WO2022092964A1 - Composition pour la prévention ou le traitement d'une maladie intestinale inflammatoire - Google Patents
Composition pour la prévention ou le traitement d'une maladie intestinale inflammatoire Download PDFInfo
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- WO2022092964A1 WO2022092964A1 PCT/KR2021/015569 KR2021015569W WO2022092964A1 WO 2022092964 A1 WO2022092964 A1 WO 2022092964A1 KR 2021015569 W KR2021015569 W KR 2021015569W WO 2022092964 A1 WO2022092964 A1 WO 2022092964A1
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- WIPO (PCT)
- Prior art keywords
- composition
- inflammatory bowel
- bowel disease
- preventing
- treating inflammatory
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the gastrointestinal tract is home to numerous microbes, and these intestinal microbiota are essential for maintaining intestinal homeostasis and function.
- these intestinal microbiota are essential for maintaining intestinal homeostasis and function.
- intestinal flora is rapidly changed due to the influx of antibiotics or pathogens into the intestine or the intestinal flora is continuously unstable, intestinal imbalance is caused and chronic inflammatory bowel disease develops.
- the gut microbiota which is a microbial community that is formed simultaneously with development after fertilization, refers to a microbial community including bacteria, archaea, eukaryotes, and viruses that exist in the gut.
- the intestinal flora has ndemism and diversity derived from the genetic characteristics of various environments and hosts in the composition of the initial colony, and gradually stabilizes as an adult. However, even after growth, the intestinal flora may undergo very large changes due to diet, genetic and epigenetic composition, and the like.
- insulin-added prebiotics change the gut flora by stimulating the growth of bacteria that produce short-chain fatty acids (SCFAs), as well as toxins secreted by certain gut bacteria.
- SCFAs short-chain fatty acids
- the composition of the intestinal microflora may change as a result of intestinal inflammation.
- infections may be caused due to a decrease in bacteria including beneficial bacteria.
- dysbiosis a change in the composition of the unique intestinal flora in the gastrointestinal tract to an imbalanced state for any reason is called dysbiosis, and an environmentally induced intestinal imbalance is often irreversible and alters host metabolism to cause other diseases. It can cause or exacerbate existing diseases.
- IBD inflammatory bowel disease
- FMT fecal microbiota transplantation
- FMT fecal microbiota transplantation
- the inventors of the present invention paying attention to the fact that there is a significant difference in the colony of intestinal microorganisms according to countries or races, analyzed the flora of a large number of healthy Koreans through the above-mentioned molecular ecology analysis method, It was confirmed that microorganisms with
- the inventors of the present invention live in the intestine of a healthy Korean, and successfully dominate the intestine of the recipient to form a continuous and stable colony and finally contain a specific strain capable of preventing and alleviating inflammatory bowel disease. composition has been developed.
- Bacteroides thetaiotaomicron Bacteroides thetaiotaomicron
- Bacteroides uniformis Bacteroides uniformis
- Ruminococcus faesis Ruminococcus faecis
- Bacteroides thetaiotaomicron Bacteroides thetaiotaomicron
- Bacteroides uniformis Bacteroides uniformis
- Ruminococcus faesis Ruminococcus faecis
- the composition for preventing or treating inflammatory bowel disease may include Bacteroides uniformis and Luminococcus phaesis in a ratio of about 1 to Bacteroides thetaiotaomicron 1, respectively. and may be formulated and provided in a rectal administered form or an orally ingestible form.
- the composition for preventing or treating inflammatory bowel disease may further include a pharmaceutically acceptable carrier, excipient or diluent.
- the content of Bacteroides thetaiomicron, Bacteroides uniformis and Luminococcus phaesis may be 10 5 to 10 11 CFU/ml, respectively, but preferably, 5 It may be X 10 8 CFU/ml, but is not limited thereto.
- the inflammatory bowel disease may include at least one of ulcerative colitis, Crohn's disease, collagen colitis, lymphatic colitis, ischemic colitis, convertible colitis, and Behcet's syndrome, but is limited thereto No, it can include all of the various diseases that can be induced in the intestine.
- the composition for preventing or treating inflammatory bowel disease may have a reduced activity (disease activity index) of inflammatory bowel disease based on the time of administration of the composition.
