WO2019051789A1 - Anaerofustis stercorihominis et ses applications - Google Patents

Anaerofustis stercorihominis et ses applications Download PDF

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WO2019051789A1
WO2019051789A1 PCT/CN2017/101914 CN2017101914W WO2019051789A1 WO 2019051789 A1 WO2019051789 A1 WO 2019051789A1 CN 2017101914 W CN2017101914 W CN 2017101914W WO 2019051789 A1 WO2019051789 A1 WO 2019051789A1
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composition
anaerobic
bacterium
bacteria
another preferred
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PCT/CN2017/101914
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English (en)
Chinese (zh)
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邹远强
肖亮
李晓平
余靖宏
刘传
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深圳华大生命科学研究院
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Priority to CN201780094884.3A priority Critical patent/CN111448306B/zh
Priority to PCT/CN2017/101914 priority patent/WO2019051789A1/fr
Publication of WO2019051789A1 publication Critical patent/WO2019051789A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor

Definitions

  • the present invention relates to the field of microorganisms, and in particular to Anaerofustis stercorihominis and uses thereof.
  • IBD Inflammatory bowel disease
  • UC ulcerative enteritis
  • CD Crohn's disease
  • Ulcerative colitis is an important type of inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the cause of the disease is unknown.
  • the main lesion is in the submucosal layer of the colonic mucosa. It is a chronic disease. Intestinal disease.
  • the causes of ulcerative enteritis include host genetic susceptibility, intestinal flora and intestinal mucosal immune response.
  • the clinicopathological manifestations include persistent abdominal pain, diarrhea and mucous bloody stools, and the disease is repeated. The number of patients affected showed a clear upward trend.
  • the drugs for ulcerative enteritis mainly include salicylic acid, adrenal glucocorticoids, and immunological preparations.
  • Salicylic acid drugs can better inhibit prostaglandin synthesis and scavenge oxygen free radicals, thereby achieving the purpose of relieving inflammation, but it can only be relieved in a short period of time and cannot be cured.
  • the most common salicylate western medicine for the treatment of ulcerative enteritis (UC) is sulfasalazine (SASP), which is mainly for patients with mild, moderate and chronic UC.
  • Adrenal glucocorticoids are patients with severe or explosive UC.
  • Preferred drugs such as betamethasone; immunosuppressants such as cyclosporine can inhibit ulcerative enteritis (UC) by inhibiting the production of T-cell IL-2 and affecting the progression of the immune response.
  • the three drugs for ulcerative enteritis can alleviate UC to a certain extent, but there are also some side effects.
  • the side effects of salicylate are gastrointestinal reactions, headache, reticulocyte increase, Sperm reduction and allergic reactions caused by rash, hepatotoxicity, leukopenia, anemia, etc., these drugs also have antibacterial effects, easily lead to bacterial flora disorder and increased drug resistance.
  • Adrenal glucocorticoids can cause metabolic disorders, water retention and other side effects. They can only be used as emergency medications and cannot be taken for a long time.
  • Immunosuppressive therapy is highly dependent on drugs, and has a long treatment period, which is easy to cause nephrotoxicity. Sexual and secondary infections can only be used as a means of adjuvant therapy.
  • a bacterium of anaerobic bacterium characterized in that the anaerobic bacterium of the anaerobic bacterium is Anaerofustis stercorihominis.
  • sequence of the 16s rDNA of the anaerobic C. faecalis is shown in SEQ ID NO.: 1.
  • the anaerobic bacteria of the anaerobic bacterium is Anaerofustis stercorihominis AM25-6, and the accession number is GDMCC 60087.
  • the anaerobic bacterium is derived from the gut, animal feces, fermentation tanks, and/or anaerobic reactors.
  • the anaerobic bacterium is derived from a human or a non-human mammal.
  • non-human mammals include rodents (e.g., mice, rats), primates (e.g., monkeys).
  • a second aspect of the present invention provides a composition
  • a composition comprising: (a) a safe and effective amount of the anaerobic bacteria of the genus of the first aspect of the present invention and/or a metabolite thereof; and (b) A food acceptable carrier or a pharmaceutically acceptable carrier.
  • the composition further comprises a growth factor (preferably, a milk growth factor).
  • a growth factor preferably, a milk growth factor
  • the composition is selected from the group consisting of a food composition, a health care composition, a pharmaceutical composition, a beverage composition, a feed composition, or a combination thereof.
  • the composition is an oral preparation.
  • the composition is a liquid formulation, a solid formulation, or a semi-solid formulation.
