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WO2015178653A1 - Composition utilisable en vue du traitement ou de la prévention d'une maladie métabolique et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de bactéries de l'espèce akkermansia muciniphila - Google Patents

Composition utilisable en vue du traitement ou de la prévention d'une maladie métabolique et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de bactéries de l'espèce akkermansia muciniphila Download PDF

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Publication number
WO2015178653A1
WO2015178653A1 PCT/KR2015/004983 KR2015004983W WO2015178653A1 WO 2015178653 A1 WO2015178653 A1 WO 2015178653A1 KR 2015004983 W KR2015004983 W KR 2015004983W WO 2015178653 A1 WO2015178653 A1 WO 2015178653A1
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WIPO (PCT)
Prior art keywords
extracellular vesicles
akkermansia muciniphila
derived
composition
metabolic diseases
Prior art date
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Ceased
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PCT/KR2015/004983
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English (en)
Korean (ko)
Inventor
김윤근
박현택
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Ewha Womans University
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Ewha Womans University
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Publication date
Priority claimed from KR1020150068864A external-priority patent/KR101740893B1/ko
Application filed by Ewha Womans University filed Critical Ewha Womans University
Priority to JP2017514237A priority Critical patent/JP6316501B2/ja
Priority to CN201580025750.7A priority patent/CN106535907A/zh
Priority to EP15796520.3A priority patent/EP3165227B2/fr
Priority to CA2949644A priority patent/CA2949644C/fr
Priority to US15/312,419 priority patent/US20170087195A1/en
Priority to AU2015262214A priority patent/AU2015262214B2/en
Publication of WO2015178653A1 publication Critical patent/WO2015178653A1/fr
Anticipated expiration legal-status Critical
Priority to US16/824,111 priority patent/US11291694B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom

Definitions

  • the present invention relates to the treatment, prevention or amelioration of metabolic diseases containing extracellular vesicles derived from Akkermansia muciniphila as an active ingredient, pharmaceuticals and food compositions.
  • Metabolic disease refers to diseases caused by metabolic disorders in vivo. In general, it is caused by an imbalance of sugars, lipids, proteins, vitamins, electrolytes, and water. Examples include obesity, diabetes, hyperlipidemia, arteriosclerosis, and high blood pressure. Among them, type 2 diabetes is characterized by an increase in resistance to insulin, which is mainly diabetes in adulthood. Decreased insulin receptors, or their sensitivity, or problems with secondary messengers that cause intracellular glycogen synthesis, reduce insulin sensitivity. Therefore, type 2 diabetes is called insulin independent diabetes and accounts for 85 to 90% of diabetes.
  • extracellular vesicles have been found in various secretions, excreta, or tissue washes of humans or animals, and extracellular vesicles present in tissues are known to reflect the state of tissues secreting vesicles. It has been reported that it can be used.
  • the large intestine has about 10 times as many intestinal symbiotic bacteria as the number of host cells.
  • Akkermansia muciniphila is a Gram-negative bacterium that survives in the intestines of mammals including humans and breaks down mucus and is known to be associated with diabetes and obesity. Also, Akkermansia muciniphila is known to exacerbate inflammatory enteritis. Recently, the present inventors have reported that Akkermansia muciniphila secretes extracellular vesicles and that extracellular vesicles derived from the bacterium have an effect of preventing inflammatory enteritis (Kang CS et al. Extracellular vesicles derived from Gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis.PLOS ONE 2013).
  • AMPK 5 'AMP-activated protein kinase
  • Activating AMPK is known to inhibit cholesterol and triglyceride synthesis in the liver, increase fatty acid oxidation, glucose uptake in muscle, and regulate insulin secretion in the pancreas. It is known that metformin or exercise that restores insulin resistance among diabetic agents improves metabolic diseases by activating AMPK.
  • the inventors have found that extracellular vesicles secreted by Akkermansia muciniphila inhibit obesity and diabetes induced by high fat diet and restore insulin resistance, which is important for the pathogenesis of diabetes caused by high fat diet, which can occur through AMPK activation. It was found that the present invention was completed.
  • an object of the present invention is to provide a pharmaceutical and food composition for the treatment or prevention of metabolic diseases such as obesity, diabetes, hyperlipidemia and hypertension using extracellular vesicles derived from Akkermansia muciniphila.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of metabolic diseases containing an extracellular vesicle derived from Akkermansia muciniphila bacteria as an active ingredient.
  • the present invention also provides a food composition for preventing or ameliorating metabolic diseases, which contains extracellular vesicles derived from Akkermansia muciniphila .
  • the present invention also provides a method for preventing or treating metabolic diseases, comprising administering to a subject extracellular vesicles derived from Akkermansia muciniphila .
  • the present invention also provides a use of extracellular vesicles derived from Akkermansia muciniphila bacteria for the prevention or treatment of metabolic diseases.
  • the extracellular vesicles are characterized in that they are secreted naturally or artificially from the Akkermansia muciniphila bacteria.
  • the extracellular vesicles are characterized in that the average diameter of 20 to 300nm, preferably 50 to 200nm.
  • the metabolic disease is characterized in that selected from the group consisting of obesity, diabetes, hyperlipidemia and hypertension.
  • the food is characterized in that the fermented food is fermented by the addition of Akkermansia muciniphila bacteria.
  • the pharmaceutical composition containing an extracellular vesicle derived from Akkermansia muciniphila of the present invention as an active ingredient can treat and prevent metabolic diseases such as obesity, diabetes, hyperlipidemia and hypertension induced by a high fat diet.
  • the fermented food composition containing extracellular vesicles derived from Akkermansia muciniphila of the present invention can prevent and improve metabolic diseases such as obesity, diabetes, hyperlipidemia and hypertension induced by a high fat diet.
  • Figure 1 shows the results of observing the extracellular vesicles isolated from Akkermansia muciniphila culture with an electron microscope.
  • Figure 2 is a result of measuring the average diameter of extracellular vesicles derived from Akkermansia muciniphila by light scattering method.
  • FIG. 3 shows the results of comparative evaluation of protein expression patterns of Akkermansia muciniphila and extracellular vesicles derived from Akkermansia muciniphila by SDS-PAGE.
  • Figure 4 shows that the secretion of inflammatory cytokines (IL-6) by LPS in macrophages is suppressed by extracellular vesicle (EV) pretreatment derived from Akkermansia muciniphila.
  • IL-6 inflammatory cytokines
  • EV extracellular vesicle
  • Figure 5 is an experimental protocol for confirming the therapeutic effect of metabolic diseases after direct administration of Akkermansia muciniphila-derived extracellular vesicles (EV) into the stomach in obese and diabetic mouse models induced by high fat diet.
  • EV Akkermansia muciniphila-derived extracellular vesicles
  • Figure 6 shows the results of observing weight change after direct administration of Akkermansia muciniphila-derived extracellular vesicles (Akk EV) into the stomach in a metabolic disease mouse model induced by high fat diet.
  • Akkermansia muciniphila-derived extracellular vesicles Akk EV
  • Figure 7 shows the results of fasting blood glucose levels after direct administration of Akkermansia muciniphila-derived extracellular vesicles (Akk EV) into the stomach in a metabolic disease mouse model induced by high fat diet.
  • Akkermansia muciniphila-derived extracellular vesicles Akk EV
