WO2012073924A1 - Agent de prévention et/ou d'amélioration de l'endométriose, et composition pour aliment ou boisson le contenant - Google Patents

Agent de prévention et/ou d'amélioration de l'endométriose, et composition pour aliment ou boisson le contenant Download PDF

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WO2012073924A1
WO2012073924A1 PCT/JP2011/077464 JP2011077464W WO2012073924A1 WO 2012073924 A1 WO2012073924 A1 WO 2012073924A1 JP 2011077464 W JP2011077464 W JP 2011077464W WO 2012073924 A1 WO2012073924 A1 WO 2012073924A1
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lactic acid
endometriosis
food
acid bacterium
acid bacteria
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PCT/JP2011/077464
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English (en)
Japanese (ja)
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伊藤　裕之
紀宏 指原
秀二 池上
再思 紀
内田　勝幸
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株式会社明治
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Priority to JP2012546872A priority Critical patent/JP5667642B2/ja
Priority to SG2013041355A priority patent/SG190719A1/en
Priority to CN201180057181.6A priority patent/CN103249421B/zh
Publication of WO2012073924A1 publication Critical patent/WO2012073924A1/fr
Priority to HK14100961.9A priority patent/HK1187825A1/xx

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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
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
    • A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/11—Lactobacillus
    • A23V2400/145—Gasseri

Definitions

  • the present invention relates to an agent for preventing and / or improving endometriosis.
  • the present invention relates to an agent for preventing and / or improving endometriosis comprising a specific lactic acid bacterium, and a food or beverage composition comprising the lactic acid bacterium.
  • Endometriosis is a disease in which the endometrium or similar tissue detached during menstruation flows back in the fallopian tube and grows in the peritoneal cavity outside the uterus, affecting 6 to 10% of women in reproductive life It is one of the most serious gynecological diseases. Although there are many unclear points regarding the pathogenesis, many reports have revealed that this is caused by abnormalities in the immune surveillance system in the abdominal cavity. Usually, immunocompetent cells such as macrophages and NK cells eliminate endometrial tissue flowing into the abdominal cavity. However, if the function of these immunocompetent cells decreases for some reason, it is believed that endometrial tissue will engraft and grow in the abdominal cavity.
  • Non-Patent Document 1 NK cell theory that the decrease in the function of removing ectopic endometrial cells by NK cells in the peritoneal cavity is involved in the onset and growth of endometriosis.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • gastrointestinal disorders such as erosive lesions and ulcers due to their pharmacological properties of inhibiting cyclooxygenase to inhibit the production of prostaglandins having mucosal protective functions from arachidonic acid.
  • hormonal side effects have been observed in endometriosis therapy using danazol or gonadotropin-releasing hormone agonists.
  • IL-12 is a cytokine having an action of activating Th1 cells, NK cells and the like, and an ectopic endometrial cell growth inhibitory effect has been reported (Non-patent Document 2).
  • an object of the present invention is to provide an agent for preventing and / or improving endometriosis based on the enhancement of NK activity. Moreover, this invention aims at provision of the food-drinks composition for prevention and / or improvement of endometriosis containing the said lactic acid bacteria. Furthermore, this invention aims at provision of the method of preventing and / or improving endometriosis. In particular, an object of the present invention is to provide a preventive and / or ameliorating agent for endometriosis that can be taken orally, has no side effects, and can obtain high safety and pain effects.
  • the inventors of the present invention have so far examined IL-12 inducibility by probiotic lactic acid bacteria.
  • various studies were conducted on the possibility that lactic acid bacteria that promote IL-12 production and enhance the cytotoxic activity of NK cells have an effect of improving endometriosis.
  • the present inventors have conducted extensive research. As a result, it was recognized that certain types of lactic acid bacteria, in particular, Lactobacillus lactic acid bacteria, have excellent growth-inhibiting effects on endometriotic lesions, and the present invention has been completed.
  • lactic acid bacteria are effective in improving QOL in those suffering from endometriosis, and have completed the present invention.
  • one aspect of the present invention is an agent for preventing and / or improving endometriosis comprising lactic acid bacteria.
  • the lactic acid bacterium contained in the agent for preventing and / or improving endometriosis is not limited in any way, but is preferably Lactobacillus genus, more preferably Lactobacillus gasseri, particularly Lactobacillus gasseri OLL2809 strain. Most preferably it is.