- the colonization of Teroides thetaiotaomicron, Bacteroides uniformis and Luminococcus phaesis is about 24 hours after administration of the composition to the subject in the intestine. It may be 10% or more, but is not limited thereto, and may represent a different dominance rate depending on the state of the individual.
- the step of culturing each strain of Bacteroides thetaiotaomicron, Bacteroides uniformis and Luminococcus phaesis, centrifuging each cultured strain It provides a method for preparing a composition for preventing or treating inflammatory bowel disease, comprising the steps of separating, diluting each of the centrifuged strains, and mixing each of the diluted strains into one.
- the culturing step may include culturing each strain in a liquid medium, and in this case, the liquid medium may be GAM (Gifu Anaerobic Medium), but is not limited thereto. It may include all of the various media in which each strain can be cultured.
- GAM Ga Anaerobic Medium
- the centrifugation step may be performed at 4,000 to 5,000 rpm for 5 to 15 minutes, and the diluting step is to be diluted so that each strain is 10 5 to 10 11 CFU/ml.
- Bacteroides uniformis and Luminococcus phaesis may be mixed in a ratio of about 1, respectively, with respect to Bacteroides thetaiotaomicron 1, but this It is not limited, and may be mixed and used in various proportions depending on the subject.
- the pharmaceutical composition according to an embodiment of the present invention may be formulated in various forms.
- the pharmaceutical composition when the pharmaceutical composition is prepared as a solid preparation, it may be prepared in the form of a tablet, pill, powder, granule, or capsule.
- the solid preparation may further contain one or more excipients, for example, starch, calcium carbonate, sucrose, lactose or gelatin.
- the composition of the solid preparation may further include lubricants such as magnesium stearate and talc in addition to simple excipients.
- the pharmaceutical composition according to an embodiment of the present invention is prepared as a liquid formulation, it is prepared from aqueous solutions, suspensions, and pharmaceutically acceptable fats and oils, alcohols or organic solvents, esters, emulsions, syrups or elixirs, and non-foaming granules. can be prepared in the form of reconstituted suspensions, and effervescent formulations reconstituted from effervescent granules.
- the composition of the liquid formulation may be orally administered as a liquid dosage form in combination with an inert carrier.
- Suitable inert carriers may include pharmaceutically acceptable inert carriers such as ethanol, glycerol, and water.
- composition of the liquid formulation may further include a solvent, a preservative, an emulsifier, a suspending agent, a diluent, a sweetener, a thickener, and a melting aid.
- the composition of the liquid formulation may further include a coloring agent and a flavoring agent.
- the present invention uses a specific microbial community distributed in large numbers in the intestine of healthy Koreans to induce balance and stabilization of the intestinal flora or to substantially inhibit specific pathogenic microorganisms that cause intestinal infections. It can be used as a pharmaceutical composition for preventing or treating intestinal diseases.
- 1 and 2 show a procedure of a method for preparing a composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention.
- Figures 4a and 4b show the results of changes in the intestinal flora according to the treatment of the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention.
- 6 to 7b show the results of the host intestinal status according to the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention.
- the term “individual” may refer to any animal, including humans, that may or may not have inflammatory bowel disease, but is not limited thereto. In addition, the subject may refer to any animal other than humans.
- inflammatory bowel disease is a disease that repeatedly improves and recurs and causes chronic inflammation and ulcers in the intestine, which may be caused by environmental, immune and genetic factors, ulcerative colitis, Crohn's disease, collagen colitis, lymphocytic colitis, ischemic colitis, convertible colitis and Behcet's syndrome may include, but are not limited thereto.
- the term “alleviation” may refer to any action in which the condition of inflammatory bowel disease is improved or beneficial by administration of the composition according to the present invention.
- the term "administration" refers to introducing the pharmaceutical composition of the present invention to a subject by any suitable method, and the route of administration is to be administered through various routes, either oral or parenteral, as long as it can reach the target tissue.
- the pharmaceutical composition according to an embodiment of the present invention may be appropriately administered to a subject according to a conventional method, administration route, and dosage used in the art according to purpose or necessity.
- administration routes include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, and parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
- an appropriate dosage and number of administration may be selected according to methods known in the art, and the amount and frequency of administration of the pharmaceutical composition of the present invention actually administered depends on the type of symptom to be treated, administration route, sex, health It can be appropriately determined by various factors such as the condition, diet, age and weight of the individual, and the severity of the disease.
