WO2019139279A1 - Nanovésicules issues de bactéries morganella et utilisations associées - Google Patents

Nanovésicules issues de bactéries morganella et utilisations associées Download PDF

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WO2019139279A1
WO2019139279A1 PCT/KR2018/016494 KR2018016494W WO2019139279A1 WO 2019139279 A1 WO2019139279 A1 WO 2019139279A1 KR 2018016494 W KR2018016494 W KR 2018016494W WO 2019139279 A1 WO2019139279 A1 WO 2019139279A1
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cancer
disease
vesicles
morganella
derived
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PCT/KR2018/016494
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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 KR1020180158636A external-priority patent/KR102095355B1/ko
Application filed by 주식회사 엠디헬스케어 filed Critical 주식회사 엠디헬스케어
Priority to EP18900497.1A priority Critical patent/EP3739067A4/fr
Priority to CN201880086010.8A priority patent/CN111587294A/zh
Priority to JP2020557894A priority patent/JP2021510309A/ja
Priority to US16/399,919 priority patent/US10858670B2/en
Publication of WO2019139279A1 publication Critical patent/WO2019139279A1/fr
Priority to US17/082,008 priority patent/US11898156B2/en
Priority to JP2021185327A priority patent/JP7264531B2/ja

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
    • 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 a nano-vesicle derived from a bacterium belonging to the genus Morganella and a use thereof. More specifically, the present invention relates to a nano-vesicle derived from a bacterium belonging to the genus Morganella, A method for diagnosing cardiovascular diseases such as myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, etc., diabetes, and Parkinson's disease, and prevention or prevention of the above diseases or inflammatory diseases including the vesicles, ≪ / RTI >
  • Inflammation is a local or systemic defense mechanism against damage or infection of cells and tissues. It mainly affects the humoral mediator that is the immune system, or stimulates the local or systemic effector system It is caused by a series of biological reactions that occur.
  • Major inflammatory diseases include gastrointestinal diseases such as gastritis and inflammatory bowel disease, oral diseases such as periodontitis, respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), rhinitis, skin diseases such as atopic dermatitis, hair loss, psoriasis, degenerative arthritis, Arthritis such as rheumatoid arthritis; And metabolic diseases such as obesity, diabetes, and liver cirrhosis.
  • COPD chronic obstructive pulmonary disease
  • rhinitis skin diseases such as atopic dermatitis, hair loss, psoriasis, degenerative arthritis
  • Arthritis such as rheumatoid arthritis
  • metabolic diseases such as obesity, diabetes, and liver cir
  • microbiota or microbiome refers to a microbial community, including true bacteria, archaea, and eukarya in a given settlement.
  • the mucous membrane forms a physical barrier that can not pass through particles of 200 nanometers (nm) or larger, and can not pass through the mucous membrane when the bacteria are symbiotic to the mucous membrane.
  • the bacterial-derived vesicles are less than 100 nanometers in size, It passes through epithelial cells through the mucosa and is absorbed by our body.
  • the locally secreted bacterial-derived vesicles are absorbed through the mucosal epithelial cells or keratinocytes to induce a local inflammatory reaction, as well as being absorbed into our body and distributed in each organ to regulate immune and inflammatory responses in the organs absorbed do.
  • E. coli Eshcherichia
  • the vesicles derived from pathogenic Gram-negative bacteria such as E. coli when absorbed into the blood vessels, promote the systemic inflammatory reaction and blood coagulation through the endothelial cell inflammatory reaction and are also absorbed into the muscle cells acting on the insulin, It triggers diabetes.
  • beneficial bacteria-derived vesicles can regulate disease by controlling immune function and metabolic dysfunction by pathogenic vesicles (Choi YW et al., Gut microbe-derived extracellular vesicles induce insulin resistance, thereby impairing glucose metabolism in skeletal muscle. Scientific Reports, 2015.).
  • Th17 immune response characterized by IL-17 cytokine secretion, which upon exposure to bacterial-derived vesicles secretes IL-6, which induces a Th17 immune response.