  • Another embodiment of the present invention is a food and drink composition for preventing and / or improving endometriosis comprising an effective amount of lactic acid bacteria.
  • the lactic acid bacteria are not limited in any way, but are preferably belonging to the genus Lactobacillus, more preferably Lactobacillus gasseri, and particularly Lactobacillus. Most preferred is gasseri OLL2809 strain.
  • the said food / beverage product composition is fermented milk food / beverage products, and it is preferable that it is yogurt food / beverage products, such as a yoghurt and a yoghurt drink, but it is not limited to these.
  • Still another embodiment of the present invention is a method for preventing and / or improving endometriosis characterized by administering a desired amount of a composition containing an effective amount of lactic acid bacteria.
  • the lactic acid bacteria are preferably of the genus Lactobacillus, more preferably Lactobacillus gasseri, and most preferably Lactobacillus gasseri OLL2809.
  • the dose is preferably at least 2 mg / kg / day, but is not limited thereto.
  • the present invention relates to the following [1] to [19].
  • [1] A drug for preventing and / or improving endometriosis comprising lactic acid bacteria.
  • a food and beverage composition for preventing and / or improving endometriosis comprising an effective amount of lactic acid bacteria.
  • the food / beverage composition according to [8], wherein the food / beverage composition is a fermented milk food / beverage product.
  • the food or beverage composition according to [9], wherein the fermented milk food or beverage is yogurt.
  • a method for preventing and / or improving endometriosis which comprises administering a desired amount of a composition containing an effective amount of lactic acid bacteria.
  • the method according to [11], wherein the lactic acid bacterium is Lactobacillus gasseri OLL2809 strain.
  • the method according to any one of [11] to [14], wherein the dose is at least 2 mg / kg / day.
  • a lactic acid bacterium for use in the prevention and / or improvement of endometriosis [17] The lactic acid bacterium according to [16], wherein the lactic acid bacterium belongs to the genus Lactobacillus. [18] The lactic acid bacterium according to [16], wherein the lactic acid bacterium is Lactobacillus gasseri. [19] The lactic acid bacterium according to [16], wherein the lactic acid bacterium is Lactobacillus gasseri OLL2809 strain.
  • the present invention relates to the following [101] to [112].
  • [101] A preventive and therapeutic agent for endometriosis comprising lactic acid bacteria.
  • a method for preventing and treating endometriosis comprising administering a desired amount of a composition containing an effective amount of lactic acid bacteria.
  • an agent for preventing and / or improving endometriosis comprising certain lactic acid bacteria, in particular, Lactobacillus lactic acid bacteria.
  • the Lactobacillus lactic acid bacterium of the present invention is characterized by enhanced NK activity and enhances self-immunity, thereby exhibiting an unprecedented high improvement effect on endometriosis, particularly menstrual pain and dysmenorrhea Became clear. Accordingly, Lactobacillus lactic acid bacteria can be used for the prevention and / or improvement of these diseases.
  • the agent for preventing and / or improving endometriosis of the present invention is effective in improving QOL in endometriosis sufferers.
  • the agent for preventing and / or improving endometriosis of the present invention can be easily taken by oral ingestion.
  • the prevention and improvement by hormone agents and the like may have side effects, but in the case of the present invention, there is no concern.
  • it is safe enough to be handled as food.
  • the preventive and / or ameliorating agent of the present invention is low in the ingestion by the patient, and can prevent and / or improve endometriosis without burdening life.
  • the preventive and / or ameliorating agent for endometriosis according to the present invention has an unprecedented alleviating effect on pain peculiar to the disease, it is particularly effective for improving QOL in patients suffering from endometriosis. .
  • the present invention provides a preventive and / or ameliorating agent for endometriosis including lactic acid bacteria (hereinafter referred to as “preventive / improving agent of the present invention”).
  • the preventive / ameliorating agent of the present invention can also be expressed as follows.
  • prevention and / or improvement can also be expressed as “prevention and / or improvement”. Therefore, “prevention and / or improvement” of the present invention includes ⁇ Prevention and improvement ⁇ Prevention ⁇ Improvement is included. In the present specification, “improvement” can also be expressed as “treatment”.
  • the preventive / ameliorating agent of the present invention contains lactic acid bacteria as its active ingredient.
  • Lactic acid bacteria are not limited as long as they have a high ability to induce IL-12 production.
