WO2018030732A1 - Nanovésicules dérivées de bactéries du genre bacillus et leur utilisation - Google Patents

Nanovésicules dérivées de bactéries du genre bacillus et leur utilisation Download PDF

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WO2018030732A1
WO2018030732A1 PCT/KR2017/008497 KR2017008497W WO2018030732A1 WO 2018030732 A1 WO2018030732 A1 WO 2018030732A1 KR 2017008497 W KR2017008497 W KR 2017008497W WO 2018030732 A1 WO2018030732 A1 WO 2018030732A1
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Prior art keywords
vesicles
derived
cancer
bacillus
bacteria
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PCT/KR2017/008497
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English (en)
Korean (ko)
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김윤근
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주식회사 엠디헬스케어
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Priority claimed from KR1020170098860A external-priority patent/KR102085787B1/ko
Application filed by 주식회사 엠디헬스케어 filed Critical 주식회사 엠디헬스케어
Priority to CN201780049499.7A priority Critical patent/CN109789173B/zh
Priority to US16/325,023 priority patent/US20190177783A1/en
Priority to EP17839750.1A priority patent/EP3498285A4/fr
Priority to JP2019507291A priority patent/JP6839265B2/ja
Publication of WO2018030732A1 publication Critical patent/WO2018030732A1/fr

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    • 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
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/99—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from microorganisms other than algae or fungi, e.g. protozoa or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to nanovesicles derived from Bacillus bacteria and their use, and more particularly to methods of diagnosing cancer, inflammatory diseases, or metabolic diseases using nanovesicles derived from Bacillus bacteria, and preventing or treating the vesicles. It relates to a composition for.
  • chronic infectious diseases which were previously recognized as infectious diseases, have become less important, while chronic diseases caused by the incompatibility between humans and microbiomes are the major diseases that determine quality of life and human life. Changed.
  • the chronic disease is characterized by chronic inflammation accompanied by immune dysfunction, cancer, chronic inflammatory diseases, metabolic diseases, etc. have become a major problem in public health.
  • Inflammation is a local or systemic defense against damage or infection of cells and tissues, primarily by the direct response of humoral mediators that make up the immune system, or by stimulating local or systemic effector systems. It is caused by a cascade of biological reactions that take place.
  • Major inflammatory diseases include gastroenteritis, digestive diseases such as inflammatory bowelitis, oral diseases such as periodontitis, asthma, chronic obstructive pulmonary disease (COPD), respiratory diseases such as rhinitis, atopic dermatitis, hair loss, skin diseases such as psoriasis, degenerative arthritis, Arthritis, such as rheumatoid arthritis; And obesity, diabetes mellitus, cirrhosis and the like metabolic diseases.
  • COPD chronic obstructive pulmonary disease
  • rhinitis atopic dermatitis
  • hair loss skin diseases
  • skin diseases such as psoriasis, degenerative arthritis
  • Arthritis such as rheumatoid arthritis
  • obesity
  • microbiota refers to a microbial community including microbes, archaea and eukarya that exist in a given settlement, and the intestinal microbiota is important for human physiology. It plays a role and is known to greatly affect human health and disease through interaction with human cells.
  • symbiotic bacteria and archaea that symbiotic to our body secrete nanometer-sized vesicles (nanovesicle) to exchange information, such as genes, proteins to other cells.
  • the mucous membrane forms a physical protective film that particles larger than 200 nanometers (nm) in size can't pass through. If the bacteria are symbiotic bacteria, the mucosa cannot pass through the mucous membrane, but the bacteria-derived vesicles are 100 nanometers in size or less. It passes through epithelial cells through the mucous membrane and is absorbed by our body.
  • Pathogenic bacteria-derived vesicles absorbed by our bodies are inflammatory diseases such as inflammatory skin diseases such as atopic dermatitis, inflammatory respiratory diseases such as chronic rhinitis, asthma and chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. It is found to be an important factor in the etiology of. In addition, diabetes, obesity and the like has been attracting attention as it is recently found that there is a close relationship with the occurrence of metabolic diseases and solid cancers, such as lung cancer, stomach cancer, colon cancer. However, there have been no cases of diagnosing cancer, chronic inflammatory diseases, or metabolic diseases by quantifying Bacillus bacteria-derived vesicles in clinical samples.
  • Bacillus is a Gram-positive bacillus belonging to the Firmicutes portal, which grows in anaerobic as well as aerobic environments, and can survive for a long time in the form of spores in stress situations.
  • Bacillus bacteria Bacillus subtilis is a Gram-positive bacillus that can grow in non-pathogenic and aerobic environments, and is widely distributed in the natural world such as dry grass, sewage, soil, and dust.
