore, it is presumed that the same anti-inflammatory effect is exerted by allowing the Bifidobacterium itself to reach the intestine while remaining alive. From the above, B. Infantis LMG23728 and B.I.
  • Blebe FERM BP-11175 genus Bifidobacterium or a culture thereof can be used as an active ingredient of a composition for promoting expression of an inflammation control gene or a composition for suppressing inflammatory cytokine production.
  • Example 2 B. B. anti-inflammatory activity was demonstrated in Example 1 in mice administered with the culture supernatant of Breve FERM BP-11175. More than (i) change in body weight, (ii) large intestine length, (iii) DAI, and expression levels of inflammation control genes ((ix) MKP-1, () compared to mice administered with the culture supernatant of Infantis LMG23728 x) Muc-1 and (xi) IL-10) were more prominent (good) values.
  • the culture supernatant of Breve FERM BP-11175 is a comparative example of Example 1. It was found to have a higher anti-inflammatory effect than the culture supernatant of Breve LMG23729.
  • the expression of ACE2, AgtR2, and Mas-1 which are the evaluation items of Example 1 is also shown in FIG. It can be said that the gene expression promoting effect is equal to or higher than that of the mouse administered with the culture supernatant of Infantis LMG23728.
  • the expression levels of TNF- ⁇ and IL-23 which are the evaluation items of Example 1, were measured according to B.
  • a composition for promoting the expression of an inflammation control gene or a composition for suppressing the production of inflammatory cytokines which has a high effect.
  • a composition for promoting the expression of an inflammation control gene or a composition for suppressing the production of inflammatory cytokines which has little resistance to infants and children and is excellent in safety.

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Abstract

La présente invention aborde le problème de la fourniture d'une composition destinée à favoriser l'expression d'un gène anti-inflammatoire et d'une composition destinée à inhiber la production d'une cytokine inflammatoire. Un moyen pour résoudre le problème consiste à utiliser, en tant que principe actif, une bactérie appartenant au genre Bifidobacterium, c'est-à-dire, Bifidobacterium longum subsp. infantis LMG23728 et/ou Bifidobacterium breve FERM BP-11175 ou une culture correspondante.
PCT/JP2018/010882 2017-03-30 2018-03-19 Composition favorisant l'expression d'un gène anti-inflammatoire Ceased WO2018180728A1 (fr)

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CN112546074A (zh) * 2020-12-24 2021-03-26 江南大学 一株能够抑制IL-23、Th17轴相关炎症因子释放的短双歧杆菌及其应用
CN113164772A (zh) * 2018-12-07 2021-07-23 森永乳业株式会社 用于抑制诺如病毒感染的组合物
CN113293113A (zh) * 2021-06-21 2021-08-24 美益添生物医药(武汉)有限公司 一株长双歧杆菌mi-186及其应用
WO2021235486A1 (fr) * 2020-05-22 2021-11-25 森永乳業株式会社 Composition pour favoriser le développement du tractus intestinal, composition pour améliorer la fonction pulmonaire et composition pour augmenter la fonction immunitaire
JP2021182890A (ja) * 2020-05-22 2021-12-02 森永乳業株式会社 免疫機能向上用組成物
JP2021183574A (ja) * 2020-05-22 2021-12-02 森永乳業株式会社 腸管発達促進用組成物、および腸疾患の予防、治療または症状軽減用組成物
WO2022041658A1 (fr) * 2020-08-24 2022-03-03 汤臣倍健股份有限公司 Bifidobacterium breve 207-1 et son utilisation
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WO2023141119A1 (fr) * 2022-01-18 2023-07-27 The Regents Of The University Of California Compositions bactériennes et méthodes de traitement du cancer et de maladies immunitaires
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JP2023550962A (ja) * 2020-11-24 2023-12-06 ジョンソン アンド ジョンソン コンシューマー インコーポレイテッド アトピー性疾患を予防、遅延、又は改善する方法
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WO2020070369A1 (fr) * 2018-10-05 2020-04-09 Consejo Superior De Investigaciones Científicas Souche de bifidobacterium longum sub. infantis et son utilisation
ES2752798A1 (es) * 2018-10-05 2020-04-06 Consejo Superior Investigacion Cepa de Bifidobacterium longum sub. infantis y uso de la misma
CN113164772A (zh) * 2018-12-07 2021-07-23 森永乳业株式会社 用于抑制诺如病毒感染的组合物
WO2020251044A1 (fr) * 2019-06-13 2020-12-17 森永乳業株式会社 Composition ayant pour principe actif une bactérie bifidobacterium
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US11767503B2 (en) 2020-08-24 2023-09-26 BYHEALTH Co., Ltd. Bifidobacterium breve 207-1 and use thereof
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