  • Th17 inflammation is characterized by neutrophil infiltration and TNF-alpha secreted by inflammatory cells such as macrophages plays an important role in the process of inflammation.
  • the present invention can diagnose disease by confirming that the vesicles derived from the genus Morganella are significantly reduced in clinical samples of patients suffering from cancer, cardiovascular diseases, metabolic diseases, inflammatory diseases, and neuropsychiatric disorders Respectively.
  • the vesicles were isolated from Morganella Morgani and analyzed for their characteristics. As a result, it was confirmed that the vesicles could be used as a composition for preventing or treating malignant diseases, cardiovascular diseases, metabolic diseases, inflammatory diseases and neuropsychiatric diseases.
  • the present inventors have conducted intensive studies to solve the conventional problems as described above. As a result of the meta genome analysis, the present inventors have found that malignant diseases such as gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, , Myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, diabetes mellitus, and Parkinson's disease were significantly reduced in the clinical samples of patients with Morganella subspecies.
  • malignant diseases such as gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, , Myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, diabetes mellitus, and Parkinson's disease were significantly reduced in the clinical samples of patients with Morganella subspecies.
  • the present invention provides a method for diagnosis of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, diabetes, And a method of providing the same.
  • the present invention also relates to a pharmaceutical composition for preventing or treating gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, , Diabetes, Parkinson's disease, or inflammatory diseases.
  • the present invention provides a pharmaceutical composition for treating gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, Fibrinolysis, angina pectoris, stroke, diabetes, or Parkinson's disease:
  • the present invention also relates to a method for the treatment or prophylaxis of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, A method of diagnosing Parkinson's disease is provided:
  • the sample in step (a) may be blood, urine, or feces.
  • the primer pair in step (b) may be a primer of SEQ ID NO: 1 or SEQ ID NO: 2.
  • the present invention also relates to a pharmaceutical composition for preventing or treating gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, Angina pectoris, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • the present invention also provides a pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of angina pectoris, angina pectoris, stroke,
  • the present invention also relates to a pharmaceutical composition for preventing or treating gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, Angina pectoris, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • the present invention also relates to a method for treating cancer of the stomach, colon, pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, colon cancer, There is provided a method of preventing or treating at least one disease selected from the group consisting of lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • at least one disease selected from the group consisting of lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • the present invention also relates to a method for the treatment and prophylaxis of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, , Parkinson's disease, and inflammatory diseases.
  • the inflammatory disease is atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease, sepsis, Inflammatory bowel disease, chronic inflammatory disease due to inflammatory osteolysis, viral or bacterial infection, colitis, ulcerative colitis, inflammatory bowel disease, arthritis, rheumatoid arthritis, reactive arthritis, osteoarthritis Lyme disease, Borreliosis, Neurogenic-Borrelia, Tuberculosis, Sarcoidosis, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Sarcoidosis, lupus, alopecia areata, tuberculosis lupus, lupus nephritis,
  • the inflammatory disease may be a disease mediated by IL-6 or TNF-a.
  • the vesicles may have an average diameter of 10 to 200 nm.
  • the vesicles may be naturally or artificially secreted from Morganella spp.
  • the morgellella bacteria-derived vesicle may be secreted from Morganella Morgani.
  • the present inventors confirmed that intestinal bacteria are not absorbed into the body but they are absorbed into the body through epithelial cells in the case of bacterial-derived vesicles, and are excreted through the kidneys, liver, and lungs systemically, Colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, angina pectoris, stroke , Diabetes mellitus, and Parkinson's disease were significantly lower than those of normal persons.
  • morganella morgani a kind of bacterium belonging to the genus Morganella, was cultured in vitro to separate the vesicles and, when administered to the inflammatory cells in vitro, significantly suppressed the inflammatory mediator secretion by the pathogenic vesicles.
  • the present inventors have found that the bacterium derived from Morganella bacterium according to the present invention is useful for the treatment of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, , Atrial fibrillation, angina pectoris, stroke, diabetes, and Parkinson's disease, and foods or medicines for the above diseases or inflammatory diseases.
  • FIG. 1A is a photograph showing distribution patterns of bacteria and vesicles by time after oral administration of bacteria and bacterial-derived vesicles (EV) to a mouse.
