CN111819295A - Nano-vesicles derived from Coprinus strain bacteria and application thereof - Google Patents
Nano-vesicles derived from Coprinus strain bacteria and application thereof Download PDFInfo
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- CN111819295A CN111819295A CN201980017651.2A CN201980017651A CN111819295A CN 111819295 A CN111819295 A CN 111819295A CN 201980017651 A CN201980017651 A CN 201980017651A CN 111819295 A CN111819295 A CN 111819295A
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Abstract
The present invention relates to vesicles derived from bacteria of the genus chrysosporium and uses thereof. The inventors have experimentally confirmed that vesicles in clinical samples obtained from patients with gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or alzheimer's disease are significantly reduced compared to normal persons, and when vesicles isolated from the strain are administered, secretion of inflammatory mediators caused by pathogenic vesicles (e.g., vesicles derived from escherichia coli) is significantly inhibited, and therefore, the vesicles derived from the bacteria of the genus chrysosporium according to the present invention can be effectively used for the development of a method for diagnosing stomach cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or alzheimer's disease, and for the development of a composition for preventing, treating, or alleviating the above-mentioned diseases or inflammatory diseases accompanied by immune dysfunction.
Description
Technical Field
The present invention relates to nanovesicles derived from bacteria of the genus chrysosporium (genus collinesella) and uses thereof, and more particularly, to a method for diagnosing stomach cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, and alzheimer's disease by using nanovesicles derived from bacteria of the genus chrysosporium, and a composition for preventing, alleviating, or treating gastritis, stomach cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, alzheimer's disease, or inflammatory disease comprising the vesicles.
Background
Since the beginning of the 21 st century, acute infectious diseases, which have been considered epidemic in the past, have become less important, and chronic inflammatory diseases accompanied by immune dysfunction due to disharmony between human and microbial communities have changed disease patterns, becoming major diseases that determine quality of life and human longevity. As intractable chronic diseases in the 21 st century, cancer, cardiovascular diseases, chronic pulmonary diseases, metabolic diseases, and neuropsychiatric diseases have become important problems of national public health, and have become major diseases that determine the life span and quality of life of human beings.
As is well known, the number of coexisting microorganisms in the human body has reached 100 trillion, which is 10 times of the number of human cells, and the number of microbial genes is more than 100 times of the number of human genes. A microbiota or group of microorganisms refers to a community of microorganisms, including bacteria, archaea and eukaryotes present in a given habitat.
Bacteria present in our body and bacteria present in the surrounding environment secrete nano-sized vesicles to exchange information about genes, low-molecular compounds, proteins, and the like with other cells. The mucosa forms a physical defense membrane through which particles having a size of 200 nanometers (nm) or more cannot pass, and thus bacteria coexisting in the mucosa cannot pass, but vesicles derived from the bacteria have a size of 100 nm or less and are relatively freely passed through epithelial cells through the mucosa and then absorbed into our body. Vesicles derived from bacteria, which are locally secreted by bacteria, are absorbed through mucosal epithelial cells to cause local inflammatory reactions, while vesicles passing through epithelial cells are absorbed through lymphatic system to be distributed in various organs, and immune and inflammatory reactions are regulated in the organs where the vesicles are distributed. For example, vesicles derived from pathogenic gram-negative bacteria such as escherichia coli locally cause colitis, and when taken up into blood vessels, promote systemic inflammatory reactions and blood coagulation through an intravascular dermatitis reaction, and cause insulin resistance and diabetes when taken up into insulin-acting muscle cells. On the other hand, vesicles derived from beneficial bacteria can control diseases by controlling immune and metabolic dysfunctions caused by pathogenic vesicles.
As an immune response to factors such as bacteria-derived vesicles, a Th17 immune response, which is characterized by secretion of interleukin (hereinafter, IL) -17 cytokines, occurs, and IL-6 is secreted when exposed to bacteria-derived vesicles, thereby inducing a Th17 immune response. Inflammation caused by the Th17 immune response is characterized by neutrophil infiltration, and in the process of inflammation, tumor necrosis factor- α (hereinafter referred to as TNF- α) secreted from inflammatory cells such as neutrophils and macrophages plays an important role.
Inflammation is a local or systemic protective mechanism against damage or infection of cells and tissues, usually caused by a series of biological reactions that occur because the humoral mediators that make up the immune system react directly to the damage or infection or stimulate local or systemic effector systems. Examples of major inflammatory diseases include digestive system diseases such as gastritis and inflammatory bowel disease; oral diseases such as periodontitis; respiratory diseases such as asthma; chronic Obstructive Pulmonary Disease (COPD) and rhinitis; skin diseases such as atopic dermatitis, alopecia and psoriasis; arthritis, such as degenerative arthritis and rheumatoid arthritis; and metabolic diseases such as obesity, diabetes, and cirrhosis.
Meanwhile, the bacteria of the genus chrysosporium are anaerobic gram-positive bacteria which are present symbiotically in the oral cavity, stomach and intestine, wherein the chrysogenum (collinesla aerofaciens) produce substances such as hydrogen and ethanol by fermenting various carbohydrates. It has been reported that, among irritable bowel syndrome patients, Coprinus aerogenes, one of the main bacteria isolated from human intestines, is decreased. However, there has been no report on the extracellular secretion of vesicles by a bacterium of the genus Coriolis, and particularly no report on the use of vesicles for the diagnosis and treatment of intractable diseases such as cancer or heart and brain diseases.
Disclosure of Invention
[ problem ] to provide a method for producing a semiconductor device
As a result of earnest studies to solve the above conventional problems, the inventors confirmed that the content of vesicles derived from a bacterium of the genus chrysosporium is significantly reduced in a sample obtained from a patient suffering from gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, and alzheimer's disease, as compared to a normal individual, by metagenomic analysis. Further, it has been confirmed that Coprinus aerogenes belonging to Coprinus bacteria is isolated from the human digestive system and cultured in vitro to isolate vesicles, and then secretion of IL-6 and TNF- α by pathogenic vesicles is significantly inhibited when macrophages are treated with vesicles isolated from these bacteria, and based on this, the present invention has been completed.