  • subtypes of Bacillus subtilis natto Bacillus subtilis natto (Bacillus subtilis natto) can grow in anaerobic environment, attach to crested soybeans when they make cheonggukjang, and multiply by blocking the air with heat formed near 40 °C.
  • Cheonggukjang is a traditional Korean food made from fermented soybeans, similar to Japanese natto. It takes several months to ferment soybean paste but fermented soybeans can be eaten in 2-3 days. In other words, the soybeans can be made on the shortest date of fermented soybeans. Cheonggukjang made by natural fermentation is soaked in hot water for 10-20 hours, then poured with water and boiled. Put a few straws in a bowl, put it in a bowl, cool it to 60 °C, put it in a warm place and cover it with blankets or blankets, and keep it at 45 °C, and then the natto bacteria such as natto breed and become fermented substances.
  • compositions used to treat or prevent chronic inflammatory diseases are largely divided into steroidal and nonsteroidal compositions, many of which are accompanied by various side effects.
  • TNF- ⁇ is increasing in the etiology of inflammatory diseases such as rheumatoid arthritis, hair loss, inflammatory bowel disease, and the like, and TNF- ⁇ inhibitors have been spotlighted as therapeutic agents for rheumatoid arthritis.
  • it has not been used to diagnose cancer, chronic inflammatory disease, or metabolic disease by quantifying genes in vesicles secreted from bacteria of Bacillus or Bacillus subtilis, or to prevent or treat inflammatory diseases through the vesicles. to be.
  • the present inventors earnestly studied to solve the above-mentioned conventional problems, and as a result of analyzing the bacteria-derived vesicle metagenome present in human samples, solid cancers such as liver cancer, bladder cancer, breast cancer, and ovarian cancer, asthma, and atopic dermatitis
  • solid cancers such as liver cancer, bladder cancer, breast cancer, and ovarian cancer
  • asthma and atopic dermatitis
  • the contents of the bacterium derived from Bacillus bacterium were significantly reduced, and the vesicles were isolated by culturing Bacillus bacteria, especially Bacillus subtilis, in vitro.
  • the present invention was completed based on this.
  • an object of the present invention is to provide an information providing method for diagnosing cancer, chronic inflammatory diseases, and metabolic diseases.
  • Another object of the present invention is to provide a composition for preventing or treating cancer, chronic inflammatory diseases, and metabolic diseases, including the bacterium-derived vesicles as an active ingredient.
  • the present invention provides a method for providing information for the diagnosis of cancer, chronic inflammatory diseases, or metabolic diseases comprising the following steps.
  • the cancer may be liver cancer, bladder cancer, breast cancer, or ovarian cancer.
  • the chronic inflammatory disease may be asthma, chronic hepatitis, or atopic dermatitis.
  • the metabolic disease may be diabetes or cirrhosis of the liver.
  • the patient derived sample may be blood, urine, or stool.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of cancer, inflammatory diseases, or metabolic diseases, comprising the bacterium-derived vesicles as an active ingredient.
  • the present invention provides a health functional food composition for improving cancer, inflammatory disease, or metabolic disease, comprising the bacterium-derived vesicles as an active ingredient.
  • the present invention provides an inhalant composition for preventing or treating cancer, inflammatory disease, or metabolic disease, comprising a bacterium-derived vesicle derived as an active ingredient.
  • the present invention provides a cosmetic composition for improving inflammatory disease, comprising a bacterium-derived vesicle derived as an active ingredient.
  • Bacillus bacteria-derived vesicles may be vesicles derived from Bacillus subtilis.
  • Bacillus subtilis-derived vesicles may be natto-derived vesicles.
  • the cancer is selected from the group consisting of liver cancer, bladder cancer, breast cancer, and ovarian cancer;
  • the inflammatory disease is selected from the group consisting of asthma, chronic hepatitis, hair loss, rheumatoid arthritis, inflammatory growth inflammation, and atopic dermatitis;
  • the metabolic disease may be diabetes or cirrhosis of the liver.
  • the inflammatory disease may be one or more diseases selected from the group consisting of rheumatoid arthritis, hair loss, and inflammatory growth inflammation in which the inflammatory cytokine IL-6 or TNF- ⁇ is involved in the pathogenesis.
  • the vesicles may have an average diameter of 10 to 200 nm.
  • the vesicles may be secreted naturally or artificially from bacteria of the genus Bacillus.
  • the vesicles may be isolated from the culture medium of bacteria in Bacillus.