  • the dosage form of the composition is selected from the group consisting of powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual Tablets, or a combination thereof.
  • the food composition comprises an emulsion preparation, a solution preparation, a powder preparation, or a suspension preparation.
  • the food composition comprises a dairy product, a milk powder, or an emulsion.
  • the liquid formulation is selected from the group consisting of a solution preparation or a suspension product.
  • the composition contains 1 x 10-1 x 10 15 cfu/mL or cfu/g Anaerofustis stercorihominis AM25-6, preferably 1 x 10 4 - 1 x 10 10 cfu/mL or cfu /g Anaerofustis stercorihominis AM25-6, based on the total volume or total weight of the composition.
  • the composition contains 0.0001 to 99% by weight, preferably 0.1 to 90% by weight of the anaerobic bacteria and/or metabolite thereof, to the total of the composition. Weight meter.
  • the composition is a unit dosage form (one tablet, one capsule or one vial), and the mass of the composition in each unit dosage form is from 0.05 to 5 g, preferably from 0.1 to 1 g.
  • composition further contains other probiotics and/or prebiotics.
  • the probiotic is selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof.
  • the prebiotic is selected from the group consisting of oligofructose (FOS), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), and low soybean.
  • the composition further contains a substance (e.g., a protective agent) that helps maintain the activity of the anaerobic bacteria of the faeces.
  • a substance e.g., a protective agent
  • the substance (such as a protective agent) that contributes to maintaining the activity of the anaerobic bacteria of the genus is selected from the group consisting of cysteine, glutathione, butyl hydroxyanisole, and dibutyl group.
  • cysteine glutathione
  • glutathione butyl hydroxyanisole
  • dibutyl group a group consisting of cysteine, glutathione, butyl hydroxyanisole, and dibutyl group.
  • Toluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • the weight ratio of the substance (e.g., protective agent) which contributes to maintaining the activity of the anaerobic bacteria of the faeces is 0.1-2%, preferably 0.5-1.5%, more preferably 0.5. -1.0% based on the total weight of the composition.
  • the content of the substance (such as a protective agent) which contributes to maintaining the activity of the anaerobic bacteria of the genus Escherichia coli is 1 mg to 20 mg, preferably 5 mg to 15 mg, more preferably 1 g of the composition. Ground, 5mg-10mg.
  • a third aspect of the invention provides the use of the anaerobic bacterium of the first aspect of the invention, or the composition of the second aspect of the invention, for the preparation of a composition or formulation, the composition Or a formulation for preventing and/or treating an inflammation-related disease.
  • the inflammation-related disease is selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, or a combination thereof.
  • the inflammation-related disease is selected from the group consisting of ulcerative enteritis, gastritis, common enteritis, or a combination thereof.
  • the formulation comprises a microecological formulation.
  • a fourth aspect of the invention provides the use of the anaerobic bar bacterium of the first aspect of the invention, or the composition of the second aspect of the invention, for the preparation of a composition or formulation, the composition Or the formulation is for one or more uses selected from the group consisting of:
  • controlling the reduction in body weight of the mammal means that the body weight of the experimental group is reduced by no more than 10%, preferably no more than 5%, more preferably than the mammal of the model group. , no more than 2%.
  • the improving intestinal lesions in the mammal comprises slowing the shortening of the length of the colon, and/or reducing the inflammatory response of the colon.
  • the mammal comprises a human or a non-human mammal.
  • non-human mammals include rodents (e.g., mice, rats), primates (e.g., monkeys).
  • the anaerobic bacterium of the first aspect of the invention and/or its metabolite is mixed with a food acceptable carrier or a pharmaceutically acceptable carrier to form the composition of the second aspect of the invention.
  • the method further comprises the step of mixing with a growth factor.
  • the process further comprises the step of mixing with a substance (e.g., a protective agent) that helps maintain the activity of the anaerobic bacteria of the faeces.
  • a substance e.g., a protective agent
  • the substance (such as a protective agent) that contributes to maintaining the activity of the anaerobic bacteria of the genus is selected from the group consisting of cysteine, glutathione, butyl hydroxyanisole, and dibutyl group.
  • cysteine glutathione
  • glutathione butyl hydroxyanisole
  • dibutyl group a group consisting of cysteine, glutathione, butyl hydroxyanisole, and dibutyl group.
  • Toluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • the method further comprises the step of mixing with a probiotic, and/or a prebiotic.
  • the probiotic is selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof.
  • the prebiotic is selected from the group consisting of oligofructose (FOS), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), and low soybean.