Accordingly, it is an object of the present invention to provide a method for providing information for diagnosing gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment or alzheimer's disease.
Further, it is another object of the present invention to provide a composition for preventing, treating or alleviating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from bacteria of the genus coriolus as an active ingredient.
However, the technical problems to be achieved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned may be clearly understood by those skilled in the art from the following description.
[ technical solution ] A
In order to achieve the above object of the present invention, the present invention provides a method of providing information for diagnosing stomach cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or alzheimer's disease, the method comprising the steps of:
(a) extracting DNA from extracellular vesicles isolated from a sample of a normal individual and a sample of a subject;
(b) performing Polymerase Chain Reaction (PCR) on the extracted DNA using paired primers prepared based on a gene sequence present in 16S rDNA to obtain each PCR product; and
(c) the cases in which the content of extracellular vesicles derived from the bacteria of the genus Coriolis is lower than that of the normal individual sample are classified as gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or Alzheimer's disease by quantitative analysis of the PCR product.
In addition, the present invention provides a method for diagnosing gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment or alzheimer's disease, the method comprising the steps of:
(a) extracting DNA from extracellular vesicles isolated from a sample of a normal individual and a sample of a subject;
(b) performing Polymerase Chain Reaction (PCR) on the extracted DNA using paired primers prepared based on a gene sequence present in 16S rDNA to obtain each PCR product; and
(c) the case in which the content of extracellular vesicles derived from the Coriolis bacteria is lower than that of the normal individual sample is determined as gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or Alzheimer's disease by quantitative analysis of the PCR product.
As an exemplary embodiment of the present invention, the sample in step (a) may be blood.
As another embodiment of the present invention, the pair of primers in step (b) may be primers of SEQ ID No.1 and SEQ ID No. 2.
Further, the present invention provides a pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from the bacterium of the genus coriolus as an active ingredient.
In addition, the present invention provides a food composition for preventing or alleviating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from the bacteria of the genus coriolus as an active ingredient.
In addition, the present invention provides an inhalant composition for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, and inflammatory diseases, comprising vesicles derived from the bacteria of the genus coriolus as an active ingredient.
In one embodiment of the invention, the inflammatory disease may be selected from one or more of the diseases in the group consisting of: atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory enteritis, sepsis, septic shock, pulmonary fibrosis, undifferentiated spondylopathy, undifferentiated arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by viral or bacterial infections, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, reactive arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, hashimoto's thyroiditis, graves ' disease, leprosy, syphilis, lyme disease, neurolyme disease, tuberculosis, sarcoidosis, lupus, chilblain-like, lupus erythematosus-like tuberculosis, lupus nephritis, inflammatory bowel disease, septic shock, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, pericarditis, cystic fibrosis, hashimoto's disease, leprosy disease, lupus erythematosus-like tuberculosis, lupus erythematosus-like, Systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Crohn's disease, Sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis.
Further, the present invention provides a cosmetic composition for preventing or alleviating inflammatory diseases, comprising vesicles derived from a bacterium of the genus chrysosporium as an effective ingredient.
In one embodiment of the present invention, the inflammatory disease may be one or more diseases selected from atopic dermatitis, acne and psoriasis.
In another embodiment of the present invention, the inflammatory disease may be a disease mediated by interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha).
Further, the present invention provides a method for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, the method comprising the steps of: administering to the subject a pharmaceutical composition comprising vesicles derived from a bacterium of the genus Coprinus as an active ingredient.
Furthermore, the present invention provides the use of vesicles derived from bacteria of the genus coriolus for the prevention or treatment of one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases.
In another embodiment of the invention, the average diameter of the vesicles may be from 10 to 200 nm.
In another embodiment of the invention, the vesicles may be naturally or artificially secreted by a bacterium of the genus coriolus.
In one embodiment of the present invention, the vesicle derived from a bacterium of the genus chrysosporium may be a vesicle derived from chrysosporium (collinesla aerofaciens).
[ PROBLEMS ] the present invention
The inventors confirmed that intestinal bacteria are not absorbed into the body through epithelial cells, but vesicles derived from the bacteria are absorbed, distributed systemically, and then excreted out of the body through the kidney, liver, and lung, and also confirmed that vesicles derived from bacteria of the genus coriolus present in the blood of patients with gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, and alzheimer's disease are significantly reduced compared to normal individuals by metagenomic analysis of vesicles derived from bacteria present in the blood of patients. In addition, when corilina aerogenes, which is one of the bacteria of the genus corilina, is cultured in vitro to isolate vesicles, which are then administered to inflammatory cells in vitro, it was confirmed that secretion of inflammatory mediators mediated by pathogenic vesicles is significantly inhibited. Accordingly, it is expected that the vesicles derived from the bacteria of the genus corinth according to the present invention may be effectively used in a method for diagnosing stomach cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, and alzheimer's disease, and a composition for preventing, treating, or alleviating gastritis, stomach cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, or inflammatory disease.
Drawings
Fig. 1A is a series of photographs of distribution patterns of bacteria and bacteria-derived vesicles (EV) captured by time after oral administration of the bacteria and the bacteria-derived vesicles (EV) to mice, and fig. 1B is a result of evaluating the in vivo distribution patterns of the bacteria and the vesicles by collecting blood, kidneys, liver, and various organs 12 hours after oral administration of the bacteria and the vesicles.
Fig. 2 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysosporium after metagenomic analysis of vesicles derived from bacteria present in blood of gastric cancer patients and normal individuals.
Fig. 3 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of pancreatic cancer patients and normal individuals.
Fig. 4 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of cholangiocarcinoma patients and normal individuals.