- the term “probiotic” refers to a type of microorganism that is associated with a health benefit in a host organism and/or a reduction in the risk and/or symptoms of a disease, disorder, condition or event in the host organism.
- the composition for preventing or treating inflammatory bowel disease used in various embodiments of the present invention may be formulated as a probiotic, a product, a functional food, or a health food, and may also be formulated as a pharmaceutical composition.
- microbiome may refer to the totality of microorganisms (bacteria, fungi, protists) and their genetic elements (genome) in a specific environment, and includes gastrointestinal, oral, bronchial, skin, vaginal It may include a variety of microorganisms such as, but preferably may be a gastrointestinal microorganism, but is not limited thereto.
- the term “about” may mean including ⁇ 10% of the stated value.
- prevention may refer to any action that suppresses or delays the onset of a disease by administration of a pharmaceutical composition.
- treatment refers to abrogating, substantially inhibiting, slowing or reversing the progression of a disease, and substantially reducing the clinical or aesthetic symptoms of a disease. to improve or substantially prevent the appearance of clinical or esthetic symptoms of the disease.
- the method for preparing a composition for preventing or treating inflammatory bowel disease is Bacteroides thetaiotaomicron ( Bacteroides thetaiotaomicron ), Bacteroides uniformis ( Bacteroides uniformis ) and Luminococcus phaesis ( Ruminococcus faecis ) of culturing each strain (S110), centrifuging each cultured strain (S120), diluting each centrifuged strain (S130), and mixing each diluted strain into one (S140).
- Bacteroides thetaiotaomicron Bacteroides thetaiotaomicron
- Bacteroides uniformis Bacteroides uniformis
- Luminococcus phaesis Ruminococcus faecis
- the culturing step (S110) may include the step of culturing each strain first and the step of culturing each of the cultured strains second. More specifically, referring to FIG. 2 , the first culture of the culturing step (S110) is a GAM (Gifu anaerobic media) medium in which a stock solution for B. thetaiotaomicron , B. uniformis, and R. faecis strains is dispensed. In anaerobic conditions (anaerobic condition) to culture for 24 hours, and replacing the strain cultured for 24 hours with a new medium includes the process of culturing 1 to 3 passages. At this time, the temperature in the culture environment conditions may be 36 °C to 38 °C, preferably 36.5 °C to 37.5 °C, but is not limited thereto.
- the above-described subcultured strain is transferred to a high volume volume and cultured under anaerobic conditions for 24 hours.
- the second culture is a large culture process to increase the number of bacteria, and at this time, if the transplanted strain is not subjected to subculture, that is, the first culture, the strain may not grow as much as desired under anaerobic conditions. . Accordingly, in the culturing step (S110), for stabilization of each strain, the first culture, which is a subculture, is essentially performed, and then the second culture should be performed.
- the step of centrifuging each cultured strain may be performed.
- the centrifugation step (S120) may be performed at 4,000 to 5,000 rpm for 5 to 15 minutes.
- a step (S130) of diluting each centrifuged strain may be performed.
- the bacteria that have subsided after centrifugation are diluted with PBS, and the OD value is adjusted to 600 so that the content of each bacteria is 10 5 to 10 11 CFU/ml.
- the content of the bacteria may be 10 5 to 10 11 CFU/ml, but is not limited thereto, and preferably 10 8 CFU/ml.
- each strain diluted to the same concentration may be mixed in the same amount, that is, in a 1:1:1 ratio, but is not limited thereto.
- the composition for preventing or treating inflammatory bowel disease is a powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., through the above-described diluents and excipients, oral dosage forms, external preparations, etc. , in the form of suppositories and sterile injectable solutions.
- composition for preventing or treating inflammatory bowel disease may be provided as a food composition as well as a pharmaceutical composition. Accordingly, in the mixing step (S140), an additional component that is commonly used in the food composition to improve odor, taste, vision, and the like may be further included.
- FIG. 3A representative bacteria in the Korean gastrointestinal tract selected by the inventors of the present invention are shown.
- Bacteroides thetaiotaomicron Bacteroides thetaiotaomicron
- Bacteroides uniformis Bacteroides ) uniformis
- Ruminococcus faecis appear to be dominant over the host's gastrointestinal tract.