  • the present invention also provides a method for preventing or treating cancer, inflammatory diseases, or metabolic diseases, comprising administering to a subject a pharmaceutical composition comprising a bacterium-derived bacterium-derived vesicle as an active ingredient.
  • the present invention also provides a preventive or therapeutic use for inflammatory diseases of vesicles derived from Bacillus genus.
  • the present inventors confirmed that the intestinal bacteria are not absorbed into the body, but the bacteria-derived vesicles are absorbed into the body and distributed systemically and excreted externally through the kidneys, liver, and lungs.
  • Bacterial-derived bacteria of Bacillus present in the blood of patients with metabolic diseases such as solid cancers such as liver cancer, bladder cancer, breast cancer, ovarian cancer, asthma, atopic dermatitis, diabetes, liver cirrhosis, etc. It was confirmed that the vesicles were significantly reduced compared to the normal persons.
  • the bacterium-derived vesicles according to the present invention are useful for the diagnosis or prediction method of cancer, chronic inflammatory disease, or metabolic disease, and for the prevention or treatment of food, inhalants, cosmetics, or drugs.
  • a standard strain of Bacillus subtilis a subtilis of Bacillus subtilis and Natto, a subtype of Bacillus subtilis
  • the bacterium-derived vesicles according to the present invention are useful for the diagnosis or prediction method of cancer, chronic inflammatory disease, or metabolic disease, and for the prevention or treatment of food, inhalants, cosmetics, or drugs.
  • Figure 1a is a photograph of the distribution of bacteria and vesicles over time after the oral administration of bacteria and bacteria-derived vesicles (EV) to the mouse.
  • Figure 1b is a 12 hours after oral administration, blood, kidneys, liver, and various organs were extracted to evaluate the distribution of bacteria and vesicles in the body.
  • FIG. 2 is a diagram schematically illustrating a method of analyzing bacterial-derived vesicle metagenome in human derivatives.
  • Figure 3 is a result of comparing the distribution of bacteria-derived vesicles of the genus Bacillus after the analysis of bacteria-derived vesicles metagenome present in liver cancer patients and normal blood.
  • Figure 4 is a result of comparing the distribution of bacteria-derived vesicles of the genus Bacillus after the analysis of bacteria-derived vesicles metagenome present in bladder cancer patients and normal blood.
  • 5 is a result of comparing the distribution of bacteria-derived vesicles of the genus Bacillus after analyzing the bacteria-derived vesicles metagenome present in breast cancer patients and normal blood.
  • Figure 6 is a result of comparing the distribution of bacteria-derived vesicles of the genus Bacillus after the analysis of bacterial-derived vesicles metagenome present in ovarian cancer patients and normal blood.
  • 11 is a result of comparing the distribution of bacteria-derived vesicles of the genus Escherichia after the analysis of bacteria-derived vesicles metagenome present in diabetic patients and normal blood.
  • Figure 12a is a result of measuring the form and size of Bacillus subtilis derived from Bacillus subtilis in the Bacillus subtilis culture medium by ultracentrifugation method (a).
  • Figure 12b is a result of measuring the form and size of Bacillus subtilis derived from Bacillus subtilis through the dynamic light scattering method (b) for the vesicles separated by the ultracentrifugation method in Bacillus subtilis culture.
  • FIG. 13A shows E. coli vesicles (E. coli EV), a causative factor in cancer, inflammatory disease and metabolic disease, as a positive control group, Bacillus subtilis EV and Natto bacteria-derived vesicles ( Bacillus subtilis natto EV). ) Is treated with macrophages (Raw 264.7) at various concentrations, and IL-6 concentration is measured by ELISA to compare the degree of secretion of inflammatory mediators [NC: negative control (PBS), EV: extracellular vesicle].
  • NC negative control
  • EV extracellular vesicle
  • E. coli EV E. coli vesicles
  • a causative factor in cancer inflammatory diseases, and metabolic diseases
  • Bacillus subtilis EVs and Bacillus subtilis natto EVs Bacillus subtilis natto EVs
  • EC E. coli vesicles
  • FIG. 14A is for evaluating the anti-inflammatory effects of Bacillus subtilis and Bacillus subtilis Natto strains (Lactobacillus), a macrophage line (Raw 264.7) as a control drug Lactobacillus plantarum vesicles ( L. plantarum EV) , Bacillus subtilis EV and Natto-derived vesicles ( Bacillus subtilis natto EV) were pretreated and treated with E. coli-derived vesicles as a causative agent of inflammation after 12 hours. Measurement results [NC: negative control (PBS), PC: positive control, EV: extracellular vesicle].