Fig. 5 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysolepsis after metagenomic analysis of vesicles derived from bacteria present in blood of ovarian cancer patients and normal individuals.
Fig. 6 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysosporium after metagenomic analysis of vesicles derived from bacteria present in blood of bladder cancer patients and normal individuals.
Fig. 7 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of patients with myocardial infarction and normal individuals.
Fig. 8 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of patients with atrial fibrillation and normal individuals.
Fig. 9 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of COPD patients and normal individuals.
Fig. 10 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysosporium after metagenomic analysis of vesicles derived from bacteria present in blood of diabetic patients and normal individuals.
Fig. 11 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysosporium after metagenomic analysis of vesicles derived from bacteria present in blood of patients with mild cognitive impairment and normal individuals.
Fig. 12 is a result of comparing the distribution of vesicles derived from bacteria of the genus chrysorella after metagenomic analysis of vesicles derived from bacteria present in blood of alzheimer's disease patients and normal individuals.
FIG. 13 is a graph evaluating the effect on the secretion of the inflammatory mediators IL-6 and TNF-alpha by E.coli EV by pretreatment of vesicles derived from Coprinus aerogenes prior to treatment of pathogenic vesicles such as E.coli EV to evaluate the anti-inflammatory and immunomodulatory effects of vesicles derived from Coprinus aerogenes (PC: positive control; LP: Lactobacillus plantarum EV; CA: Coprinus aerogenes EV).
Detailed Description
The present invention relates to vesicles derived from bacteria of the genus chrysosporium and uses thereof.
The inventors confirmed through metagenomic analysis that vesicles derived from a bacterium of the genus chrysosporium are significantly reduced in clinical samples obtained from patients with gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, and alzheimer's disease, as compared to normal individuals, thereby diagnosing the disease. In addition, by isolating vesicles from corynebacterium aerogenes, which is a bacterium belonging to the genus corynebacterium, and analyzing the characteristics thereof, it was confirmed that the vesicles can modulate immune response by inflammation and pathogenic factors of cancer, and can be used in a composition for preventing, treating or alleviating diseases such as gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, and inflammatory diseases.
Accordingly, the present invention provides a method of providing information for diagnosing gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or alzheimer's disease, the method comprising the steps of:
(a) extracting DNA from extracellular vesicles isolated from a sample of a normal individual and a sample of a subject;
(b) performing Polymerase Chain Reaction (PCR) on the extracted DNA using paired primers prepared based on a gene sequence present in 16S rDNA to obtain each PCR product; and
(c) the case in which the content of extracellular vesicles derived from the Coriolis bacteria is lower than that of the normal individual sample is determined as gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or Alzheimer's disease by quantitative analysis of the PCR product.
As used herein, the term "diagnosis" refers to the determination of a disease condition of a patient in a broad sense and in all aspects. The determination is made as to the entity, cause, pathogenesis, severity, detailed aspect of the disease, presence or absence of complications, prognosis, etc. of the disease. The diagnosis in the present invention refers to determination of occurrence or non-occurrence of gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, alzheimer's disease, degree of disease, and the like.
As used herein, the term "nanovesicle" or "vesicle" refers to a structure composed of nano-sized membranes secreted from various bacteria. Vesicles or Outer Membrane Vesicles (OMVs) derived from gram-negative bacteria have endotoxins (lipopolysaccharides), toxic proteins, bacterial DNA and RNA, and vesicles derived from gram-positive bacteria have peptidoglycans and lipoteichoic acids, which are cell wall components of the bacteria, in addition to proteins and nucleic acids. In the present invention, the nanovesicles or vesicles are naturally secreted or artificially produced by a bacterium of the genus Coriolus, are spherical, and have an average diameter of 10 to 200 nm.
As used herein, the term "metagenome" also refers to microbiome, and refers to the entire genome including all viruses, bacteria, fungi, etc., in independent areas such as soil and animal intestines, and is generally used as a concept of genome explaining analysis of uncultured microorganisms by identifying a large number of microorganisms at a time using a sequence analyzer. In particular, metagenome does not refer to the genome of one species, but refers to a mixed genome, the genome of all species as one environmental unit. When a species is defined in the course of the development of omics biology, the metagenome is a term derived from the point of view of forming the complete species, which is formed by various species interacting with each other as well as a functionally present species. Technically, metagenome is the target of a technology that identifies all species in one environment by analyzing all DNA and RNA (regardless of species) using a rapid sequence analysis method, and studies interactions and metabolism.
In the present invention, the sample in step (a) may be blood, but is not limited thereto.
In the present invention, the primer set in step (b) may be primers of SEQ ID No.1 and SEQ ID No. 2.
Another aspect of the present invention provides a composition for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from the coriolus bacteria as an active ingredient.
In the present invention, the composition includes a pharmaceutical composition, an oral composition or an inhalant composition. The composition of the present invention may be prepared in the form of an oral spray or a nasal spray.
The term "inflammatory disease" as used herein refers to a disease caused by an inflammatory reaction in a mammal, and in the present invention, the inflammatory disease may be one or more diseases selected from the group consisting of: atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory enteritis, sepsis, septic shock, pulmonary fibrosis, undifferentiated spondylopathy, undifferentiated arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by viral or bacterial infections, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, reactive arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, hashimoto's thyroiditis, graves ' disease, leprosy, syphilis, lyme disease, neurolyme disease, tuberculosis, sarcoidosis, lupus, chilblain-like, lupus erythematosus-like tuberculosis, lupus nephritis, inflammatory bowel disease, septic shock, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, pericarditis, cystic fibrosis, hashimoto's disease, leprosy disease, lupus erythematosus-like tuberculosis, lupus erythematosus-like, Systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, crohn's disease, sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, parkinson's disease, and multiple sclerosis, but the invention is not limited thereto.