  • Lactic acid bacteria have been classified into the genus Lactococcus, Lactobacillus, Leuconostoc, Pediococcus, Streptococcus, Wissella, Tetragenococcus, Oenococcus, Enterococcus, and Vacococ. These lactic acid bacteria can be used for the preventive / ameliorating agent of the present invention.
  • Preferred examples include Lactobacillus lactic acid bacteria, more preferred Lactobacillus gasseri, and particularly preferred Lactobacillus gasseri OLL2809 strain (accession number: NITE BP-72), but is not limited thereto. Moreover, you may use combining 2 or more types of lactic acid bacteria from which a kind differs.
  • the present inventors have deposited Lactobacillus gasseri OLL2809 strain to the Patent Microorganism Deposit Center, National Institute of Technology and Evaluation.
  • the contents specifying the deposit are described below.
  • Lactobacillus gasseri OLL2809 The strain (Accession No .: NITE BP-72) is a Gram-positive bacilli, and the colony morphology on Lactobacilli MRS Agar, Difcoo is round, pale yellow, flat. Physiological characteristics include homolactic fermentation, growth at 45 ° C., fermentability to glucose, mannose, fructose, galactose, sucrose, cellobiose, lactose and trehalose.
  • Lactobacillus gasseri OLL2809 (Accession Number: NITE BP-72)
  • a medium usually used for culturing lactic acid bacteria is used. That is, any medium can be used as long as it contains a nitrogen source, an inorganic substance and other nutrients in addition to the main carbon source.
  • the carbon source lactose, glucose, sucrose, fructose, starch hydrolyzate, waste molasses and the like can be used according to the assimilation ability of the bacteria used.
  • the nitrogen source organic nitrogen-containing substances such as casein hydrolyzate, whey protein hydrolyzate, and soy protein hydrolyzate can be used.
  • meat extract, fish extract, yeast extract and the like are used as growth promoters.
  • Cultivation is preferably performed under anaerobic conditions, but may be performed under microaerobic conditions such as liquid stationary culture that is usually used.
  • anaerobic culture known methods such as a method of culturing under a carbon gas gas layer can be applied, but other methods may be used.
  • the culture temperature is preferably 30 to 40 ° C. However, other temperature conditions may be used as long as the temperature allows the bacteria to grow.
  • the pH of the medium during the culture is preferably maintained at 6.0 to 7.0, but may be other pH conditions as long as the temperature allows the bacteria to grow. It can also be cultured under batch culture conditions.
  • the culture time is usually preferably 10 to 24 hours, but may be any other culture time as long as the bacteria can grow.
  • Lactobacillus gasseri that can be used in the present invention are also Gram-positive bacilli and other physiological characteristics exhibit the same characteristics as Lactobacillus gasseri OLL2809. Such Lactobacillus gasseri can be separated from human feces and the like based on physiological characteristics by those skilled in the art. Culture can also be performed by the same method as described above for Lactobacillus gasseri OLL2809.
  • the preventive / ameliorating agent of the present invention may contain lactic acid bacteria as they are, or may be contained as a processed product of lactic acid bacteria obtained by subjecting lactic acid bacteria to some kind of treatment.
  • lactic acid bacteria suspensions lactic acid bacteria cultures (cells, culture supernatant (including medium components)), lactic acid bacteria fermentation products (lactic acid bacteria beverages, sour milk, yogurt, etc.), concentrates, pastes processed into pastes, Spray dried product, freeze dried product (at least one selected from spray dried product, freeze dried product, vacuum dried product, drum dried product), vacuum dried product, drum dried product, liquid dispersed in medium, diluted with diluent
  • a diluted product obtained by crushing a diluted product or a dried product obtained by a mill or the like can be used as a processed product.
  • lactic acid bacteria live cells, wet bacteria, dry bacteria and the like can be used as appropriate. It may be dead cells subjected to sterilization, that is, heat sterilization treatment, radiation sterilization treatment, or crushing treatment. These processing steps may be used alone or in combination.
  • the preventive / ameliorating agent of the present invention can be used alone for the prevention or improvement of endometriosis in humans and animals. Or it can also be orally administered by mixing with other ingredients that can be usually used in pharmaceuticals and foods. It can also be used in combination with other compounds, microorganisms and the like that are known to have an effect of preventing or improving endometriosis.
  • the prevention and treatment effects of endometriosis can also be confirmed by subjective evaluation using a visual analog scale (VAS) or a dysmenorrhea score, as shown in the examples.