  • FIG. 1B is a photograph of blood, kidney , Liver and various organs were extracted to evaluate the distribution patterns of bacteria and vesicles in the body.
  • FIGS. 2A to 2C show the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes existing in gastric cancer patients and the normal faeces (2a), blood (2b), and urine (2c) to be.
  • FIG. 3 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes present in colon cancer patients and normal urine.
  • FIG. 4 shows the results of a comparison of the distribution of vesicles derived from bacteria belonging to the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes present in pancreatic cancer patients and normal human blood.
  • FIG. 5 shows the results of a comparison of the distribution of vesicles derived from bacteria belonging to the genus Morganella after carrying out the analysis of bacterium-derived vesicle metagenomes present in patients with biliary cancer and normal human blood.
  • FIG. 6 shows the results of a comparison of the distribution of vesicles derived from bacteria belonging to the genus Morganella after carrying out the analysis of microbial-derived vesicle metagenomes present in breast cancer patients and normal urine.
  • FIGS. 7A and 7B show the results of a comparison of the distribution of vesicles derived from Morganella subsp. Bacterium after the analysis of the bacterial-derived vesicle metagenomes existing in ovarian cancer patients and normal blood (7a) and urine (7b).
  • FIGS. 8A and 8B are the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of bacterial-derived vesicle metagenomes existing in bladder cancer patients and normal blood (8a) and urine (8b).
  • Fig. 9 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes present in prostate cancer patients and normal urine.
  • Fig. 10 shows the results of a comparison of the distribution of vesicles derived from Morganella subsp. Bacterium after the analysis of the bacterial-derived vesicle metagenomes in lymphoma patients and normal blood.
  • FIG. 11 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes existing in the myocardial infarction patient and the normal blood.
  • FIG. 12 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after carrying out the analysis of microbial-derived vesicle metagenomes present in blood of cardiomyopathy patients and normal subjects.
  • FIG. 13 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes existing in the blood of atrial fibrillation and normal human.
  • FIG. 14 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after carrying out the analysis of the bacterial-derived vesicle metagenomes present in blood of the patients with angina pectoris and normal.
  • 16A and 16B are the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes existing in the blood (16a) and the urine (16b) of diabetic patients and normal subjects.
  • Fig. 17 shows the results of a comparison of the distribution of vesicles derived from the genus Morganella after the analysis of the bacterial-derived vesicle metagenomes present in Parkinson's disease patients and normal urine.
  • 19A and 19B show the results of pretreatment of Morganella Morgani vesicles prior to the treatment of E. coli EV, a pathogenic vesicle, to evaluate the anti-inflammatory effect of Morganella morganii-derived vesicles, (19a) and TNF-alpha (19b) secreted by the transfected cells.
  • Figure 20 is a know the Nella know going to compare the effect of each other, derived from different strains package for anti-inflammatory properties of the resulting package, separated from the other before the parcel pathogenic E. coli vesicles (E. coli EV) processing know (NC: negative control; PC: positive control; L. plantarum: Lactobacillus plantarum) was prepared by pretreating vesicles derived from Kanera morgani (MMR101, MMR201) and evaluating the effect on the secretion of TNF- ⁇ by E. coli vesicles.
  • E. coli EV E. coli EV
  • NC negative control
  • PC positive control
  • L. plantarum Lactobacillus plantarum
  • 21 is a graph showing the effect of heat treatment or acid treatment on the antiinflammatory effect of Morganella morgani-deficient vesicles in the presence of heat treated or acid treated Morganella Morgana before treatment with E. coli EV, a pathogenic vesicle, (NC: negative control; PC: positive control; L. plantarum: Lactobacillus plantarum) was pre-treated with vesicles derived from MMR101 and MMR201 and evaluated for TNF- ⁇ secretion by E. coli vesicles.
  • NC negative control
  • PC positive control
  • L. plantarum Lactobacillus plantarum
  • vesicle derived from Morganella morgani is administered to a mouse to evaluate the anticancer efficacy of Morganella morgani-derived vesicles.