The term "prevention" as used herein refers to the inhibition of all behaviors of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, inflammatory diseases or similar diseases or delaying their onset by administering a composition according to the invention.
As used herein, the term "treatment" refers to all behaviors that reduce or beneficially alter the symptoms of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, inflammatory diseases or similar diseases by administering a composition according to the present invention.
As used herein, the term "alleviating" refers to all actions that at least reduce a parameter (e.g., the extent of symptoms) associated with the condition being treated.
Vesicles can be isolated from a culture fluid comprising a bacterium of the genus Coriolus by using one or more methods selected from centrifugation, ultracentrifugation, high pressure processing, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical disintegration, chemical processing, filtration through a filter, gel filtration chromatography, free flow electrophoresis, and capillary electrophoresis. In addition, processes such as washing for removing impurities and concentration of the obtained vesicles may be further included.
The pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are generally used in the formulation, and include, but are not limited to, physiological saline (saline), sterile water, ringer's solution, buffered saline, cyclodextrin, glucose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like, and may further include other typical additives such as antioxidants and buffers, if necessary. In addition, the composition may be formulated into injectable preparations such as aqueous solutions, suspensions and emulsions, pills, capsules, granules or tablets by additionally adding diluents, dispersants, surfactants, binders, lubricants and the like. With respect to suitable pharmaceutically acceptable carriers and formulations, the compositions can be formulated according to each ingredient, preferably by using the method disclosed in Remington's medicament (the ramington literature). The formulation of the pharmaceutical composition of the present invention is not particularly limited, but may be formulated into injections, inhalants, external preparations for skin, oral preparations, and the like.
The pharmaceutical composition of the present invention may be orally administered or parenterally administered (e.g., intravenous, subcutaneous, intradermal, intranasal or intratracheal administration) according to a desired method, and the dosage may vary according to the condition and body weight of a patient, the severity of a disease, a pharmaceutical preparation, and the administration route and duration, but may be appropriately selected by one of ordinary skill in the art.
The pharmaceutical composition according to the invention is administered in a pharmaceutically effective amount. In the present invention, 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 dosage level may be determined depending on factors including the type of disease of a patient, the severity of the disease, pharmaceutical activity, sensitivity to a drug, administration time, administration route, excretion rate, treatment period, and concurrent use of a drug, and other factors well known in the medical field. The composition according to the present invention may be administered as a therapeutic agent alone or in combination with other therapeutic agents, may be administered sequentially or simultaneously with the therapeutic agents in the related art, and may be administered in a single dose or multiple doses. In view of all the above factors, it is important to administer the composition in the minimum amount that can achieve the maximum effect without any side effects, which can be readily determined by one of ordinary skill in the art.
Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex and body weight of a patient, and is usually 0.001 to 150mg of the composition per 1 kg of body weight, preferably 0.01 to 100mg per 1 kg of body weight, and may be administered daily or every other day, or once to three times daily. However, the above dose is not intended to limit the scope of the present invention in any way, since the dose may be increased or decreased depending on the administration route, severity of obesity, sex, body weight or age.
Another aspect of the present invention provides a food composition for preventing or alleviating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from a bacterium of the genus coriolus as an active ingredient.
The food composition of the present invention includes a health functional food composition. The food composition according to the present invention may be used by adding the active ingredient to food as it is, or may be used together with other food or food ingredients, but may be used as appropriate according to typical methods. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of its use (for prevention or alleviation). Generally, when preparing a food or beverage, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials. However, for long-term intake for health and hygiene purposes or for health control purposes, the amount may be less than the above range.
Other ingredients are not particularly limited except that the food composition of the present invention contains the active ingredient in a designated ratio as an essential ingredient, and the food composition of the present invention may contain various flavors, natural carbohydrates, etc. as additional ingredients, as in a typical beverage. Examples of the above natural carbohydrates include conventional sugars such as monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, and the like; and polysaccharides such as dextrin, cyclodextrin and the like; and sugar alcohols such as xylitol, sorbitol and erythritol. As a flavoring agent other than the above-described flavoring agents, natural flavoring agents (thaumatin, stevia extracts such as rebaudioside a, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
In addition to the additives, the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents (e.g., synthetic flavoring agents and natural flavoring agents), coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages, and the like. These ingredients may be used alone or in combination thereof. The proportion of these additives may also be appropriately selected by those of ordinary skill in the art. In the inhalation composition of the present invention, the active ingredient may be used as it is or together with other ingredients, and may be suitably used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of its use (for prophylaxis or treatment).
In the present invention, the inflammatory disease may be a disease mediated by IL-6 or TNF- α, but the present invention is not limited thereto.
Another aspect of the present invention provides a cosmetic composition for preventing or reducing inflammatory diseases, comprising vesicles derived from a bacterium of the genus coriolus as an active ingredient.
In the present invention, the cosmetic composition may be used for preventing or alleviating inflammatory diseases selected from atopic dermatitis, acne and psoriasis, but the present invention is not limited thereto.
The cosmetic composition of the present invention may contain ingredients conventionally used in cosmetic compositions and vesicles derived from bacteria of the genus chrysosporium, and may include, for example, conventional additives (e.g., antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances) and carriers.