  • Akk EV Akkermansia muciniphila-derived extracellular vesicles
  • FIG. 9 shows 48 hours of anti-CD3 antibody and anti-CD28 antibody after anti-CD3 antibody and anti-CD28 antibody were isolated by in vitro administration of Akkermansia muciniphila-derived extracellular vesicles (Akk EV) in the gastrointestinal model of high-fat diet-induced metabolic disease. After stimulation, the concentrations of IFN- ⁇ and IL-17 in the supernatant were measured.
  • Akkermansia muciniphila-derived extracellular vesicles Akk EV
  • 11 is a result of directly evaluating Akkermansia muciniphila bacteria and Akkermansia muciniphila-derived extracellular vesicles (EV) in the gastrointestinal tract of mice, and comparing their distribution patterns in the body.
  • EV extracellular vesicles
  • FIG. 12 shows blood and various organs (heart, lung, liver, kidney, spleen, fat, 12 hours after direct administration of Akkermansia muciniphila bacteria and Akkermansia muciniphila-derived extracellular vesicles (EV) to the mouse stomach, respectively. Muscles) were extracted, and their distribution patterns were compared and evaluated.
  • FIG. 13 is a result of directly administering Akkermansia muciniphila bacteria and Akkermansia muciniphila-derived extracellular vesicles (EV) to the mouse colon, and then comparing them to penetrate the intestinal barrier and to absorb them into tissues.
  • EV extracellular vesicles
  • Figure 15 shows the results of confirming the activation of AMPK 60 minutes after administration of Akkermansia muciniphila-derived extracellular vesicles (EV) in various concentrations (0.1, 1, 10ug / mL) to myocytes in vitro.
  • EV Akkermansia muciniphila-derived extracellular vesicles
  • Figure 16 shows the results of confirming the activation of AMPK at various times (10, 20, 30, 60min) after administration of 1ug of Akkermansia muciniphila-derived extracellular vesicles (EV) to myocytes in vitro.
  • FIG. 18 shows the results of comparative evaluation of glucose uptake after administration of extracellular vesicles derived from insulin, metformin and Akkermansia muciniphila (EV) to myocytes in vitro.
  • FIG. 19 shows the results of comparing and evaluating the expression of GLUT4 transporter, a glucose uptake receptor, after administration of extracellular vesicles derived from insulin, metformin, and Akkermansia muciniphila (EV) to myocytes.
  • GLUT4 transporter a glucose uptake receptor
  • the present invention relates to a pharmaceutical / food composition for treating, preventing or ameliorating metabolic diseases, which contains as an active ingredient extracellular vesicles derived from intestinal bacteria, particularly Akkermansia muciniphila.
  • the present inventors observed that when extracellular vesicles derived from Akkermansia muciniphila were administered to the stomach, obesity was suppressed, insulin resistance by fatty acids was restored, and the phenotype of diabetes was suppressed. It was confirmed that the immune function is improved.
  • the present inventors confirmed that the protein expression patterns of Akkermansia muciniphila bacteria themselves and Akkermansia muciniphila-derived extracellular vesicles are different.
  • the present inventors compared the in vivo absorption patterns of Akkermansia muciniphila bacteria and Akkermansia muciniphila-derived extracellular vesicles, it was found that the uptake of extracellular vesicles is much better.
  • the present inventors confirmed that when Akkermansia muciniphila-derived extracellular vesicles were administered to muscle cells, expression of glucose uptake receptor (GLUT4) was promoted in muscle cells by AMPK activation and eventually glucose uptake was increased.
  • GLUT4 glucose uptake receptor
  • 'metabolic disease' refers to a disease caused by metabolic disorders in vivo. In general, it is caused by imbalance of sugars, lipids, proteins, vitamins, electrolytes, and water. Representative examples include obesity, diabetes, hyperlipidemia, and atherosclerosis caused by a high fat diet.
  • the term 'treatment or prevention of metabolic diseases' includes the reduction, alleviation and improvement of symptoms of metabolic diseases, and the meaning of including lowering the possibility of developing metabolic diseases.
  • 'extracellular vesicles derived from Akkermansia muciniphila' may be isolated from a culture medium of Akkermansia muciniphila, or may be isolated from a food fermented with Akkermansia muciniphila.
  • the method for separating the extracellular vesicles from the bacterial culture medium or the fermented food product containing bacteria is not particularly limited as long as it includes extracellular vesicles, for example, in bacterial culture medium or fermented food, centrifugation, ultra-fast centrifugation, filtration by filter, Extracellular vesicles can be separated using methods such as gel filtration chromatography, pre-flow electrophoresis, capillary electrophoresis, separation with polymers, and combinations thereof. In addition, it may further include a process for washing to remove impurities, concentration of the obtained extracellular vesicles and the like.
  • the extracellular vesicles are naturally secreted or include extracellularly secreted extracellular vesicles.
  • the extracellular vesicles separated by the above method may have an average diameter of 20 to 300 nm, but preferably 30 to 200 nm.
  • the composition for the treatment or prevention of metabolic diseases may be prepared as a pharmaceutical composition.
  • a pharmaceutical composition it is possible to administer the extracellular vesicles of the present invention for use in treatment and prophylaxis, it is preferred that the extracellular vesicles are included as active ingredients of the pharmaceutical composition.
  • the pharmaceutical composition may contain the isolated extracellular vesicles as an active ingredient, and may include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are conventionally used in the preparation, and include, but are not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If not necessary, it may further include other conventional additives such as antioxidants, buffers and the like.
  • diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • Suitable pharmaceutically acceptable carriers and formulations may be preferably formulated according to each component using the methods disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.