  • IP cancer cells
  • PO oral administration
  • the present invention relates to vesicles derived from Morganella spp. And their use.
  • the present inventors have found that metagenomic analysis enables the diagnosis of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, It was confirmed that the content of Morganella microbes-derived vesicles was significantly reduced in the sample derived from the diseased patient, and the present invention was completed on the basis thereof.
  • the present invention provides a method of treating or preventing gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, Providing a method for providing information for diagnosis of Parkinson's disease.
  • the term " diagnosis " used in the present invention means, in a broad sense, judging the actual conditions of a patient in all aspects.
  • the contents of the judgment are the pathology, etiology, pathology, severity, details of the disease, presence of complications, and prognosis.
  • the diagnosis is made based on whether or not the disease is gastric cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, angelic angina, stroke, diabetes, And so on.
  • nano-vesicle or vesicle means a nano-sized membrane structure secreted by various bacteria.
  • Gram-negative bacteria-derived vesicles or outer membrane vesicles have not only lipopolysaccharides but also toxic proteins and bacterial DNA and RNA, and gram-positive bacteria-derived vesicles Has peptidoglycan and lipoteichoic acid which are cell wall components of bacteria as well as protein and nucleic acid.
  • nano-vesicles or vesicles are naturally secreted or artificially produced in bacteria belonging to the genus Morganella, and are spherical in shape and have an average diameter of 10 to 200 nm.
  • the vesicles can be obtained by culturing a culture containing Morganella bacterium by centrifugation, ultracentrifugation, high pressure treatment, extrusion, sonication, cell lysis, homogenization, freezing-thawing, electroporation, mechanical degradation, May be separated using one or more methods selected from the group consisting of filtration, gel filtration chromatography, pre-flow electrophoresis, and capillary electrophoresis. Further, it may further include processes such as washing for removal of impurities and concentration of the resulting vesicles.
  • a metagenome refers to the total of all genomes including all viruses, bacteria, fungi, etc. in an isolated area such as soil, animal field, etc., and refers to a microorganism It is used as a concept of a genome to explain the identification of many microorganisms at once using a sequencer for analysis.
  • a metagenome is not a genome or a genome, but a kind of mixed genome as a genome of all species of an environmental unit. This is a term derived from the viewpoint that when defining a species in the course of omics biology development, it functions not only as an existing species but also as a species that interacts with various species to form a complete species.
  • it is the subject of techniques that analyze all DNA and RNA regardless of species, identify all species in an environment, identify interactions, and metabolism using rapid sequencing.
  • the sample in step (a) may be blood, urine, or feces, but is not limited thereto.
  • the primer pair in step (b) may be a primer of SEQ ID NO: 1 or SEQ ID NO: 2.
  • the present invention provides a pharmaceutical composition for treating gastric cancer, colon cancer, pancreatic cancer, breast cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, , Atrial fibrillation, angina pectoris, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • the present invention provides a pharmaceutical composition for preventing or treating gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction,
  • a food composition for the prevention or amelioration of at least one disease selected from the group consisting of inflammatory diseases, pathologies, atrial fibrillation, angioedema, stroke, diabetes, Parkinson's disease, and inflammatory diseases.
  • the inflammatory diseases are selected from the group consisting of atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease, sepsis, Inflammatory bowel disease, ulcerative colitis, inflammatory bowel disease, arthritis, rheumatoid arthritis, reactive arthritis, osteoarthritis, arthritis, osteoarthritis, arthritis, osteoarthritis, , osteoarthritis, , Lyme disease, Borreliosis, Neurogenic-Borrelia, Tuberculosis, Sarcoidosis (including, but not limited to, osteoporosis, atherosclerosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves disease, Sarcoidosis),
  • the inflammatory disease may be a disease mediated by interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-a) Do not.
  • IL-6 interleukin-6
  • TNF-a tumor necrosis factor-alpha
  • &quot prevention " refers to all actions that inhibit or delay the onset of cancer, inflammatory disease, cardiovascular disease, metabolic disease, or neuropsychiatric disorder by administration of the food or pharmaceutical composition according to the present invention do.