In addition, the composition of the present invention may be used by mixing a conventionally used organic sunscreen agent in addition to vesicles derived from a bacterium of the genus chrysosporium, as long as it does not impair the skin-protecting effect by reacting with the vesicles derived from a bacterium of the genus chrysosporium. The organic sunscreen may be selected from one or more of the group consisting of: glyceryl PABA, cresyl trazodioxane (drometrizole trisiloxane), cresyl trazodioxane (drometrizole), trioleyl digallate (digalloyl triallate), disodium phenylbisbenzimidazole tetrasulfonate (disodiphenyl diphenyl benzimidozole tetrasulfonate), diethylhexyl butyrylamide triazone (diethylhexyl butyrylamidotriazone), diethylamino hydroxybenzoyl hexyl benzoate (diethylhexyl benzoylphenyl benzoate), DEA-methoxycinnamate (DEA-methoxycinnamate), Lawson/dihydroxyacetone mixture (a Lawson/dihydrobenzoyl mixture), methylenebis-benzotriazolyl tetramethylbutylphenol (methyibenzophenone-benzophenone), 4-methylbenzylidene, o-methylbenzylidene methyl benzoate (camphor-8-methoxybenzoyl-benzophenone), benzophenone (4-methoxybenzoyl-8-oxybenzoyl benzophenone), benzophenone (tolylbenzophenone-8-methoxybenzoyl-benzophenone), benzophenone (tolyloxy-benzophenone), benzophenone (4-methylbenzylidene, methyl benzoate (camphor-8-oxybenzoyl-benzophenone), benzophenone (benzophenone-phenoxybenzophenone-8-methoxybenzoyl-oxybenzoyl-8 (camphor-oxybenzoyl-benzophenone), benzophenone (benzophenone-phenoxybenzophenone), and benzophenone (benzophenone-and benzophenone-bis-phenoxybenzophenone-4-phenoxybenzophenone-and benzophenone (e) can be-phenoxybenzophenone-and benzophenone-and a-bis-phenoxybenzophenone-and a-benzophenone-and a-benzophenone-and a-, Bis-ethylhexyloxyphenol methoxyphenyl triazine, cinnamate, ethyldihydroxypropyl PABA, octadiene, ethylhexyl dimethyl PABA, ethylhexyl methoxycinnamate, ethylhexyl salicylate, ethylhexyl ethyl triazone, isoamyl p-methoxycinnamate, polysiloxane-15 (benzylidene malonate polysiloxane), polysilicone-15 (dimethicodiethylbenzosulfonate), terephthalylidene dicamphor sulfonic acid (terephthalylidene dicamphor sulfonic acid) and salts thereof, TEA-salicylate, and aminobenzoic acid (PABA).
Products that may comprise the cosmetic compositions of the present invention include, for example, cosmetics such as astringents, skin lotions, nourishing lotions, various types of creams, essences, masks (packs) and foundations, cleansers, face washes, soaps, care agents and tonics. Specific formulations of the cosmetic composition of the present invention include skin lotions, skin softeners, skin lotions, astringents, lotions, creams, moisturizing lotions, nutritional lotions, massage creams, nutritional creams, moisturizing creams, hand creams, essences, nourishing essences, masks, soaps, shampoos, cleansing foams, cleansing lotions, cleansing creams, body lotions, body washes, lotions, lipsticks, foundation, loose powder, and eye shadow cream.
In one embodiment of the present invention, by orally administering bacteria and vesicles derived from bacteria to mice and observing the in vivo absorption, distribution and excretion patterns of the bacteria and vesicles, it was confirmed that, although bacteria are not absorbed through the intestinal mucosa, the vesicles derived from bacteria are absorbed and distributed systemically within 5 minutes after administration and are excreted through the kidney, liver, and the like (see example 1).
In another embodiment of the present invention, the bacterial metagenomic analysis is performed by using vesicles isolated from blood or feces of normal individuals whose age and sex are matched with patients suffering from gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, and alzheimer's disease. The results confirmed that vesicles derived from bacteria of the genus coriolus were significantly reduced in clinical samples of patients with gastric cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, and alzheimer's disease, compared to samples of normal individuals (see examples 3 to 13).
In another embodiment of the present invention, coriolus aerogenes was isolated and cultured from gastric juice to evaluate whether vesicles secreted therefrom have immunomodulatory and anti-inflammatory effects, and it was confirmed that secretion of IL-6 and TNF- α caused by the escherichia coli vesicles (e.coli EV) was effectively inhibited by the coriolus aerogenes-derived vesicles by evaluating secretion of inflammatory mediators via treatment of escherichia coli (e.coli EV) as a causative factor of inflammatory diseases after treating macrophages with different concentrations of coriolus aerogenes-derived vesicles (see example 14).
[ modes for the invention ]
Hereinafter, preferred embodiments will be presented to aid in understanding the present invention. However, the following examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
Examples
Example 1.Analysis of in vivo absorption, distribution and excretion patterns of intestinal bacteria and vesicles derived from bacteria
To assess whether intestinal bacteria and vesicles derived from bacteria are absorbed systemically through the gastrointestinal tract, experiments were performed in the following manner. First, a 50 μ g dose of each of enteric bacteria with fluorescent markers and vesicles derived from enteric bacteria was administered to the stomach of a mouse through the gastrointestinal tract, and fluorescence was measured after 0 minutes, 5 minutes, 3 hours, 6 hours, and 12 hours. As a result of observing the whole image of the mouse, as shown in fig. 1A, the bacteria were not absorbed systemically, but vesicles derived from the bacteria were absorbed systemically 5 minutes after the administration, and intense fluorescence was observed in the bladder 3 hours after the administration, so that it can be seen that the vesicles were excreted to the urinary tract. Furthermore, it can be seen that vesicles are present in vivo until 12 hours post-administration (see figure 1A).
In addition, in order to evaluate the mode in which enteric bacteria and vesicles derived from enteric bacteria were permeated into each organ after systemic absorption, 50 μ g of bacteria and vesicles derived from bacteria carrying a fluorescent label were administered in the same manner as described above, and then urine, heart, lung, liver, kidney, spleen, fat, and muscle were collected 12 hours after administration. As a result of the observed fluorescence in the collected tissue, as shown in fig. 1B, it can be seen that vesicles derived from bacteria are distributed in urine, heart, lung, liver, spleen, fat, muscle, and kidney, but bacteria are not absorbed (see fig. 1B).