  • VAS visual analog scale
  • dysmenorrhea score as shown in the examples.
  • the dose of the prophylactic / ameliorating agent of the present invention can be appropriately set in consideration of various factors such as the administration route, the age, weight, and symptoms of animals to be administered including humans. Although the present invention is not limited to this, it is preferable to administer at least 2 mg / kg / day as an active ingredient. However, when ingested for the purpose of prevention and / or improvement over a long period of time, the amount may be smaller than the above range. Alternatively, since the active ingredient of the preventive / ameliorating agent of the present invention has no problem with regard to food safety, it can be used in a larger amount than the above range.
  • the preventive / ameliorating agent of the present invention can be administered either orally or parenterally (intramuscular, subcutaneous, intravenous, suppository, transdermal, transgastric tube, etc.).
  • the dosage form of the preventive / improving agent of the present invention can be selected according to the purpose of prevention, the purpose of improvement, the route of administration, etc., for example, tablets, coated tablets, pills, capsules, granules, powders , Liquids, suspensions, emulsions, syrups, injections, suppositories, dipping agents, decoction, tinctures and the like.
  • These various preparations are prepared according to conventional methods as necessary with respect to the active ingredient, such as fillers, extenders, excipients, binders, humectants, disintegrants, surfactants, lubricants, coloring agents, flavoring agents.
  • the pharmaceutical composition can be formulated using known adjuvants that can be usually used in the pharmaceutical preparation technical field, such as solubilizing agents, suspension agents, and coating agents. Moreover, you may contain a coloring agent, a preservative, a fragrance
  • the lactic acid bacteria can be used in the form of any medicine or food or drink.
  • it is expected to prevent and / or improve endometriosis by directly administering it as a pharmaceutical, or by directly ingesting it as a special-purpose food such as a food for specified health use or a nutritional functional food.
  • this invention provides the food-drinks composition for prevention and / or improvement of endometriosis which contains an effective amount of the lactic acid bacteria which comprise the prevention / amelioration agent of this invention.
  • the form of the food and drink composition include prepared milk powder and fermented milk food and drink.
  • fermented milk food and drink include, but are not limited to, yogurt and cheese.
  • the food / beverage composition of the present invention can be applied to fermented milk such as yogurt, beverages and the like as well as health functional foods and foods for the sick.
  • the health functional food system was established not only for regular foods but also for foods in the form of tablets, capsules, etc., based on domestic and foreign trends and consistency with the conventional food system for specified health use. It consists of two types of food for specified health use (individual permission type) and functional food for nutrition (standard type). It is possible to prevent and / or improve endometriosis by directly ingesting it as a special-purpose food such as a food for specified health use or a nutritional functional food containing the lactic acid bacteria constituting the preventive / ameliorating agent of the present invention.
  • the food / beverage composition of the present invention specifically includes various food / beverage products (milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crust, prepared milk powder, liquid food, food for the sick, Lactic acid bacteria constituting the preventive / improving agent of the present invention may be added to foods such as infant milk powder, foods such as lactating milk powder, and nutritional foods, and ingested.
  • the active ingredient can be used as it is, or can be used in accordance with a conventional method for ordinary food and beverage compositions such as mixing with other foods or food ingredients.
  • the state of the food / beverage products normally used for example, any of solid (powder, granule, etc.), paste, liquid or suspension may be sufficient.
  • sugar, a lipid, vitamins, minerals, organic acid, organic in the food-drinks composition containing the lactic acid bacteria which comprise the prevention / improving agent of this invention.
  • Bases, fruit juices, flavors and the like can be used as main components.
  • proteins include whole milk powder, skim milk powder, partially skimmed milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, ⁇ -casein, ⁇ -casein, ⁇ -casein, ⁇ -lactoglobulin , ⁇ -lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and plant proteins, hydrolysates thereof; butter, whey minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose, etc. And various milk-derived components.
  • saccharide examples include saccharides, processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.
  • lipid examples include animal oils such as lard, fish oil, etc., fractionated oils, hydrogenated oil, transesterified oil, etc .; palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils.
  • vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline.
  • minerals include, for example, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium, and whey minerals.
  • organic acid include malic acid, citric acid, lactic acid, and tartaric acid. These components can be used in combination of two or more, and synthetic products and / or foods containing a large amount thereof may be used.