  • " treatment " used in the present invention refers to any action that improves or alleviates symptoms of cancer, inflammatory disease, cardiovascular disease, metabolic disease, or neuropsychiatric disease by administration of the pharmaceutical composition according to the present invention .
  • &quot means all actions that at least reduce the degree of symptom associated with the condition being treated.
  • bacterial and bacterial-derived vesicles were orally administered to mice to evaluate the absorption, distribution, and excretion of bacteria and vesicles in the body.
  • the vesicles were not absorbed through the intestinal membrane, And was excreted through kidneys, liver, and the like (see Example 1).
  • the mouse macrophage cell line, Raw 264.7 cells was inoculated with morganella morganii (MMR101, (MMR101, MMR201, MMR202) were treated with various concentrations (0.1, 1, 10 ⁇ g / ml) and then evaluated for apoptosis. As a result, was not observed (see Example 17).
  • a strain of Morganella morgani was cultured to evaluate whether the vesicles secreted therefrom had an anticancer therapeutic effect.
  • a cancer model was prepared by subcutaneous injection of a cancer cell line, and the morphology of cancer tissues was measured for 20 days after oral administration of morganella morgani-derived vesicles administered orally or intraperitoneally to mice from 4 days before the cancer cell line treatment.
  • the vesicles were administered intraperitoneally and orally, the size of cancer tissues was decreased compared with the control group, and it was confirmed that the vesicles were remarkably decreased when administered orally (see Example 20).
  • the pharmaceutical composition according to the present invention may comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are those conventionally used in the formulation and include, but are not limited to, saline, sterilized water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, And may further contain other conventional additives such as antioxidants and buffers as needed.
  • it may be formulated into injectable formulations, pills, capsules, granules, or tablets such as aqueous solutions, suspensions, emulsions and the like by additionally adding diluents, dispersants, surfactants, binders, lubricants and the like.
  • Suitable pharmaceutically acceptable carriers and formulations can be suitably formulated according to the respective ingredients using the methods disclosed in Remington's reference.
  • the pharmaceutical composition of the present invention is not particularly limited to a formulation, but may be formulated into an injection, an inhalant, an external preparation for skin, or an oral ingestion agent.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenous, subcutaneous, skin, nasal, or airway) according to the desired method, The type of administration, the route of administration, and the time, but may be suitably selected by those skilled in the art.
  • a pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the type of disease, severity, activity of the drug, The time of administration, the route of administration and the rate of excretion, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.
  • the composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, and body weight of the patient. Generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight is administered daily or every other day Or one to three times a day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
  • the food composition of the present invention comprises a health functional food composition.
  • the food composition according to the present invention can be used as it is or in combination with other food or food ingredients, and can be suitably used according to conventional methods.
  • the amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement).
  • the composition of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material, in the production of food or beverage.
  • the amount may be less than the above range.
  • the food composition of the present invention has no particular limitation on the ingredients other than those containing the active ingredient as an essential ingredient in the indicated ratios 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 polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • Natural flavors tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above .
  • the ratio of the above-mentioned natural carbohydrate can be appropriately determined by a person skilled in the art.
  • the food composition of the present invention can be used as a flavoring agent such as a variety of nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, chocolate etc.), pectic acid and its salts, Salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. These components may be used independently or in combination. The ratios of these additives can also be appropriately selected by those skilled in the art.
  • Example 1 Analysis of intestinal absorption, distribution, and excretion of intestinal bacteria and bacterial-derived vesicles
  • Example 2 Analysis of bacterial-derived vesicle metagenomes in clinical samples
  • the DNA extracted by the above method was amplified using the 16S rDNA primer described above, followed by sequencing (Illumina MiSeq sequencer), and the result was output to a Standard Flowgram Format (SFF) file and analyzed using GS FLX software (v2.9) (.Fasta) and nucleotide quality score files, then check the reliability of the lead, and remove the portion of the window (20 bps) with an average base call accuracy of less than 99% (Phred score ⁇ 20) Respectively.