  • NBS negative control
  • PC positive control
  • EV extracellular vesicle
  • 14B is for evaluating the anti-inflammatory effect of Bacillus subtilis and Bacillus subtilis Natto strains (Lactobacillus), a macrophage line (Raw 264.7) as a control drug Lactobacillus plantarum vesicles ( L. plantarum EV) , Bacillus subtilis EV and Natto-derived vesicles ( Bacillus subtilis natto EV) were pretreated and treated with E. coli-derived vesicles as a causative agent of inflammation after 12 hours, and then TNF- ⁇ concentration was determined by ELISA. Measurement results [NC: negative control (PBS), PC: positive control, EV: extracellular vesicle].
  • the present invention relates to vesicles derived from bacteria of the genus Bacillus and uses thereof.
  • the present inventors conducted meta-genome analysis of bacterium-derived vesicles from Bacillus-derived samples from patients with metabolic diseases such as liver cancer, bladder cancer, breast cancer, ovarian cancer, solid cancers such as asthma, atopic dermatitis, diabetes and liver cirrhosis.
  • metabolic diseases such as liver cancer, bladder cancer, breast cancer, ovarian cancer, solid cancers such as asthma, atopic dermatitis, diabetes and liver cirrhosis.
  • the standard bacterium belonging to the bacterium of Bacillus and the natto bacteria-derived vesicles were isolated and administered to inflammatory cells.
  • the present invention was completed based on this.
  • the present invention provides a method for providing information for the diagnosis of cancer, chronic inflammatory diseases, and metabolic diseases comprising the following steps.
  • the present invention provides information for diagnosing diabetes comprising the following steps Provide the method of providing.
  • Diagnosis means, in a broad sense, to determine the actual condition of a patient in all aspects. The content of the judgment is the name of the disease, the etiology, the type of disease, the seriousness, the detailed mode of the condition, the presence or absence of complications, and the prognosis. Diagnosis in the present invention is to determine the onset of cancer, chronic inflammatory diseases, or metabolic diseases and the level of the disease.
  • the present invention provides a food, cosmetic, inhalant, or drug composition for preventing or treating cancer, chronic inflammatory disease, or metabolic disease, comprising a bacterium-derived vesicle of Bacillus as an active ingredient. .
  • prophylaxis means any action that inhibits or delays the development of cancer, chronic inflammatory diseases, or metabolic diseases by administration of a food, cosmetic, inhalant, or drug composition according to the present invention.
  • treatment means any action in which symptoms for cancer, chronic inflammatory diseases, or metabolic diseases are improved or beneficially changed by administration of a food, cosmetic, inhalant, or drug composition according to the present invention.
  • the Bacillus bacteria-derived vesicles of the present invention may be isolated from a culture of Bacillus bacteria or food fermented with Bacillus bacteria, preferably from a culture solution of Bacillus subtilis or natto bacteria or from foods fermented with Bacillus subtilis or natto bacteria. And, it may be natural or artificial secreted from Bacillus subtilis or natto bacteria, but is not limited thereto.
  • the method for separating the vesicles from the culture solution or fermented food of the bacterium of the present invention is not particularly limited as long as the vesicles.
  • centrifugation, ultra-fast centrifugation, filtration by filter, gel filtration chromatography, pre-flow electrophoresis, or capillary electrophoresis, and combinations thereof may be used to separate the vesicles and also remove impurities. It may further include a process for washing, concentration of the obtained vesicles and the like.
  • the vesicles separated by the method in the present invention may have an average diameter of 10 to 1000 nm, more preferably 40 to 100 nm, but is not limited thereto.
  • the pharmaceutical composition according to the present invention includes a bacterium-derived vesicle derived from Bacillus as an active ingredient, and may include a pharmaceutically acceptable carrier.
  • Such pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, external preparation for skin, oral ingestion, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, skin, nasal, airways) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • the composition according to the invention is administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment, and the effective dose level refers to the type, severity, drug activity, and drug of the patient. Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
  • the composition according to the present invention may be administered as a separate therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
  • the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight is administered daily or every other day or 1 It can be administered in 1 to 3 times a day.
  • the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
  • the present invention provides a health functional food composition for improving cancer, inflammatory disease, or metabolic disease, comprising the bacterium-derived vesicles as an active ingredient.
  • improvement means any action that at least reduces the parameters associated with the condition being treated, for example the extent of symptoms.
  • the active ingredient may be added to the food as it is, or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the compositions of the invention are added in amounts of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
  • the amount may be below the above range.
  • the health functional food composition of the present invention in addition to containing the active ingredient as an essential ingredient in the indicated ratio, is not particularly limited to other ingredients, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
  • the nutraceutical composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors such as synthetic and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • these components can be used independently or in combination.