  • the amount of the lactic acid bacteria constituting the preventive / improving agent or the food / beverage composition of the present invention can be arbitrarily determined according to the purpose and application (drug, food / beverage product composition). Although the present invention is not limited to this, the content is usually preferably 0.001 to 100% (w / w), particularly 0.01 to 100% (w / w) based on the total amount.
  • lactic acid bacteria When lactic acid bacteria are used for the production of food / beverage product compositions and drugs, the production method can be carried out by methods well known to those skilled in the art. If it is a person skilled in the art, the process which mixes a lactic acid bacterium or its processed product with other ingredients, a molding process, a sterilization process, a fermentation process, a baking process, a drying process, a cooling process, a granulation process, a packaging process, etc. are suitably combined and desired. It is possible to make food and drugs.
  • yogurt can be manufactured through a step of preparing a starter using lactic acid bacteria, a step of adding the starter to pretreated milk, a step of culturing, a cooling step, a flavoring step, a filling step, and the like.
  • a process of adding lactic acid bacteria of the present invention as a starter to milk that has been pretreated such as sterilization and the like a process of adding rennet to produce a cheese curd, a card cutting process, whey discharge It can be manufactured through a process, a salting process, an aging process, and the like.
  • a specific lactic acid bacterium for example, Lactobacillus gasseri
  • another lactic acid bacterium is used as a starter, and the specific lactic acid bacterium (for example, Lactobacillus gasseri) or a processed product thereof is added during the production process. Also good.
  • the present invention also relates to a method for preventing and / or improving endometriosis, which comprises the step of orally administering lactic acid bacteria to animals.
  • Mammals are examples of subjects to which lactic acid bacteria are administered. Mammals include humans and mammals other than humans, preferably humans and monkeys, more preferably humans.
  • the present invention also relates to a lactic acid bacterium for use in preventing and / or improving endometriosis.
  • the present invention relates to the use of lactic acid bacteria in the manufacture of an agent for preventing and / or improving endometriosis.
  • the present invention also relates to the use of lactic acid bacteria for the prevention and / or amelioration of endometriosis.
  • the present invention also relates to a method for producing an agent for preventing and / or improving endometriosis, which comprises a step of blending lactic acid bacteria and a pharmaceutically acceptable carrier.
  • lactic acid bacteria include, but are not limited to, lactic acid bacteria belonging to the genus Lactobacillus, more preferably Lactobacillus gasseri, and particularly preferably Lactobacillus gasseri OLL2809.
  • this invention provides the growth inhibitor of the lesioned part of endometriosis containing lactic acid bacteria.
  • the present invention also provides a method for inhibiting the growth of a lesion site of endometriosis comprising the step of administering lactic acid bacteria to an animal.
  • the present invention relates to a lactic acid bacterium for use in the suppression of the growth of lesions of endometriosis.
  • this invention relates to use of the lactic acid bacteria in manufacture of the growth inhibitor of the lesioned part of endometriosis.
  • this invention relates to use of the lactic acid bacteria for suppressing the growth of the lesion part of endometriosis.
  • this invention relates to the manufacturing method of the growth inhibitor of the lesioned part of endometriosis including the process of mix
  • the growth inhibitor of the present invention can contain a carrier suitable for oral administration.
  • the growth inhibitor of the present invention can be administered also as a food for the purpose of suppressing the growth of the lesion part of endometriosis.
  • Endometriosis occurs mainly in cells such as the peritoneum, ovary and uterus, Douglas fossa, the surface of organs such as the intestine and rectum, the inside of the ovary, and the muscle layer of the uterus.
  • Whether or not the growth of the lesioned part is suppressed by the growth inhibitor of the present invention can be determined, for example, by measuring the area, volume, and weight of the lesioned part by a method well known to those skilled in the art. It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.
  • Example 1 Endometriosis model mice were prepared by the following method, and the prevention and improvement effects of the preventive / ameliorating agent of the present invention were examined.
  • mice Six-week-old female BALB / c mice (Japan SLC Co., Ltd.) that had undergone ovariectomy at the age of 5 weeks were used. Mice were fed a CRF-1 diet (Oriental Yeast Co., Ltd.) and were housed in a room controlled at room temperature 21 ⁇ 2 ° C., humidity 55 ⁇ 15%, and light / dark cycle every 12 hours in cages divided into groups. . Food and water were ad libitum.
  • mice (100 ⁇ g / kg) was intramuscularly administered to the thigh.