Example 2.Metagenomic analysis of vesicles derived from bacteria in clinical samples
After the blood was first placed in a 10ml tube and the suspension was settled by centrifugation (3,500 Xg, 10 min, 4 ℃), only the supernatant was transferred to a new 10ml tube. After removing bacteria and impurities using a 0.22- μm filter, they were transferred to a Centriprep tube (centrifugal filter 50kD) and centrifuged at 1,500 Xg and 4 ℃ for 15 minutes, and substances less than 50kD were discarded, and the residue was concentrated to 10 ml. After removing bacteria and impurities again using a 0.22- μm filter, the supernatant was discarded by performing ultra-high speed centrifugation using a 90Ti type rotor at 150,000 Xg and 4 ℃ for 3 hours, and the aggregated pellet (pellet) was dissolved in physiological saline (PBS).
Mu.l of vesicles isolated by the above method were boiled at 100 ℃ to extract internal DNA from lipids, and then cooled on ice for 5 minutes. Then, in order to remove the remaining suspended matter, the DNA was centrifuged at 10,000 Xg at 4 ℃ for 30 minutes, and only the supernatant was collected. Also, the amount of DNA was quantified by using Nanodrop. Thereafter, in order to confirm the presence or absence of the bacteria-derived DNA in the extracted DNA, PCR was performed using 16s rDNA primers shown in table 1 below, and the presence of the bacteria-derived gene in the extracted gene was confirmed.
[ Table 1]
DNA extracted by the above method was amplified using 16S rDNA primers and then sequenced (illumina miseq sequencer), the results were exported as a Standard Flowsheet Format (SFF) file, which was converted into a sequence file (. fasta) and a nucleotide quality score file using GS FLX software (v2.9), and then confirmed for reliable estimates of reading, and where the window (20bps) of average base detection accuracy was less than 99% (Phred score <20) was deleted. For the Operational Taxonomy Unit (OTU) analysis, the classification was performed on phyla, classes, orders, families and genus levels per OUT by clustering according to sequence similarity using UCLUST and USEARCH based on sequence similarities of 94%, 90%, 85%, 80% and 75%, respectively, and the analysis was performed on bacteria having a sequence similarity of 97% or higher on the genus level using the 16S RNA sequence databases (108,453 sequences) of BLASTN and greengenes (qiime).
Example 3.Metagenomic analysis of bacterially-derived vesicles in blood of gastric cancer patients
Genes were extracted from vesicles present in blood of 66 gastric cancer patients and 198 normal individuals (both age and sex matched) and the distribution of vesicles derived from bacteria of the genus coriolus was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacterium belonging to the genus chrysosporium were significantly reduced in blood from a gastric cancer patient compared with blood derived from a normal individual (see table 2 and fig. 2).
[ Table 2]
Example 4.Metagenomic analysis of bacterially-derived vesicles in blood of pancreatic cancer patients
Genes were extracted from vesicles present in the blood of 176 pancreatic cancer patients and 271 normal individuals (both age and sex matched) and the distribution of vesicles derived from bacteria of the genus chrysolepsis was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the colibacillus bacteria were significantly reduced in blood from pancreatic cancer patients compared with blood derived from normal individuals (see table 3 and fig. 3).
[ Table 3]
Example 5.Metagenomic analysis of bacterially-derived vesicles in blood of cholangiocarcinoma patients
Genes were extracted from vesicles present in blood of 79 patients with cholangiocarcinoma and 259 normal individuals (both age and sex matched) and the distribution of vesicles derived from bacteria of the genus Coprinus was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacteria of the genus chrysosporium were significantly reduced in blood from a biliary duct cancer patient compared with blood derived from a normal individual (see table 4 and fig. 4).
[ Table 4]
Example 6.Metagenomic analysis of bacterially-derived vesicles in blood of ovarian cancer patients
Genes were extracted from vesicles present in blood of 137 ovarian cancer patients and 139 normal individuals (both age and sex matched) and the distribution of vesicles derived from bacteria of the genus coriolus was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacterium belonging to the genus chrysosporium were significantly reduced in blood from ovarian cancer patients as compared with blood derived from normal individuals (see table 5 and fig. 5).
[ Table 5]
Example 7.Metagenomic analysis of bacterially-derived vesicles in blood of bladder cancer patients
Genes were extracted from vesicles present in blood of 91 bladder cancer patients and 176 normal individuals (both groups matched in age and sex), and the distribution of vesicles derived from bacteria of the genus chrysosporium was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacteria of the genus chrysosporium were significantly reduced in blood from patients with bladder cancer, as compared with blood derived from normal individuals (see table 6 and fig. 6).
[ Table 6]
Example 8.Metagenomic analysis of bacterially-derived vesicles in blood of patients with myocardial infarction
Genes were extracted from vesicles present in blood of 57 patients with myocardial infarction and 163 normal individuals (both groups matched in age and sex), and the distribution of vesicles derived from bacteria of the genus coriolus was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacterium belonging to the genus chrysosporium were significantly reduced in blood from patients with myocardial infarction compared to blood derived from normal individuals (see table 7 and fig. 7).
[ Table 7]
Example 9.Metagenomic analysis of bacterially derived vesicles in the blood of patients with atrial fibrillation
Genes were extracted from vesicles present in blood of 34 patients with atrial fibrillation and 62 normal individuals (both age and sex matched) and the distribution of vesicles derived from bacteria of the genus chrysolepsis was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacteria of the genus chrysosporium were significantly reduced in blood from patients with atrial fibrillation compared to blood derived from normal individuals (see table 8 and fig. 8).
[ Table 8]
Example 10.Metagenomic analysis of bacterially derived vesicles in the blood of COPD patients
Genes were extracted from vesicles present in blood of 205 COPD patients and 231 normal individuals (both age and sex matched in both groups), and the distribution of vesicles derived from colibacillus bacteria was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacteria of the genus chrysosporium were significantly reduced in blood from COPD patients compared with blood derived from normal individuals (see table 9 and fig. 9).