- FIG. 3B the results of the intestinal flora of the sterile (GF) mouse model according to the transplantation of the aforementioned 12 types of flora are shown.
- GF sterile
- Bacteroides thetaiotaomicron and Escherichia coli appear to be most dominant, but after 24 hours, Bacteroides thetaiotaomicron, Bacteroides uniformis and lumino It appears that caucus phaesis is most dominant at a similar rate. Furthermore, from 24 hours after inoculation, the dominance rate for Bacteroides thetaiotaomicron, Bacteroides uniformis and Luminococcus phaesis in the sterile mouse model appears to be 10% or more, respectively. Furthermore, it appears that the above-mentioned three types of microorganisms are stably maintained in the intestine until 33 days.
- microorganisms Bacteroides thetaiotaomicron, Bacteroides uniformis, and Luminococcus phaesis, appear to have the best fixative ability and dominance in the intestine. Therefore, when the above-mentioned three kinds of microorganisms are transplanted into the intestine, it is possible to most stably maintain the flora in the intestine.
- a composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention of microorganisms were selected.
- FIG. 4A it is a result of a change in the distribution of intestinal flora according to the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention.
- the mouse model was compared by administering Examples and Comparative Examples after mixing DSS (dextran sulfate sodium) with drinking water and orally administering it to make an acute inflammatory bowel disease model induced by dysbiosis.
- the example refers to a group treated with a composition comprising three types of microorganisms of Bacteroides thetaiotaomicron, Bacteroides uniformis and Luminococcus phaesis, and Comparative Example is PBS as a control. processing group.
- each strain having a content of 10 5 to 10 11 CFU/ml was mixed in the same proportion and used through the same process as described in FIGS.
- the group treated with the example is Muribaculum intestinale ), Akermansia mushiniphila, Luminococcus alves, Bacteroides thetaiotaomicron and Bacteroides uniformis order It appears to be dominant in the intestine, and Bacteroides thetaiotaomicron and Bacteroides uniformis appear to occupy a ratio of 9% to 10%, respectively.
- the intestinal flora is more diversified, and pathogens such as Akkermansia mushiniphila, which can cause inflammatory bowel disease, are reduced. That is, as pathogens that can cause inflammatory bowel disease are reduced, inflammatory bowel disease can be improved through the treatment of Examples. Furthermore, the intestinal flora can have more abundance and diversity through the treatment of Examples, and thus, various protective and therapeutic effects against more diverse diseases can be exhibited.
- Bacteroides thetaiotaomicron, Bacteroides uniformis and Luminococcus phaesis appear to have good dominance ability in the intestine, but the persistence to maintain this is Bacteroides thetaiotaomicron and Bacteroides uniformis appear to be the best.
- compositions comprising at least one of Bacteroides thetaiotaomicron, Bacteroides uniformis, and Luminococcus phaesis
- Bacteroides uniformis Bacteroides uniformis
- Luminococcus phaesis a composition comprising at least one of Bacteroides thetaiotaomicron, Bacteroides uniformis, and Luminococcus phaesis
- the evaluation of the activity for inflammatory bowel disease in a mouse model of intestinal disease according to the administration of the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention is shown.
- the disease activity was measured daily during the experiment period by giving a score according to the degree of weight loss (change), the hardness of the stool, and the presence or absence of gross bloody stool.
- DAI disease activity index
- FIG. 6 an observation image result of the intestinal tissue of a mouse model of intestinal disease according to the administration of the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention is shown.
- the intestinal epithelial tissue was densely constructed without dropping, and it appeared that a layer of a certain thickness was maintained. In other words, it appears that the intestinal tissue damaged by DSS treatment is restored to the shape of a normal intestinal epithelial tissue.
- composition for preventing or treating inflammatory bowel disease has an effect of normally restoring damaged intestinal epithelial tissue in an inflammatory bowel disease individual.
- FIG. 7A an observation image result for the length of intestinal tissue of a mouse model of intestinal disease according to the administration of the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention is shown.
- the determination of the length of the intestinal tissue is a method for confirming the state of inflammatory bowel disease, and in the case of an individual having inflammatory bowel disease, shortening of the intestine occurs as a representative symptom. Accordingly, it is possible to confirm the state of inflammatory bowel disease through the confirmation of the length of the intestinal tissue.