  • Donor mice were subjected to ovariectomy and estrogen administration 7 days before the transplantation day, similar to recipient mice. Ovariectomy and estrogen administration were performed to adjust the sexual cycle of all mice to the estrus.
  • Mouse IL-12 recombinant (Wako Pure Chemical Industries, Ltd.) was suspended in PBS, and 0.15 ⁇ g / 0.4 ml was administered intraperitoneally for 5 consecutive days from 2 days before to 2 days after transplantation. The other groups received only the solvent under the same conditions.
  • Lactobacillus gasseri OLL2809 was subjected to activation culture (37 ° C., 18 hours) twice in Lactobacillus MRS broth (Difco). 1% of the activated cells were inoculated in the same medium and cultured at 37 ° C. for 18 hours. After collection, the cells were washed twice with physiological saline and once with sterilized distilled water. Sterilized by heating at 75 ° C. for 60 minutes and lyophilized. The lyophilized cells were suspended in water at a concentration of 2 mg / 0.5 ml, and a dose of 2 mg / 0.5 ml / body was used with a stomach tube for a period from the date of transplantation to the day before the dissection (day 20). The gastric tube was administered. The other groups received only the solvent under the same conditions.
  • mice On the 21st day after the endometrial transplantation, the mice were euthanized by cervical dislocation and the abdominal cavity lavage fluid was collected, followed by laparotomy. After measuring the size (long diameter, short diameter) of the endometrial lesion using calipers, it was extracted and weighed. When the lesion part formed a cyst, it was performed after the cyst fluid was aspirated.
  • peritoneal lavage fluid After collecting 0.5 ml of peritoneal lavage fluid from the peritoneal cells, 4 ml of PBS containing 1% FCS was injected into the peritoneal cavity, and 3 ml of the lavage fluid was collected. Cells in 0.5 ml of peritoneal lavage fluid collected for cytokine measurement were collected by centrifugation and combined into peritoneal cells.
  • Trizol reagent (Invitrogen, Calsbad, CA) was used for total RNA from peritoneal cells. Using 1 ⁇ g of the extracted total RNA as a template, reverse transcription to cDNA was performed using PrimeScript RT reagent Kit (Takara Bio Inc.). Real-time PCR was measured with ABI Prism 7300 (Applied Biosystems, Foster City, CA) using FastStart Universal SYBR Green Master reagent (Roche, Indianapolis, IN). Oligonucleotide primers for IL-2 gene are described in Overbergb et al. Was in reference (Overbergb L, Giulietti A, Valckx D, Decallonne B, Bouillon R, and Matbieu C.
  • the IL-2 gene is a cytokine produced mainly by Th1 cells and promotes differentiation and proliferation of B cells, T cells, NK cells, etc., and has been shown to suppress endometriosis in rats (Velasco). I., Quereda F, Bermejo R, Campos A, and Acien P. Intraperitoneal recombinant interleukin-2 activates leukocytes in ratentriosis. The expression level of IL-2 gene was enhanced by administration of Lactobacillus gasseri OLL2809, and the effectiveness of the preventive / ameliorating agent of the present invention could be verified.
  • NCR1 Natural Cytotoxicity triggering receptor 1
  • Ly94 NKp46 in humans and has been shown to be expressed on the surface of activated NK cells.
  • Example 2 In Example 2 below, the improvement effect on menstrual pain and dysmenorrhea in patients suffering from endometriosis with the preventive / ameliorating agent of the present invention was examined.
  • Symptoms (1) Secondary dysmenorrhea that is gradually progressing, (2) lower abdominal or pelvic pain, (3) Sexual discomfort or pain, (4) Intermittent diarrhea, constipation, anal pain, (5) Infertility.
  • Physical signs (6) Rectal uterine fossa, nodule of uterine sacral ligament under the posterior wall of the uterus, (7) A cystic, fixed mass around the uterine appendage. Selection criteria: (1) Patients aged between 18 and 45 years, (2) Patients who have menstruation every month and have a cycle of 28 ⁇ 3 days.
  • Exclusion criteria (1) Patients who have received hormone therapy within the past 3 months, (2) Patients with a history of severe liver damage, kidney damage, myocardial infarction or blood disease, (3) A patient with or suspected of having a malignant tumor, (4) Patients with CA-125 of 100 IU / ml or more, (5) A patient who has an endometrial lesion in the peritoneal incision, (6) Patients who develop diarrhea after dairy consumption, (7) Patients who are receiving allergic disease improvement, (8) Patients taking drugs (such as constipation-improving drugs or gastrointestinal drugs) that may affect the test results, (9) Patients taking foods (fermented milk and beverages containing lactic acid bacteria, etc.) that are thought to affect the test results for at least 4 days a week.