  • SFF Standard Flowgram Format
  • GS FLX software v2.9
  • .Fasta nucleotide quality score files
  • Genus is 94%, family is 90%, order is 85%, class is 80%, phylum is 75%
  • Example 3 Analysis of vesicle metagenomes from gastric cancer stool, blood and urine bacteria
  • Example 4 Analysis of vesicle metagenomes derived from urine bacteria in patients with colorectal cancer
  • the urine samples were collected from 38 patients with colorectal cancer and 38 healthy adults who matched the age and sex by the method of Example 2.
  • the genes were extracted from the vesicles present in the urine and analyzed by metagenome. The distribution of the resulting vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella were significantly reduced in the feces of colon cancer patients compared to normal human urine (see Table 5 and FIG. 3).
  • Example 5 Analysis of vesicle meta-genome derived from blood bacteria of pancreatic cancer patients
  • Example 2 A total of 176 pancreatic cancer patients and 271 healthy persons whose age and gender matched each other were examined by the method of Example 2 were subjected to metagenome analysis by extracting genes from the vesicles present in the blood, The distribution of vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella in the blood of the pancreatic cancer patients were significantly reduced compared to the normal blood (see Table 6 and FIG. 4).
  • Example 6 Analysis of vesicle meta-genome from blood bacterium of patients with cholangiocarcinoma
  • Example 7 Analysis of vesicle metagenomes derived from urine bacteria of breast cancer patients
  • Example 8 Analysis of vesicle metagenomes derived from blood and urine bacteria of ovarian cancer patients
  • Example 9 Analysis of vesicle metagenomes from bladder cancer patient blood and urine bacteria
  • Example 10 Analysis of vesicle metagenomes derived from urine bacteria in patients with prostate cancer
  • Example 11 Analysis of vesicle meta-genomic DNA derived from blood microbes of lymphoma patients
  • the genomic DNA was extracted from the vesicles present in the blood of 63 lymphoma patients and 53 healthy persons whose age and sex were matched by the method of Example 2 to analyze the metagenome, The distribution of vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella in the blood of the lymphoma patients were significantly reduced compared to the normal blood (see Table 14 and FIG. 10).
  • Example 12 Analysis of vesicle meta genome derived from blood microbes in patients with heart disease
  • Genomic analysis was performed on the blood of 57 myocardial infarction patients and the blood of 163 normal controls matched with sex and age by the method of Example 2, and the genes were extracted from the vesicles present in the blood, The distribution of bacterial-derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella in the blood of patients suffering from myocardial infarction were significantly reduced compared to normal blood (see Table 15 and FIG. 11).
  • the genome was extracted from the vesicles present in the blood of blood of 72 patients with dilated cardiac myopathy according to the method of Example 2, and 163 blood of a normal control group matched with sex and age, The distribution of bacteria derived from Morganella was evaluated. As a result, it was confirmed that the vesicles derived from Morganella spp. Were significantly reduced in the blood of patients with dilated cardiac myopathy compared with normal blood (see Table 16 and Fig. 12).
  • Example 2 80 genes of dysmorphic angina pectoris and 80 healthy individuals matched with age and gender were analyzed by the method of Example 2, and the genes were extracted from the vesicles present in the blood to perform metagenome analysis. Then, The distribution of bacterial-derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella were significantly reduced in the blood of the patients with diastolic myopathy compared with the normal blood (see Table 18 and Fig. 14).
  • Example 13 Analysis of vesicle meta-genomes derived from blood microbes in stroke patients
  • Example 14 Analysis of vesicle meta genome derived from blood bacteria of diabetic patients
  • the genomic DNA was extracted from the vesicles present in the blood of blood of the 73 diabetic patients and the blood of 146 normal control group matched with sex and age by the method of Example 2, The distribution of bacterial-derived vesicles was evaluated. As a result, it was confirmed that the vesicles derived from the genus Morganella in the blood of the diabetic patients were significantly reduced compared to the normal blood (see Table 20 and FIG. 16a).