  • the proportion of such additives may also be appropriately selected by those skilled in the art.
  • the present invention provides an inhalant composition for preventing or treating inflammatory diseases, which comprises a bacterium-derived vesicle as an active ingredient.
  • the active ingredient may be added to the inhalant as it is, or may be used together with other ingredients, and may be appropriately used according to conventional methods.
  • the amount of the active ingredient to be mixed may be suitably determined depending on the purpose of use (prophylactic or therapeutic).
  • the present invention provides a cosmetic composition for improving inflammatory disease or hair loss comprising a bacterium-derived vesicles as an active ingredient.
  • the cosmetic composition of the present invention may include not only vesicles derived from bacteria of the genus Bacillus, but also components commonly used in cosmetic compositions, for example, conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances. And a carrier.
  • composition of the present invention in addition to the vesicles derived from the bacterium of the genus Bacillus, may be used by mixing the organic sunscreens that have been conventionally used as long as it does not impair the skin protection effect by reacting with the bacterium-derived vesicles.
  • organic sunscreen examples include glyceryl pava, drometrizole trisiloxane, drometrizole, digaloyltrioleate, disodium phenyldibenzimidazole tetrasulfonate, diethylhexyl butamidotriazone, diethylamino Hydroxybenzoylhexylbenzoate, die-methoxycinnamate, a mixture of lowson and dihydroxyacetone, methylenebis-benzotriazolyltetramethylbutylphenol, 4-methylbenzylidene camphor, menthyl anthranilate, benzophenone -3 (oxybenzone), benzophenone-4, benzophenone-8 (dioxyphenbenzone), butylmethoxydibenzoylmethane, bisethylhexyloxyphenol methoxyphenyltriazine, synoxate, ethyldihydroxypropylpava, Oct
  • Examples of products to which the cosmetic composition of the present invention may be added include, for example, cosmetics such as astringent cosmetics, soft cosmetics, nourishing cosmetics, various creams, essences, packs, foundations, and the like, cleansing agents, soaps, treatments, and essences.
  • Specific formulations of the cosmetic composition of the present invention include skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, Formulations such as soaps, shampoos, cleansing foams, cleansing lotions, cleansing creams, body lotions, body cleansers, emulsions, lipsticks, makeup bases, foundations, press powders, loose powders, eye shadows and the like.
  • the content of the bacterium-derived vesicles of the genus Bacillus of the present invention is 0.00001-30% by weight, preferably 0.5-20%, more preferably 1.0-10% by weight based on the total weight of the composition. to be.
  • the content of the bacterium-derived vesicles of the Bacillus is less than 0.00001% by weight, the ultraviolet absorbing effect is greatly reduced, and when it exceeds 30% by weight, skin irritation may occur, and formulation problems may occur.
  • the present invention provides a method for preventing or treating cancer, inflammatory disease, or metabolic disease comprising administering to a subject a composition comprising a bacterium-derived vesicle derived as an active ingredient.
  • an individual means a subject in need of treatment of a disease, and more specifically, a mammal such as a primate, mouse, rat, dog, cat, horse, and cow, which is human or non-human. Means.
  • Cancer refers to a malignant tumor that grows rapidly while infiltrating surrounding tissues and spreads or metastasizes to various parts of the body and threatens life.
  • Cells the smallest unit of the body, divide and grow normally under the control function of the cells themselves, and die off at the end of their life or damage to maintain the balance of the overall number, but for a number of reasons If a problem occurs in the cell's own regulatory function, abnormal cells that normally must die will overgrow, invading surrounding tissues and organs, forming a mass, and destroying or modifying existing structures.
  • the cancer may preferably be liver cancer, bladder cancer, breast cancer, or ovarian cancer, but is not limited thereto.
  • inflammatory disease refers to a disease caused by an inflammatory response in a mammalian body.
  • respiratory inflammatory diseases such as asthma, chronic obstructive pulmonary disease and rhinitis
  • Skin inflammatory diseases such as atopic dermatitis, psoriasis, acne, contact dermatitis, and hair loss
  • Gastrointestinal inflammatory diseases such as gastritis, peptic ulcer, and inflammatory bowel disease
  • vaginitis Arthritis, such as osteoarthritis and rheumatoid arthritis; And complications thereof.
  • the inflammatory disease is used in the sense including cancer associated with the inflammatory response, in addition to the general inflammatory disease, for example, includes breast cancer, ovarian cancer, bladder cancer, liver cancer and the like.