[ Table 9]
Example 11.Metagenomic analysis of bacterially-derived vesicles in blood of diabetic patients
Genes were extracted from vesicles present in blood of 61 diabetic patients and 122 normal individuals (both age and sex matched in both groups), and the distribution of vesicles derived from bacteria of the genus chrysolepsis was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacteria of the genus chrysosporium were significantly reduced in blood from diabetic patients as compared with blood derived from normal individuals (see table 10 and fig. 10).
[ Table 10]
Example 12.Metagenomic analysis of bacterially derived vesicles in blood of patients with mild cognitive impairment
Genes were extracted from vesicles present in blood of 51 patients with mild cognitive impairment and 72 normal individuals (both groups matched in age and sex), and the distribution of vesicles derived from bacteria of the genus chrysolepsis was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacterium belonging to the genus chrysosporium were significantly reduced in blood from patients with mild cognitive impairment as compared with blood derived from normal individuals (see table 11 and fig. 11).
[ Table 11]
Example 13.Metagenomic analysis of bacterially derived vesicles in the blood of alzheimer's patients
Genes were extracted from vesicles present in blood of 49 alzheimer's disease patients and 72 normal individuals (both groups matched in age and sex), and the distribution of vesicles derived from bacteria of the genus coriolus was evaluated after metagenomic analysis of the blood using the method of example 2. As a result, it was confirmed that vesicles derived from the bacterium belonging to the genus corilinus were significantly reduced in blood from patients with alzheimer's disease compared to blood derived from normal individuals (see table 12 and fig. 12).
[ Table 12]
Example 14.Anti-inflammatory action of vesicles from Coprinus aerogenes
According to the results of the above examples, a strain of Coprinus aerogenes belonging to the genus Coprinus was isolated from the body and cultured, and vesicles thereof were isolated. Incubating Coprinus aerogenes strain in Brain Heart Infusion (BHI) medium until absorbance (OD) in anaerobic chamber at 37 ℃600) To 1.0 to 1.5, and then subcultured. Thereafter, the culture supernatant without the strain was collected, centrifuged at 10,000g at 4 ℃ for 15 minutes, and then filtered through a 0.45- μm filter. The supernatant thus obtained was concentrated to an amount of 200mL by ultrafiltration using a quilx stand bench top system (GE Healthcare, uk) with a 100kDa hollow filter membrane. Subsequently, the concentrated supernatant was filtered again with a 0.22- μm filter and ultracentrifuged at 150,000g and 4 ℃ for 3 hours, and then the pellet was suspended in DPBS. Then, 10%, 40%, and 50% of OptiPrep was usedThe solution (Axis-Shield PoC AS, Norway) was subjected to density gradient centrifugation, and to prepare a low density solution, the OptiPrep solution was diluted with HEPES buffered saline (20mM HEPES, 150mM NaCl, pH7.4)) before use. After centrifugation at 200,000g and 4 ℃ for 2 hours, each solution fractionated from the top layer in 1mL of equal volume was ultracentrifuged at 150,000g and 4 ℃ for an additional 3 hours. Thereafter, the protein was quantified using a bicinchoninic acid (BCA) assay, and the vesicles obtained as described above were subjected to an experiment.
To examine the effect of vesicles derived from Coprinus aerogenes on the secretion of inflammatory mediators by inflammatory cells, Raw264.7 cells, which are a mouse macrophage line, were treated with vesicles derived from Coprinus aerogenes at various concentrations (0.1. mu.g/mL, 1. mu.g/mL, and 10. mu.g/mL), then treated with E.coli EV, which is a causative vesicle of inflammatory diseases, and then the secretion amounts of inflammatory mediators (IL-6 and TNF-alpha) were measured. More specifically, Raw264.7 cells were plated at 1X 10 per well5The density of cells was seeded into 24-well cell culture plates and cultured in complete DMEM for 24 hours. Thereafter, the culture supernatant was collected in a 1.5mL tube, centrifuged at 3000g for 5 minutes, and the resulting supernatant was stored at 4 ℃ and then subjected to ELISA analysis. As a result, when vesicles derived from Coprinus aerogenes were pretreated, it was confirmed that secretion of IL-6 and TNF- α by E.coli EV was significantly inhibited (see FIG. 13). This result indicates that the inflammatory response induced by vesicles derived from Coprinus aerogenes (for example, vesicles derived from Escherichia coli) can be effectively suppressed by the vesicles derived from Coprinus aerogenes.
The above description of the present invention is provided for the purpose of illustration, and it will be understood by those skilled in the art to which the present invention pertains that the present invention may be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. It is therefore to be understood that the above described embodiments are illustrative in all respects only, and not restrictive.
[ INDUSTRIAL APPLICABILITY ]
The vesicles derived from the bacteria of the genus chrysosporium according to the present invention are expected to be effectively used in a method for diagnosing stomach cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, or alzheimer's disease, and a food or pharmaceutical composition for preventing, treating, or alleviating gastritis, stomach cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, COPD, diabetes, mild cognitive impairment, alzheimer's disease, or inflammatory disease.
<110> MD healthcare Co
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<151>2019-03-04
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Claims (21)
1. A method of providing information for diagnosing gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or alzheimer's disease, the method comprising the steps of:
(a) extracting DNA from extracellular vesicles isolated from a sample of a normal individual and a sample of a subject;
(b) performing Polymerase Chain Reaction (PCR) on the extracted DNA using paired primers prepared based on a gene sequence present in 16S rDNA to obtain each PCR product; and
(c) the cases in which the content of extracellular vesicles derived from the bacteria of the genus Coriolis is lower than that of the normal individual sample are classified as gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or Alzheimer's disease by quantitative analysis of the PCR product.
2. The method of claim 1, wherein the sample in step (a) is blood.
3. A pharmaceutical composition for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from the corinth bacterium as an active ingredient.