  • the growth factor is a milk growth factor.
  • the growth factor is selected from the group consisting of a vitamin, an anthraquinone, a pyrimidine, or a combination thereof.
  • the composition is an oral preparation.
  • a sixth aspect of the invention provides a method of production comprising the steps of:
  • the step of mixing the culture product obtained in the previous step or the anaerobic coryneform bacteria and/or its metabolites with a growth factor is further included.
  • the growth factor is a milk growth factor.
  • the growth factor is selected from the group consisting of a vitamin, an anthraquinone, a pyrimidine, or a combination thereof.
  • the culture product obtained by the previous step or the anaerobic coryneform bacteria and/or its metabolites are further included to help maintain fecal anaesthesia.
  • step (c) further comprising the culture product obtained in the previous step or the anaerobic coryneform bacteria and/or metabolite thereof and probiotics and/or probiotics
  • step (c) further comprising the culture product obtained in the previous step or the anaerobic coryneform bacteria and/or metabolite thereof and probiotics and/or probiotics
  • a seventh aspect of the invention provides a method of improving intestinal lesions in a mammal, the composition of the second aspect of the invention being administered to the subject.
  • the administration comprises oral administration.
  • the administration dose is 0.01 to 5 g / 50 kg body weight / day, preferably 0.1 to 2 g / 50 kg body weight / day.
  • the subject comprises a human or a non-human mammal.
  • non-human mammals include rodents (e.g., mice, rats), primates (e.g., monkeys).
  • the method is non-diagnostic and non-therapeutic.
  • An eighth aspect of the invention provides a method of controlling body weight loss in a mammal, and/or reducing a disease activity index in a mammal, characterized in that the composition of the second aspect of the invention is administered to the subject.
  • the administration comprises oral administration.
  • the administration dose is 0.01 to 5 g / 50 kg body weight / day, preferably 0.1 to 2 g / 50 kg body weight / day.
  • the subject comprises a human or a non-human mammal.
  • non-human mammals include rodents (e.g., mice, rats), primates (e.g., monkeys).
  • the method is non-diagnostic and non-therapeutic.
  • a ninth aspect of the present invention provides a method of preventing and/or treating an inflammation-related disease, comprising the steps of:
  • composition of the second aspect of the invention is administered to the subject, thereby preventing and/or treating an inflammation-related disease.
  • the administration comprises oral administration.
  • the administration dose is 0.01 to 5 g / 50 kg body weight / day, preferably 0.1 to 2 g / 50 kg body weight / day.
  • the subject comprises a human or a non-human mammal.
  • non-human mammals include rodents (e.g., mice, rats), primates (e.g., monkeys).
  • the method is non-diagnostic and non-therapeutic.
  • Figure 1 shows a picture of colonies cultured in human fecal anaerobic bacteria Anaerofustis stercorihominis AM25-6 for 48 hours.
  • Figure 2 shows a Gram-stained picture (1000 times) of a human anaerobic bacterium Anaerofustis stercorihominis AM25-6 under a microscope.
  • Figure 3 shows the changes in body weight of Control group, model group, VSL # 3 and AM25-6 treatment groups.
  • Figure 3 shows that the body weight of the mice in the control group was basically increased slowly. The body weight of the mice in the model group induced by DSS gradually decreased. On the 7th day, the body weight of the mice in the model group was the most obvious compared with the control group. Treatment with AM25-6 and VSL # 3 slowed the decline in body weight in UC mice. On day 7, the control of weight loss in AM25-6 and VSL # 3 mice was significant compared to the model group. This indicates that the two groups of probiotics can control the weight loss caused by UC. By comparing the body weight values of the groups on the 7th day, it was found that the body weight of the AM25-6 group was slightly higher than VSL # 3, indicating that the ability of AM25-6 to control the weight loss of UC mice was slightly better than VSL # 3.
  • FIG. 4 shows the changes in the DAI index of the Control, Model, VSL # 3, and AM25-6 treatment groups.
  • the data in Figure 4 showed that the DAI of the Control group maintained a positively low level, while the DSS-induced mice gradually increased DAI due to a series of pathologies.
  • the DAI of the model group changed from the control group. It began to be significant, and the DAI of the model group reached the highest level on the 7th day. The intervention of probiotics could control the increase of DAI.
  • AM25-6 reached a significant level relative to the model group, and on the 7th day, the DAI of AM25-6 and VSL # 3 groups was determined relative to the model group. Degree of control. From the DAI value on day 7, it can be found that the DAI of AM25-6 mice is slightly lower than VSL # 3, which indicates that AM25-6 is slightly better than VSL # 3 in controlling the increase of DAI in UC mice.