  • the inflammatory disease is used in the sense including metabolic diseases related to the inflammatory response, in addition to the general inflammatory disease, for example, diabetes, obesity, cirrhosis of the liver and the like.
  • chronic inflammatory diseases preferably mean, but are not limited to, asthma, chronic hepatitis, hair loss, or atopic dermatitis.
  • metabolic disease refers to a disease in which complications occur in various organs due to metabolic disorders in a mammal's body.
  • carbohydrate metabolic disorders such as diabetes and complications thereof may be cited as cirrhosis.
  • metabolic diseases preferably include, but are not limited to, diabetes and cirrhosis.
  • nanovesicles refers to the structure of the nano-size membrane secreted by various bacteria.
  • Gram-negative bacteria-derived vesicles or outer membrane vesicles contain toxic proteins, bacterial DNA and RNA as well as lipopolysaccharides, and gram-positive bacteria-derived vesicles.
  • OMVs outer membrane vesicles
  • proteins and nucleic acids it also contains peptidoglycan and lipoteichoic acid, which are components of bacterial cell walls.
  • nanovesicles or vesicles are naturally secreted or artificially produced by bacteria of the genus Bacillus, and have a spherical shape and have an average diameter of 10 to 200 nm.
  • the term "metagenome” is also referred to as a "gunoelectric", and means a total of a genome including all viruses, bacteria, fungi, and the like in an isolated region such as soil and animal intestine, and is not mainly cultured. It is used as a concept of genome to explain the identification of many microorganisms at once using sequencer to analyze microorganisms.
  • the metagenome does not refer to one genome or genome, but to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • rapid sequencing is used to analyze all DNA and RNA, regardless of species, to identify all species in one environment, and to identify interactions and metabolism.
  • Bacterial-derived vesicles in the present invention is centrifugation, ultra-fast centrifugation, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical degradation, chemical treatment, filtration by filter, gel containing the bacteria
  • the separation can be carried out using one or more methods selected from the group consisting of filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis.
  • it may further include a process for washing to remove impurities, concentration of the obtained vesicles and the like.
  • the bacterial and bacterial-derived vesicles are orally administered to the mice to evaluate the absorption, distribution, and excretion of the bacteria and vesicles in the body. It was confirmed that it is absorbed and distributed systemically and excreted through the kidney, liver, and the like (see Example 1).
  • bacterial metagenome analysis was performed using vesicles isolated from blood of normal, matched age and gender to liver cancer, bladder cancer, breast cancer, and ovarian cancer patients. As a result, it was confirmed that bacterial vesicles of Bacillus spp. Significantly reduced in samples of patients with liver cancer, bladder cancer, breast cancer, and ovarian cancer compared to normal samples (see Examples 3, 4, 5, and 6).
  • bacterial metagenomic analysis was performed using vesicles isolated from a sample of asthma and atopic dermatitis patients and normal subjects matching the age and gender of the patient. As a result, it was confirmed that the vesicle-derived bacteria of Bacillus spp. Significantly decreased in the samples of asthma and atopic dermatitis patients compared to the normal samples (see Examples 7 and 8).
  • bacterial metagenomic analysis was performed using vesicles isolated from a sample of a diabetic and cirrhosis patient and a normal person matching the age and sex of the patient. As a result, it was confirmed that the vesicles derived from Bacillus spp. Significantly reduced in the samples of diabetic and cirrhosis patients compared to the normal samples (see Examples 9 and 10).
  • vesicles derived from Bacillus subtilis (standard strain)
  • Naxos-derived vesicles which are subtypes of Bacillus subtilis
  • there was little inflammation-inducing effect compared to E. coli-derived vesicles and when pretreatment of vesicles or Natto-derived vesicles effectively suppressed the inflammatory response caused by Escherichia coli-derived vesicles.
  • the present invention was completed based on this observation (see Examples 13 and 14).
  • the blood-labeled 50 ⁇ g of bacteria and bacteria-derived vesicles were administered in the same manner as described above, and then 12 hours after administration
  • the heart, liver, kidneys, spleen, fat and muscles were taken.
  • bacteria-derived vesicles were distributed in blood, heart, lung, liver, kidney, spleen, fat, muscle, and kidney, but the bacteria were not absorbed (see FIG. 1B).
  • DNA extracted by the above method was amplified using the above 16S rDNA primers, followed by sequencing (Illumina MiSeq sequencer), and the results were outputted in a Standard Flowgram Format (SFF) file, using GS FLX software (v2.9).