4. The pharmaceutical composition of claim 3, wherein the inflammatory disease is one or more diseases selected from the group consisting of: atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory enteritis, sepsis, septic shock, pulmonary fibrosis, undifferentiated spondylopathy, undifferentiated arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by viral or bacterial infections, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, reactive arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, hashimoto's thyroiditis, graves ' disease, leprosy, syphilis, lyme disease, neurolyme disease, tuberculosis, sarcoidosis, lupus, chilblain-like, lupus erythematosus-like tuberculosis, lupus nephritis, inflammatory bowel disease, septic shock, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, pericarditis, cystic fibrosis, hashimoto's disease, leprosy disease, lupus erythematosus-like tuberculosis, lupus erythematosus-like, Systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Crohn's disease, Sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis.
5. The pharmaceutical composition of claim 3, wherein the inflammatory disease is a disease mediated by interleukin 6(IL-6) or tumor necrosis factor-alpha (TNF-a).
6. The pharmaceutical composition of claim 3, wherein the average diameter of the vesicles is from 10 to 200 nm.
7. The pharmaceutical composition of claim 3, wherein the vesicle is naturally or artificially secreted by the bacteria of the genus Chrysosporium.
8. The pharmaceutical composition according to claim 3, wherein the vesicle derived from the bacterium of the genus Coprinus is a vesicle secreted from Coprinus aerogenes.
9. A food composition for preventing or alleviating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, Alzheimer's disease and inflammatory diseases, comprising vesicles derived from a bacterium of the genus Coriolus as an active ingredient.
10. The food composition of claim 9, wherein the inflammatory disease is one or more diseases selected from the group consisting of: atopic dermatitis, acne, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory enteritis, sepsis, septic shock, pulmonary fibrosis, undifferentiated spondylopathy, undifferentiated arthritis, inflammatory osteolysis, chronic inflammatory diseases caused by viral or bacterial infections, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, reactive arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, hashimoto's thyroiditis, graves ' disease, leprosy, syphilis, lyme disease, neurolyme disease, tuberculosis, sarcoidosis, lupus, chilblain-like, lupus erythematosus-like tuberculosis, lupus nephritis, inflammatory bowel disease, septic shock, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, scleroderma, osteoporosis, atherosclerosis, myocarditis, pericarditis, cystic fibrosis, hashimoto's disease, leprosy disease, lupus erythematosus-like tuberculosis, lupus erythematosus-like, Systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Crohn's disease, Sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis.
11. The food composition of claim 9, wherein the inflammatory disease is a disease mediated by interleukin 6(IL-6) or tumor necrosis factor-alpha (TNF-a).
12. The food composition of claim 9, wherein the average diameter of the vesicles is from 10 to 200 nm.
13. The food composition of claim 9, wherein the vesicles are naturally or artificially secreted by the bacteria of the genus chrysosporium.
14. The food composition of claim 9, wherein the vesicles derived from the bacteria of the genus chrysosporium are vesicles secreted from chrysosporium.
15. An inhalant composition for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, comprising vesicles derived from a bacterium of the genus coriolus as an active ingredient.
16. A cosmetic composition for preventing or alleviating inflammatory diseases, comprising vesicles derived from a bacterium of the genus Coriolus as an effective ingredient.
17. The cosmetic composition of claim 16, wherein the inflammatory disease is selected from one or more of atopic dermatitis, acne and psoriasis.
18. A method of diagnosing gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or alzheimer's disease, the method comprising the steps of:
(a) extracting DNA from extracellular vesicles isolated from a sample of a normal individual and a sample of a subject;
(b) performing Polymerase Chain Reaction (PCR) on the extracted DNA using paired primers prepared based on a gene sequence present in 16S rDNA to obtain each PCR product; and
(c) the case in which the content of extracellular vesicles derived from a bacterium of the genus Coriolis is lower than that of the sample of a normal individual is determined as gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, or Alzheimer's disease by quantitative analysis of the PCR product.
19. The method of claim 18, wherein the sample in step (a) is blood.
20. A method for preventing or treating one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, alzheimer's disease and inflammatory diseases, which comprises administering to a subject a pharmaceutical composition comprising vesicles derived from said coriolus bacteria as an active ingredient.
21. Use of vesicles derived from bacteria of the genus Coprinus for the prevention or treatment of one or more diseases selected from the group consisting of gastritis, gastric cancer, colitis, colon cancer, hepatitis, liver cancer, pancreatic cancer, bile duct cancer, ovarian cancer, bladder cancer, myocardial infarction, atrial fibrillation, Chronic Obstructive Pulmonary Disease (COPD), diabetes, mild cognitive impairment, Alzheimer's disease and inflammatory diseases.
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| KR1020190024703A KR102185983B1 (en) | 2018-03-06 | 2019-03-04 | Nanovesicles derived from Collinsella bacteria and Use thereof |
| KR10-2019-0024703 | 2019-03-04 | ||
| PCT/KR2019/002510 WO2019172604A1 (en) | 2018-03-06 | 2019-03-05 | Nanovesicles derived from collinsella sp. bacteria, and use thereof |
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| CN112899360A (en) * | 2021-02-02 | 2021-06-04 | 北京航空航天大学 | Application method of composition for detecting occurrence probability of Terchester-Coriolis syndrome |
| CN116855418A (en) * | 2022-09-28 | 2023-10-10 | 合肥瀚微生物科技有限公司 | Coliform bacteria capable of producing gas and having effect of preventing and/or treating inflammatory bowel disease and application thereof |
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| WO2024067591A1 (en) * | 2022-09-28 | 2024-04-04 | 合肥瀚微生物科技有限公司 | Collinsella aerofaciens capable of preventing and/or treating inflammatory bowel disease and use thereof |
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| KR20190106722A (en) | 2019-09-18 |
| KR102185983B1 (en) | 2020-12-03 |
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