  • the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, or external skin preparation.
  • the method of administering the pharmaceutical composition of the present invention is not particularly limited, but may be parenterally or orally administered, such as intravenous, subcutaneous, intraperitoneal, inhalation, dermal application or topical application, depending on the desired method.
  • Dosage varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and severity of the patient.
  • Daily dosage refers to the amount of therapeutic substance of the invention sufficient for treatment for a disease state alleviated by administration to a subject in need thereof. Effective amounts of therapeutic agents depend on the particular compound, disease state and severity thereof, and on the individual in need thereof, and can be routinely determined by one skilled in the art.
  • the dosage of the composition according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient and may be based on an adult patient weighing 70 kg. At this time, it is generally 0.01 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at regular time intervals.
  • the composition for preventing or improving metabolic diseases may be prepared as a food composition.
  • the composition of the present invention is prepared as a food composition, not only contains the extracellular vesicles as an active ingredient, but also includes components commonly added during food production, and include, for example, proteins, carbohydrates, fats, nutrients, Flavoring and flavoring agents may be included.
  • citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be further included in addition to the extracellular vesicles of the present invention.
  • composition of the present invention is made of a food composition
  • fermented foods such as kimchi itself can be used.
  • Example 1 In order to determine whether the Akkermansia muciniphila-derived extracellular vesicles obtained in Example 1 inhibit obesity and diabetes induced by a high fat diet, experiments were performed as follows.
  • Example 1 The extracellular vesicles obtained in Example 1 were applied to a normal mouse fed a regular diet (RD) for 2 months and a mouse model fed with a high fat diet (HFD) for 2 months to induce obesity and diabetes. 10 ⁇ g per mouse was administered every two days for three weeks (see FIG. 5). At this time, the control group (negative control) was used as a mouse fed a normal diet only and a group of mice administered a normal diet and extracellular vesicles.
  • RD regular diet
  • HFD high fat diet
  • Example 1 In order to determine whether the Akkermansia muciniphila-derived extracellular vesicles obtained in Example 1 also affect immune function, experiments were performed as follows.
  • the mouse blood was collected at the same time and the spleen was collected at the same time.
  • the spleens of each mouse group were extracted by using cell strainers of 100 ⁇ m and 40 ⁇ m. Centrifuge the extract for 400 ⁇ g for 5 minutes, count the number of cells, put 5 ⁇ 10 5 cells per well into the cell culture plate, and stimulate co-stimulatory molecules of T cells (stimulate cytokine secretion). 1 ⁇ g / mL and 0.5 ⁇ g / mL of anti-CD3 and anti-CD28 were added and incubated for 48 hours.
  • the supernatant of each group was removed from the cell culture plate, and the cells in the supernatant were removed by centrifugation for 5 minutes at 400 ⁇ g. Again only the supernatant was collected.
  • the supernatant collected was increased in the high-fat diet-only mouse group (HFD-Akk EV). It was confirmed that the concentration was reduced in the high fat diet mouse group (HFD + Akk EV) administered with extracellular vesicles derived from Akkermansia muciniphila.
  • Example 1 In order to determine whether the Akkermansia muciniphila-derived extracellular vesicles obtained in Example 1 restore insulin resistance, experiments were performed as follows.
  • mice cultured with mouse-derived muscle cells (C2C12, ATCC CRL-1772) were treated with 1 mM of fatty acid (sodium palmitate (SIGMA)) and 4% BSA (Bovine serum albumin) for 48 hours. Thereafter, Akkermansia muciniphila-derived extracellular vesicles were added at a concentration of 1 ⁇ g / ml and cultured for 6 hours, and insulin was treated at a concentration of 2 nM to confirm intracellular signaling.
  • fatty acid sodium palmitate (SIGMA)
  • BSA Bovine serum albumin
  • p-IRS-1 phospho-Insulin Receptor Substrate-1
  • PBS was used as a control group, and 50 ⁇ g of Akkermansia muciniphila bacteria and Akkermansia muciniphila-derived extracellular vesicles, respectively, were injected into the mouse gastrointestinal tract, followed by fluorescence at 0, 5, 3, 6 and 12 hours. Fluorescence was measured using an luminescence imaging device (IVIS; In Vivo Imaging System).
  • IVIS luminescence imaging device
  • the bacteria were not absorbed systemically, but in the case of bacteria-derived extracellular vesicles, they were absorbed systemically only 5 minutes after administration, and the bladder was strongly observed at 3 hours after administration.
  • the extracellular vesicles were found to be excreted in the urinary tract, and it was found to exist in the body until 12 hours after administration.
  • AMPK is known as an important protein for maintaining energy homeostasis
  • the following experiments were performed to evaluate the effect of Akkermansia muciniphila-derived extracellular vesicles on glucose metabolism through AMPK activation in myocytes.
  • the extracellular vesicles were treated with muscle cells at a concentration of 10 ⁇ g / ml for 0, 10, 20, 30, 60 minutes. Since the expression patterns of pAMPK and pACC, which are important indicators in AMPK signaling, were measured by western blot, as shown in FIG. 16, the expression patterns of pAMPK and pACC began to increase after 10 minutes of extracellular vesicle treatment and continued for 60 minutes. And it was found.
  • Example 8 Effect of Akkermansia muciniphila-derived extracellular vesicles on glucose uptake in muscle cells
  • GLUT4 was increased by Akkermansia musiniphila-derived extracellular vesicles (EV) compared to the control group (NT; No Treatment), which was treated by insulin (10 nm) or metformin (50 mM) treatment. The increase was similar to the increase.