  • SFF Standard Flowgram Format
  • GS FLX Standard Flowgram Format
  • OTU operational taxonomy unit
  • clustering is performed according to sequence similarity using UCLUST and USEARCH, genus 94%, family 90%, order 85%, class 80%, phylum 75% sequence similarity
  • Clustering is based on the phylum, class, order, family, and genus levels of each OTU, and BLASTN and GreenGenes' 16S RNA sequence database (108,453 sequences) is used to identify bacteria with greater than 97% sequence similarity at the genus level.
  • Was profiled QIIME).
  • Example 3 Blood-derived vesicles derived from liver cancer patients Metagenome Through analysis Bacillus Reduction of Bacterial-Derived Vesicles in Genus
  • Example 7 Blood-derived vesicles from asthma patients Metagenome Through analysis Bacillus Reduction of Bacterial-Derived Vesicles in Genus
  • Example 8 Vesicles derived from blood bacteria of atopic dermatitis patients Metagenome Through analysis Bacillus Reduction of Bacterial-Derived Vesicles in Genus
  • Example 10 Blood Bacteria Derived from Liver Cirrhosis Patients Metagenome Through analysis Bacillus Reduction of Bacterial-Derived Vesicles in Genus
  • Example 11 Blood-derived vesicles from diabetic patients Metagenome Analysis of Escherichia Genus Bacteria-Derived Vesicles
  • vesicles were isolated from the culture medium of Bacillus subtilis strains.
  • 2 L of autoclaved brain heart infusion broth (BD 237500) was isolated. After inoculation and incubation in a chamber so that the absorbance (OD) value was 1.5 for 72 hours, the culture solution was centrifuged at high speed (10,000 ⁇ g) for 20 minutes to obtain a supernatant except for the bacterial precipitation pellets. The supernatant was sequentially filtered using a 0.45 ⁇ m filter and a 0.22 ⁇ m filter, and then cultured about 14-fold concentrated using a Quixstand benchtop system. The culture medium was again subjected to ultrafast centrifugation for 2 hours at 150,000 ⁇ g, 4 ° C. to obtain pellets, and then dissolved in sterile saline (PBS) to quantify the protein.
  • PBS sterile saline
  • the form and size of Bacillus subtilis obtained from Bacillus subculture were observed and measured.
  • 50 ⁇ g / ml sample was obtained by protein quantification and observed with a JEM 1011 electron microscope (Jeol, Japan). As shown in FIG. 12A, it was confirmed that the vesicle-derived vesicles were spherical. .
  • the size of Bacillus subtilis derived from Bacillus subtilis was measured by dynamic light scattering (DLS) through zetasizer nano ZS (Malverk, UK) with a sample of 50 ⁇ g / ml, as shown in FIG. 12B. It was found that the average diameter of the derived vesicles was in the range of 40 to 100 nm.
  • Escherichia coli Eschericahia coli
  • Eschericahia coli is a major bacterium that lives not only in the large intestine but also in the surrounding environment, and is highly resistant to antibiotics.
  • E. coli-derived vesicles are found to be a major cause of chronic obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), it has become known as a major cause of chronic inflammatory diseases. Therefore, the present invention was intended to evaluate the anti-inflammatory effect of Bacillus subtilis-derived vesicles on the occurrence of inflammation caused by E. coli-derived vesicles.
  • B. subtilis EV 0.1, 1, 10 ⁇ g / ml, or B.
  • subtilis natto EV 0.1, 1, 10 ⁇ g, in the macrophage line (Raw 264.7).
  • Ml Ml
  • E. coli vesicles 1 ⁇ g / ml
  • the negative control group (NC) was treated with PBS in the same manner as in Example 13, the positive control group (PC) was treated only with E.
  • Lactobacillus plantarum vesicles 1 ⁇ g / ml
  • lactobacillus plantarum EV 1 ⁇ g / ml
  • the present inventors confirmed that the intestinal bacteria are not absorbed into the body, but the bacteria-derived vesicles are absorbed into the body and distributed systemically and excreted externally through the kidneys, liver, and lungs.
  • Bacterial-derived bacteria of Bacillus present in the blood of patients with metabolic diseases such as solid cancers such as liver cancer, bladder cancer, breast cancer, ovarian cancer, asthma, atopic dermatitis, diabetes, liver cirrhosis, etc. It was confirmed that the vesicles were significantly reduced compared to the normal persons.
  • the bacterium-derived vesicles according to the present invention are useful for the diagnosis or prediction method of cancer, chronic inflammatory disease, or metabolic disease, and for the prevention or treatment of food, inhalants, cosmetics, or drugs.