  • Example 15 Analysis of vesicle metagenomes from urine bacteria of Parkinson's disease patients
  • Example 16 Isolation of vesicles from a morganella Morgani culture
  • the M. morganii strain was isolated from one of the standard strains (MMR101) and two isolates (MMR201 and MMR202) isolated from humans in the Korean Microorganism Conservation Center (KCCM) After culturing, the vesicles were separated from the culture solution and analyzed for their characteristics. M. morganii was subcultured in an LB (Luria-Bertani) medium until the absorbance (OD 600) reached 1.0 ⁇ 1.5 in a 37 ° C incubator. Then, the culture containing the strain was recovered and centrifuged at 10,000 g at 4 ° C for 20 minutes to remove the strain, which was then filtered through a 0.22 ⁇ m filter.
  • the filtered supernatant was concentrated to a volume of 50 ml or less through a microfiltration using a 100 kDa Pellicon 2 Cassette filter membrane (Merck Millipore, US) using a MasterFlex pump system (Cole-Parmer, US). The concentrated supernatant was again filtered through a 0.22 [mu] m filter. Then, proteins were quantified by BCA assay, and the following experiments were carried out on the vesicles obtained.
  • Example 17 Cell death effect of vesicles derived from Morganella morganii
  • MMR101, MMR201, MMR202 -deleted vesicles in the mouse macrophage cell line
  • Raw 264.7 cells at various concentrations, to evaluate the cytotoxic effect of M. morganii EV in inflammatory cells (0.1, 1, 10 ⁇ ⁇ / ml), and the degree of apoptosis was evaluated. More specifically, Raw 264.7 cells were seeded at a density of 5 x 10 4 cells in 48-well cell culture plates and treated with various concentrations of Morganella morgani (MMR101, MMR201, MMR202) vesicles diluted with DMEM serum- Lt; / RTI > Cell death was measured using EZ-CYTOX (Dogen, Korea). As a result, cell death was not observed upon vesicle treatment from Morganella morgani (MMR101, MMR201, MMR202) (see Fig. 18).
  • Example 18 Anti-inflammatory effect of vesicles derived from Moganella morganis
  • morganella morgani-derived vesicles In order to examine the effect of morganella morgani-derived vesicles on inflammatory mediator release in inflammatory cells, morphogranular mor- bane (MMR101) -derived vesicles were injected into mouse macrophages Raw 264.7 cells at various concentrations (0.1, 1, / Ml), and then E. coli- derived vesicle ( E. coli) EV) to measure the secretion amount of inflammatory mediators (IL-6, TNF-a, etc.). More specifically, Raw 264.7 cells were plated on 24-well cell culture plates at 1 ⁇ 10 5 cells and then cultured in DMEM complete medium for 24 hours.
  • MMR101 morphogranular mor- bane
  • the culture supernatant was collected in a 1.5 ml tube and centrifuged at 3000 g for 5 minutes. The supernatant was collected and stored at 4 ° C for ELISA analysis.
  • IL-6 and TNF- ⁇ secretion by E. coli-derived vesicles was remarkably inhibited when the vesicles derived from Morganella morgani were pretreated (see FIGS. 19A and 19B).
  • the TNF-a secretion in macrophages was markedly higher than that in Lactobacillus plantarum vesicles when the vesicles from Morganella morgani were pretreated (see Fig. 19B).
  • morganella morganii (MMR101, MMR201, MMR202) at various concentrations (0.1, 1, 10 / / ) was pretreated with mouse macrophage cells for 12 hours, treated with 1 ⁇ g / ml of E. coli-derived vesicle, which was a pathogenic vesicle, and the secretion of TNF- ⁇ , an inflammatory cytokine, was measured by ELISA after 12 hours.
  • the antiinflammatory effect of the vesicles derived from the standard strains of Morganella morgani (MMR101) and the isolated strain (MMR201) was confirmed through Example 18, and furthermore, the stability of the vesicles and the characteristics of the active substances were examined in detail.
  • MMR101, MMR201 two types of morganella morganis-derived vesicles pretreated with macrophages (Raw 264.7) boiled at 100 ° C for 10 minutes or acid treated (pH 2.0) Respectively.