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Abstract

La présente invention concerne une composition pharmaceutique et alimentaire utilisable en vue du traitement, de la prévention ou du soulagement des symptômes d'une maladie métabolique, et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de Akkermansia muciniphila. La composition de la présente invention peut être utilisée en tant que composition pharmaceutique/alimentaire, et équivalent, en vue du traitement, de la prévention ou du soulagement des symptômes d'une maladie métabolique, en particulier une maladie métabolique telle que l'obésité, le diabète, l'hyperlipidémie, l'artériosclérose et l'hypertension, survenant en conséquence d'un régime riche en graisses ou aggravée par un tel régime. En outre, dans la présente invention, même un aliment fermenté, préparé par addition de Akkermansia muciniphila, peut être utilisé à des fins de prévention ou de soulagement des symptômes d'une maladie métabolique survenant en conséquence d'un régime riche en graisses ou aggravée par un tel régime.
PCT/KR2015/004983 2014-05-20 2015-05-19 Composition utilisable en vue du traitement ou de la prévention d'une maladie métabolique et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de bactéries de l'espèce akkermansia muciniphila Ceased WO2015178653A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2017514237A JP6316501B2 (ja) 2014-05-20 2015-05-19 アッカーマンシア・ムシニフィラ菌に由来する細胞外小胞を有効成分として含有する代謝疾患の治療または予防用の組成物
CN201580025750.7A CN106535907A (zh) 2014-05-20 2015-05-19 用于治疗或预防代谢疾病的包含作为活性成分的来源于Akkermansia muciniphila菌的胞外囊泡的组合物
EP15796520.3A EP3165227B2 (fr) 2014-05-20 2015-05-19 Composition utilisable en vue du traitement ou de la prévention d'une maladie métabolique et contenant, en tant qu'ingrédient actif, des vésicules extracellulaires provenant de bactéries de l'espèce akkermansia muciniphila
CA2949644A CA2949644C (fr) 2014-05-20 2015-05-19 Composition utilisable en vue du traitement ou de la prevention d'une maladie metabolique et contenant, en tant qu'ingredient actif, des vesicules extracellulaires provenant de bacteries de l'espece akkermansia muciniphila
US15/312,419 US20170087195A1 (en) 2014-05-20 2015-05-19 Composition for treating or preventing metabolic disease, containing, as active ingredient, extracellular vesicles derived from akkermansia muciniphila bacteria
AU2015262214A AU2015262214B2 (en) 2014-05-20 2015-05-19 Composition for treating or preventing metabolic disease, containing, as active ingredient, extracellular vesicles derived from Akkermansia muciniphila bacteria
US16/824,111 US11291694B2 (en) 2014-05-20 2020-03-19 Composition for treating or preventing metabolic disease, containing, as active ingredient, extracellular vesicles derived from Akkermansia muciniphila bacteria

Applications Claiming Priority (4)

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KR20140060409 2014-05-20
KR10-2014-0060409 2014-05-20
KR10-2015-0068864 2015-05-18
KR1020150068864A KR101740893B1 (ko) 2014-05-20 2015-05-18 Ａｋｋｅｒｍａｎｓｉａ ｍｕｃｉｎｉｐｈｉｌａ 균에서 유래하는 세포밖 소포를 유효성분으로 함유하는 대사질환의 치료 또는 예방용 조성물

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US15/312,419 A-371-Of-International US20170087195A1 (en) 2014-05-20 2015-05-19 Composition for treating or preventing metabolic disease, containing, as active ingredient, extracellular vesicles derived from akkermansia muciniphila bacteria
US16/824,111 Continuation US11291694B2 (en) 2014-05-20 2020-03-19 Composition for treating or preventing metabolic disease, containing, as active ingredient, extracellular vesicles derived from Akkermansia muciniphila bacteria

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KR20170103140A (ko) * 2016-03-03 2017-09-13 주식회사 엠디헬스케어 아커만시아 뮤시니필라균 유래 나노소포 및 이의 용도
CN109789173A (zh) * 2016-08-12 2019-05-21 Md保健株式会社 源自芽孢杆菌细菌的纳米囊泡及其用途
CN113116936A (zh) * 2021-04-02 2021-07-16 上海市第六人民医院 嗜黏蛋白艾克曼氏菌在制备β-鹅脱氧胆酸抑制剂中的应用
CN113330109A (zh) * 2018-10-11 2021-08-31 Ko生物技术有限公司 嗜黏蛋白阿克曼氏菌菌株及其用途

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