  • Anaerofustis stercorihominis has prevention and/or treatment of inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common The effect of enteritis) and rheumatoid arthritis is to feed the active composition containing the anaerobic bacteria of the genus Escherichia coli of the present invention, and it is found that the composition can control weight loss, reduce disease activity index (DAI), and improve Intestinal lesions can effectively alleviate inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common enteritis), rheumatoid arthritis).
  • inflammation-related diseases such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common enteritis)
  • DAI disease activity index
  • Intestinal lesions can effectively alleviate inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common enteritis), rheuma
  • the term "containing” means that the various ingredients may be applied together in the mixture of the invention or In the composition. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • growth factor includes milk growth factors, in particular, nutrients including vitamins, terpenoids, pyrimidines, or combinations thereof.
  • the vitamins include, but are not limited to: vitamin C, vitamin E, vitamin A, vitamin A precursor, vitamin B 6 , vitamin D 3 , vitamin K, folic acid, or a combination thereof;
  • the terpenoid includes, but is not limited to, a purine nucleoside, wherein the purine nucleoside comprises a 5'-phosphate of a purine nucleoside; the 5'-phosphate of the purine nucleoside is selected from the group consisting of: Inosinic acid (inosine-5'-phosphate; IMP), guanylic acid (guanosine-5'-phosphate; GMP), xanthosine (xanthine-5'-phosphate; XMP), Adenylate (adenosine-5'-phosphate; AMP), or a combination thereof;
  • the pyrimidine species include all substances containing a pyrimidine structure.
  • controlling the decrease in body weight of a mammal As used herein, the terms “controlling the decrease in body weight of a mammal”, “reducing the decrease in body weight of a mammal”, “controlling the decrease in body weight of a mammal”, “reducing the decrease in body weight of a mammal” are used interchangeably to refer to a mammal in During the construction of the ulcerative enteritis model, the body weight of the experimental animals also decreased due to the continual inflammation, and the percentage of weight loss was the percentage of the weight loss to the original body weight. The higher the degree of weight loss, the more serious the disease, the anaerobic bacterium of the present invention can control the decrease of body weight of the experimental animal and slow down the symptoms of the disease during the treatment of ulcerative colitis in mammals.
  • DAI Disease Activity Index
  • disease activity index refers to a combination of three conditions, including weight loss percentage, stool viscosity, and stool bleeding, in a patient (or diseased animal).
  • the terms "A. anaerobic bacterium”, “Anaerofustis stercorihominis”, “the anaerobic bacterium of the present invention” are used interchangeably.
  • the strain is Anaerofustis stercorihominis AM25-6, deposited under the number GDMCC 60087, isolated from the feces of a human (preferably, healthy male).
  • the physiological characteristics of the anaerobic bacterium were as follows: Anaerofustis stercorihominis AM25-6 was isolated using PYG medium under the anaerobic conditions of 37 °C. The colonies of AM25-6 cultured in PYG medium for 2 days were light yellow and the colonies were small.
  • Needle-shaped about 0.5mm in diameter.
  • the microscopic morphology of the cells is short rod-shaped, Gram-positive, non-spore-forming and flagella.
  • Catalase and oxidase test results are negative, can ferment a variety of carbohydrates, including glucose, mannitol, lactose, sucrose, maltose, sulphate, xylose, mannose, pine sugar, cottonseed, sorbus Alcohol, rhamnose, trehalose, mainly produces acetic acid, butyric acid, isovaleric acid, benzoic acid and lactic acid, and can produce isobutyric acid, valeric acid, 3-methylbutyric acid, succinic acid, adipic acid and Citric acid.
  • the Anaerofustis stercorihominis AM25-6 of the present invention is sensitive to the 20 common antibiotics in Table 2.
  • the present invention provides the use of S. anaerobic bacteria for treating and/or preventing inflammation-related diseases such as inflammatory bowel diseases such as ulcerative enteritis, gastritis, common enteritis, and rheumatoid arthritis.
  • inflammation-related diseases such as inflammatory bowel diseases such as ulcerative enteritis, gastritis, common enteritis, and rheumatoid arthritis.
  • the subject was induced to model with DSS (sodium dextran sulfate), and the strain Anaerofustis stercorihominis AM25-6 had one or more uses selected from the group consisting of: (i) controlling the decrease in body weight of the subject; (ii) Reduce disease activity index (DAI); (iii) improve intestinal lesions.