  • drugs such as constipation-improving drugs or gastrointestinal drugs
  • Cancellation / dropout criteria (1) Subjects who declined to continue testing due to free will, (2) Subjects who are unable to keep track of their progress, (3) Subjects who do not comply with compliance, (4) Subjects who have experienced serious complications or side effects, (5) Subjects whose study tablet intake is 80% or less or 120% or more of the specified amount.
  • controllers who were not directly involved in the study were randomly assigned to the placebo group and the active group.
  • the active group ingested two active tablets of the prophylactic / improving agent containing Lactobacillus gasseri OLL2809 of the present invention two times a day, and the placebo group ingested the placebo tablets for 12 weeks (three sexual cycles).
  • the following evaluation items were recorded every month, along with follow-up by interviews, etc., before the start of the test, 1, 2, and 3 months after the start of intake.
  • First evaluation item The degree of subjective pain by visual analog scale (VAS) and dysmenorrhea score during menstrual period.
  • Second evaluation item VAS other than menstruation and pelvic pain score total. Each score is shown in Table 1.
  • VAS during menstruation and other than menstruation was evaluated for the degree of pain due to endometriosis on a 10 cm straight line, with the left side being painless and the right side being the most severe pain experienced in the past.
  • serum CA-125 was measured before ingestion and 3 months after ingestion.
  • Blood safety tests red blood cell count, white blood cell count, platelet count, hemoglobin
  • blood biochemical tests blood glucose level, total protein, alanine aminotransferase (ALT), asparagine aminotransferase (AST), lactate dehydrogenase ( LDH), total bilirubin, ⁇ -transpeptidase, alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, total cholesterol, triglycerides, high-density lipoprotein (HDL)) and 3 months from the start of ingestion I went later.
  • ALT alanine aminotransferase
  • AST asparagine aminotransferase
  • LDH lactate dehydrogenase
  • ⁇ -transpeptidase alkaline phosphatase
  • ALP alkaline phosphatase
  • BUN blood urea nitrogen
  • creatinine uric acid
  • total cholesterol total cholesterol
  • test samples were active tablets (active tablets, manufactured by Meiji Dairies) and placebo tablets as preventive / improving agents of the present invention containing Lactobacillus gasseri OLL2809.
  • active tablets a culture concentrate of Lactobacillus gasseri OLL2809 was heat-treated at 75 ° C. for 60 minutes in a tablet of 250 mg, and 50 mg of freeze-dried powder was blended.
  • the placebo tablet was formulated with dextrin instead of the lyophilized powder.
  • Table 2 shows the background factors of subjects recorded before ingestion. There was no significant difference between the two groups in all items.
  • Fig. 3 shows the results of changes in VAS.
  • the two groups 7.73 ⁇ 0.26 in the placebo group and 7.51 ⁇ 0.22 in the active group before the start of ingestion.
  • Significant differences were observed in pain during menstruation 2 months and 3 months after the start of intake between the groups (P ⁇ 0.05 and P ⁇ 0.01, respectively). That is, the change in VAS from the start of intake to 3 months after intake was significantly improved to -3.28 ⁇ 0.36 in the active group compared to -2.00 ⁇ 0.29 in the placebo group. (P ⁇ 0.01, FIG. 4). From the above results, it was revealed that the preventive / ameliorating agent of the present invention (active tablet in this example) is effective in reducing menstrual pain.
  • Figure 5 shows the transition of the menstrual dysmenorrhea score. There was no significant difference between the two groups, 3.45 ⁇ 0.20 in the placebo group and 3.14 ⁇ 0.17 in the active group before ingestion, but 3 months later compared to placebo The active group showed a significantly low value (P ⁇ 0.05). The change in the dysmenorrhea score from the start of intake to 3 months after the intake was ⁇ 1.03 ⁇ 0.16 in the placebo group, but ⁇ 1.44 ⁇ 0.17 in the active group. The improvement tendency was shown (P ⁇ 0.1, FIG. 6). That is, it was revealed that the preventive / ameliorating agent of the present invention (active tablet in this example) is effective in improving the menstrual dysmenorrhea score.