  • a standard strain of Bacillus subtilis a subtilis of Bacillus subtilis and Natto, a subtype of Bacillus subtilis
  • the bacterium-derived vesicles according to the present invention are useful for the diagnosis or prediction method of cancer, chronic inflammatory disease, or metabolic disease, and for the prevention or treatment of food, inhalants, cosmetics, or drugs.

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Abstract

La présente invention concerne des vésicules dérivées de bactéries du genre Bacillus et leur utilisation. Les présents inventeurs ont confirmé que les vésicules présentent un niveau significativement réduit dans des prélèvements de patients affectés de cancers, tels que le cancer du foie, le cancer de la vessie, le cancer du sein, et le cancer de l'ovaire ; les maladies inflammatoires, telles que l'asthme et la dermatite atopique ; ou les maladies métaboliques, telles que le diabète et la cirrhose, comparés aux personnes normales, et les vésicules inhibaient la sécrétion des médiateurs inflammatoires par les vésicules pathogènes, telles que les vésicules dérivées d'E. coli, qui sont des facteurs responsables des maladies inflammatoires, du diabète, et similaires. Par conséquent, les vésicules dérivées de bactéries du genre Bacillus selon la présente invention peuvent avantageusement être utilisées aux fins de développer un procédé de diagnostic du cancer, de maladies inflammatoires, et de maladies métaboliques, et une composition préventive ou thérapeutique associée.
PCT/KR2017/008497 2016-08-12 2017-08-07 Nanovésicules dérivées de bactéries du genre bacillus et leur utilisation WO2018030732A1 (fr)

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US16/325,023 US20190177783A1 (en) 2016-08-12 2017-08-07 Nanovesicles derived from genus bacillus bacteria and use thereof
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CN112368398A (zh) * 2018-04-20 2021-02-12 梨花女子大学校产学协力团 利用血液微生物群落的变化预测早产风险
JP2021516054A (ja) * 2018-03-05 2021-07-01 エムディー ヘルスケア インコーポレイテッドＭｄ Ｈｅａｌｔｈｃａｒｅ Ｉｎｃ． ラクトバチルス属細菌由来のナノ小胞及びその用途
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EP3587596A4 (fr) * 2017-02-24 2020-12-16 MD Healthcare Inc. Procédé de diagnostic d'une maladie respiratoire obstructive chronique par analyse du métagénome bactérien
CN110546278A (zh) * 2017-02-24 2019-12-06 Md保健株式会社 通过细菌宏基因组分析来诊断慢性阻塞性呼吸道疾病的方法
KR20200024192A (ko) * 2018-01-12 2020-03-06 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR20190086351A (ko) * 2018-01-12 2019-07-22 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR102095355B1 (ko) 2018-01-12 2020-03-31 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR102118987B1 (ko) 2018-01-12 2020-06-05 주식회사 엠디헬스케어 모르가넬라 속 세균 유래 나노소포 및 이의 용도
KR102087105B1 (ko) 2018-02-21 2020-03-10 주식회사 엠디헬스케어 큐프리아비더스 속 세균 유래 나노소포 및 이의 용도
JP2020513799A (ja) * 2018-02-21 2020-05-21 エムディー ヘルスケア インコーポレイテッドＭｄ Ｈｅａｌｔｈｃａｒｅ Ｉｎｃ． クプリアウィドゥス属細菌由来のナノ小胞及びその使用
KR102117567B1 (ko) 2018-02-21 2020-06-02 주식회사 엠디헬스케어 큐프리아비더스 속 세균 유래 나노소포 및 이의 용도
KR20200011536A (ko) * 2018-02-21 2020-02-03 주식회사 엠디헬스케어 큐프리아비더스 속 세균 유래 나노소포 및 이의 용도
EP3567125A4 (fr) * 2018-02-21 2020-09-02 MD Healthcare Inc. Nano-vésicules dérivées de bactéries de l'espèce cupriavidus et utilisation associée
KR20190100868A (ko) * 2018-02-21 2019-08-29 주식회사 엠디헬스케어 큐프리아비더스 속 세균 유래 나노소포 및 이의 용도
US11771742B2 (en) 2018-02-21 2023-10-03 Md Healthcare Inc. Nano-vesicles derived from genus cupriavidus bacteria and use thereof
JP2021516054A (ja) * 2018-03-05 2021-07-01 エムディー ヘルスケア インコーポレイテッドＭｄ Ｈｅａｌｔｈｃａｒｅ Ｉｎｃ． ラクトバチルス属細菌由来のナノ小胞及びその用途
CN112368398A (zh) * 2018-04-20 2021-02-12 梨花女子大学校产学协力团 利用血液微生物群落的变化预测早产风险

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