- the intestinal length of the normal control group without intestinal disease it was shown to be 8 cm, and in the case of the subject treated with the example, the intestinal length was similar to that of the normal control group. On the other hand, in the case of the subject treated with the comparative example, it appears to have a length of 6 cm shorter than that of the normal control and Example.
- the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention has an effect of restoring the normal length of damaged intestinal tissue in an inflammatory bowel disease individual.
- the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention does not cause a decrease in the diversity of microorganisms due to damage to the intestinal flora, unlike chemical drugs such as antibiotics, and rapidly reduces inflammatory bowel disease has the effect of restoring it to normal. Furthermore, the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention maintains a stable intestinal flora balance for a long time, thereby suppressing intestinal imbalance that may be caused by various infectious diseases and external environmental stimuli. there is Accordingly, the composition for preventing or treating inflammatory bowel disease according to an embodiment of the present invention has the effect of enhancing the immunity of the host.
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- Molecular Biology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
La présente invention concerne une composition pour prévenir ou traiter une maladie intestinale inflammatoire, comprenant au moins deux substances parmi Bacteroides thetaiotaomicron, Bacteroides uniformis et Ruminococcus faecis.
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KR10-2020-0144497 | 2020-11-02 | ||
KR1020200144497A KR102470808B1 (ko) | 2020-11-02 | 2020-11-02 | 염증성 장질환 예방 또는 치료용 조성물 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116218735A (zh) * | 2023-03-14 | 2023-06-06 | 中国海洋大学 | 一种单形拟杆菌菌株及其培养方法和应用 |
WO2024066079A1 (fr) * | 2022-09-28 | 2024-04-04 | 中国科学院深圳先进技术研究院 | Bactérie métabolisant les acides biliaires pour la prévention et le traitement des maladies inflammatoires de l'intestin et son utilisation |
Citations (5)
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KR20150115888A (ko) * | 2013-02-04 | 2015-10-14 | 세레스 테라퓨틱스, 인코포레이티드 | 조성물 및 방법 |
JP2018108968A (ja) * | 2017-01-04 | 2018-07-12 | 国立大学法人 新潟大学 | 腸内細菌叢改善剤及びその使用 |
US20190083599A1 (en) * | 2014-08-28 | 2019-03-21 | Yale University | Compositions and Methods for Treating an Inflammatory Disease or Disorder |
WO2019118515A2 (fr) * | 2017-12-11 | 2019-06-20 | Vedanta Biosciences, Inc. | Compositions et méthodes pour supprimer des organismes pathogenes |
WO2020074569A1 (fr) * | 2018-10-09 | 2020-04-16 | 4D Pharma Research Limited | Compositions comprenant des souches bactériennes |
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2020
- 2020-11-02 KR KR1020200144497A patent/KR102470808B1/ko active IP Right Grant
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2021
- 2021-11-01 WO PCT/KR2021/015569 patent/WO2022092964A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150115888A (ko) * | 2013-02-04 | 2015-10-14 | 세레스 테라퓨틱스, 인코포레이티드 | 조성물 및 방법 |
US20190083599A1 (en) * | 2014-08-28 | 2019-03-21 | Yale University | Compositions and Methods for Treating an Inflammatory Disease or Disorder |
JP2018108968A (ja) * | 2017-01-04 | 2018-07-12 | 国立大学法人 新潟大学 | 腸内細菌叢改善剤及びその使用 |
WO2019118515A2 (fr) * | 2017-12-11 | 2019-06-20 | Vedanta Biosciences, Inc. | Compositions et méthodes pour supprimer des organismes pathogenes |
WO2020074569A1 (fr) * | 2018-10-09 | 2020-04-16 | 4D Pharma Research Limited | Compositions comprenant des souches bactériennes |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024066079A1 (fr) * | 2022-09-28 | 2024-04-04 | 中国科学院深圳先进技术研究院 | Bactérie métabolisant les acides biliaires pour la prévention et le traitement des maladies inflammatoires de l'intestin et son utilisation |
CN116218735A (zh) * | 2023-03-14 | 2023-06-06 | 中国海洋大学 | 一种单形拟杆菌菌株及其培养方法和应用 |
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Publication number | Publication date |
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KR20220059200A (ko) | 2022-05-10 |
KR102470808B1 (ko) | 2022-11-28 |
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