  • Lactobacillus gasseri OLL2809 has been shown to improve pain and dysmenorrhea derived from endometriosis in the menstrual period, and is effective in improving QOL of affected individuals.
  • it since no side effects are observed, it is useful for improving QOL in patients with endometriosis, and is considered to be a highly safe preventive / ameliorating agent.
  • a preventive and / or ameliorating agent for endometriosis comprising certain lactic acid bacteria of the present invention, particularly Lactobacillus genus lactic acid bacteria, is characterized by enhancing NK activity and enhancing its own immunity, It shows a high improvement effect that has not been known so far for endometriosis, particularly menstrual pain and dysmenorrhea. Therefore, the preventive / ameliorating agent of the present invention is useful for preventing or ameliorating these diseases. It is also effective in improving QOL in patients with endometriosis. Moreover, since the preventive / ameliorating agent of the present invention can be taken orally, it can be taken easily and endometriosis can be prevented or improved.
  • the preventive / improving agent of the present invention As a food / beverage product composition. By using a food / beverage product composition, simpler intake can be promoted. .
  • the preventive / ameliorating agent of the present invention has an unprecedented alleviating effect on pain peculiar to endometriosis. Therefore, it is effective for improving QOL particularly in those suffering from endometriosis.

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Abstract

L'invention concerne un agent de prévention et/ou d'amélioration de l'endométriose contenant le genre Lactobacillus d'une bactérie d'acide lactique, en particulier la souche OLL2809 de Lactobacillus gasseri. L'invention concerne en outre une composition pour aliment et boisson contenant la bactérie d'acide lactique pour la prévention et/ou l'amélioration de l'endométriose, et une méthode de prévention et/ou d'amélioration de l'endométriose caractérisée par l'administration de la bactérie d'acide lactique.
PCT/JP2011/077464 2010-11-29 2011-11-29 Agent de prévention et/ou d'amélioration de l'endométriose, et composition pour aliment ou boisson le contenant WO2012073924A1 (fr)

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JP2012546872A JP5667642B2 (ja) 2010-11-29 2011-11-29 子宮内膜症の予防及び／又は改善剤及びこれを含んでなる飲食品組成物
SG2013041355A SG190719A1 (en) 2010-11-29 2011-11-29 Endometriosis prevention and/or improving agent, and food or drink composition containing same
CN201180057181.6A CN103249421B (zh) 2010-11-29 2011-11-29 子宫内膜异位症的预防和/或改善剂以及含有其的饮食品组合物
HK14100961.9A HK1187825A1 (en) 2010-11-29 2014-01-29 Endometriosis prevention and or improving agent, and food or drink composition containing same

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RU2635187C1 (ru) * 2017-02-28 2017-11-09 Государственное научное учреждение Всероссийский научно-исследовательский ветеринарный институт патологии, фармакологии и терапии Российской академии сельскохозяйственных наук (ГНУ ВНИВИПФиТ Россельхозакадемии) Способ профилактики острых послеродовых и хронических скрытых воспалительных процессов в репродуктивных органах свиноматок

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CN107858416B (zh) * 2016-09-19 2021-05-28 深圳华大生命科学研究院 用于子宫内膜异位症检测的生物标志物组合及其应用
EP3854412A4 (fr) * 2018-09-20 2022-06-15 NRL Pharma, Inc. Agent et composition pour améliorer la flore bactérienne intra-utérine, et procédé pour déterminer si une flore bactérienne intra-utérine a été améliorée ou normalisée
CN113164534A (zh) * 2018-12-21 2021-07-23 金伯利-克拉克环球有限公司 用于预防或治疗失禁、膀胱过度活动症或月经痉挛的组合物和方法
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2633489C1 (ru) * 2016-11-07 2017-10-12 Государственное научное учреждение Всероссийский научно-исследовательский ветеринарный институт патологии, фармакологии и терапии Российской академии сельскохозяйственных наук (ГНУ ВНИВИПФиТ Россельхозакадемии) Способ профилактики скрытого эндометрита у свиноматок
RU2635187C1 (ru) * 2017-02-28 2017-11-09 Государственное научное учреждение Всероссийский научно-исследовательский ветеринарный институт патологии, фармакологии и терапии Российской академии сельскохозяйственных наук (ГНУ ВНИВИПФиТ Россельхозакадемии) Способ профилактики острых послеродовых и хронических скрытых воспалительных процессов в репродуктивных органах свиноматок

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