  • the anti-inflammatory effect of the vesicles derived from Morgana morgani was maintained even if the vesicles were boiled or treated with acid at 100 ° C (see FIG. 21). This suggests that the anti-inflammatory action of morganella morgana-derived vesicles is stable
  • vesicles derived from Morgana morgani were intraperitoneally injected or injected intraperitoneally into C57BL / 6 male mice at 6 weeks of age and the cancer cells (CT26 cell) And subcutaneously injected into a cancer model.
  • the vesicles derived from the isolate of Morganella morgani were intraperitoneally injected or injected daily, and the size of the cancer tissue was measured until day 24 (see FIG. 22).
  • the size of cancer tissues was reduced in the size of cancer tissues in mice administered with intraperitoneal injection of the vesicles or oral administration of the vesicles compared with the control group of oral administration of physiological saline, and in particular, (See Fig. 23). This means that the morganella morgana-derived vesicles can effectively inhibit the growth of cancer tissues.
  • the vesicles derived from the genus Morganella according to the present invention can be used for the treatment of gastric cancer, colon cancer, pancreatic cancer, cholangiocarcinoma, breast cancer, ovarian cancer, bladder cancer, prostate cancer, lymphoma, myocardial infarction, cardiomyopathy, atrial fibrillation, A diagnostic method for Parkinson's disease, and a composition for preventing or treating a food or a drug against the disease or inflammatory disease.

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Abstract

La présente invention concerne des vésicules issues de bactéries Morganella et des utilisations associées. Il a été confirmé expérimentalement par les présents inventeurs que la proportion des vésicules a été significativement réduite dans des échantillons cliniques provenant de patients atteints de maladies malignes telles que le cancer gastrique, le cancer colorectal, le cancer du pancréas, le cholangiocarcinome, le cancer du sein, le cancer de l'ovaire, le cancer de la vessie, le cancer de la prostate et le lymphome ; de maladies cardiovasculaires telles que l'infarctus du myocarde, la cardiomyopathie, la fibrillation auriculaire, l'angine de poitrine de repos, et les accidents vasculaires cérébraux ; du diabète et de la maladie de Parkinson, par comparaison avec une personne normale et que les vésicules inhibent la carcinogenèse chez des modèles d'animaux atteints du cancer tout en inhibant la sécrétion de médiateurs inflammatoires provoquée par des vésicules pathogènes. Les vésicules issues de bactéries Morganella selon la présente invention seront utilisées de manière avantageuse dans le but de développer une méthode de diagnostic de maladies malignes telles que le cancer gastrique, le cancer colorectal, le cancer du pancréas, le cholangiocarcinome, le cancer du sein, le cancer de l'ovaire, le cancer de la vessie, le cancer de la prostate et le lymphome ; de maladies cardiovasculaires telles que l'infarctus du myocarde, la cardiomyopathie, la fibrillation auriculaire, l'angine de poitrine de repos, et les accidents vasculaires cérébraux ; du diabète et de la maladie de Parkinson, et une composition pour prévenir ou traiter lesdites maladies ou des maladies inflammatoires.
PCT/KR2018/016494 2018-01-12 2018-12-21 Nanovésicules issues de bactéries morganella et utilisations associées WO2019139279A1 (fr)

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EP18900497.1A EP3739067A4 (fr) 2018-01-12 2018-12-21 Nanovésicules issues de bactéries morganella et utilisations associées
CN201880086010.8A CN111587294A (zh) 2018-01-12 2018-12-21 来源于摩根氏菌属细菌的纳米囊泡及其用途
JP2020557894A JP2021510309A (ja) 2018-01-12 2018-12-21 モルガネラ属細菌由来ナノ小胞およびその用途
US16/399,919 US10858670B2 (en) 2018-01-12 2019-04-30 Nano-vesicles derived from genus Morganella bacteria and use thereof
US17/082,008 US11898156B2 (en) 2018-01-12 2020-10-28 Nano-vesicles derived from genus Morganella bacteria and use thereof
JP2021185327A JP7264531B2 (ja) 2018-01-12 2021-11-15 モルガネラ属細菌由来ナノ小胞およびその用途

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