  • DAI Reduce disease activity index
  • C57bl/6 mice are used as test mice, and induced modeling is performed using DSS (sodium dextran sulfate) to obtain ulcerative enteritis (UC) model mice, which are subjected to Anaerofustis stercorihominis AM25- 6 treated UC model mice, compared with the untreated control group (model group), their weight loss decreased, and various inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common Indicators related to enteritis and rheumatoid arthritis have also been improved, such as improving the degree of intestinal lesions (including slowing the length of the colon, reducing the inflammatory response of the colon, etc.) and reducing the disease activity index (DAI). Therefore, the strain can be used for the prevention and/or treatment of inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common enteritis), rheumatoid arthritis).
  • inflammation-related diseases such as inflammatory
  • the present invention also provides a composition, preferably the composition comprises a food composition, a health care composition, a pharmaceutical composition, a beverage composition, or a feed composition, preferably a pharmaceutical composition.
  • the composition comprises an effective amount of C. faecalis, and in a preferred embodiment, the composition further comprises a growth factor (e.g., milk growth factor).
  • a growth factor e.g., milk growth factor
  • the composition further comprises a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof; and/or a prebiotic selected from the group consisting of oligofructose ( FOS), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligosaccharide (SOS), inulin, oligosaccharides, or combinations thereof.
  • a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof
  • a prebiotic selected from the group consisting of oligofructose ( FOS), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligosacc
  • the composition further comprises a substance (such as a protective agent) selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-iso Ascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipids, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • a substance such as a protective agent selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-iso Ascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipids, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • the weight ratio of the substance (e.g., protective agent) which contributes to maintaining the activity of the anaerobic bacteria of the faecal anaerobic bacteria is 0.1 to 2%, preferably 0.5 to 1.5%, more preferably, based on the total weight of the composition. 0.5-1.0%.
  • the composition is a liquid formulation, a solid formulation, or a semi-solid formulation.
  • the liquid formulation is selected from the group consisting of a solution product or a suspension product.
  • the dosage form of the composition is selected from the group consisting of powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual Tablet, or a combination thereof.
  • composition of the present invention may be administered in the form of an oral liquid, a tablet, an injection, an orally disintegrating tablet, a lyophilized powder preparation or a capsule, preferably an enteric solvent type (e.g., a capsule), in the present invention, if there is no special
  • excipients, pharmaceutically acceptable vehicles and carriers used in the present invention are mainly selected according to the characteristics of the suitable bacteria or their metabolites and the specific administration mode required, and are advantageous for the bacteria or its metabolites to be smoothly passed through the stomach.
  • the drug is absorbed. These substances can be selected depending on the route of administration.
  • compositions of the present invention may further comprise any additional excipients in the excipients typically used in pharmaceutical formulations, for example, to stabilize the composition itself, or to readily disperse or impart a suitable taste.
  • inulin fructose, starch, xylooligosaccharide, silica, buffering agents, and flavoring agents are suitable examples.
  • the pharmaceutical preparation of the present invention may further comprise an auxiliary active ingredient.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, an emulsifier, a suspension stabilizer, a preservative, a sweetener, a perfume, and the like.
  • the pharmaceutical composition of the present invention can be produced in a casing formulation by various known methods, so that the active ingredient of the pharmaceutical composition, that is, the microorganism, can smoothly pass through the stomach without being destroyed by gastric acid.
  • the microorganism of the present invention can be used in the form of a capsule prepared by a conventional method.
  • a standard excipient is mixed with the cold-dried microorganism of the present invention to prepare a pellet, and then the pellet is filled into a gelatin capsule.
  • the microorganisms and medicaments of the present invention allow the use of excipients such as liquid gums, celluloses, silicates or mineral oils to prepare suspensions or dispersions which can be filled into soft gelatin. In the capsule.
  • the pharmaceutical composition of the present invention can be made into an enteric tablet for oral use.
  • casing as used in this application includes coatings which are permitted for use with all conventional drugs which are not degraded by gastric acid but which are sufficiently decomposed in the small intestine and rapidly release the microorganism of the present invention.
  • the casing of the present invention is coated at about 16-30 mg per tablet, preferably 16-25 mg, more preferably 16-20 mg.
  • the thickness of the casing is 5 to 100 ⁇ m, and the thickness is preferably 20 to 80 ⁇ m.
  • the casing component is selected from conventional polymers known to the public.
  • Preferred casings of the present invention are cellulose acetate phthalate polymers or trimellitate polymers and copolymers of methacrylic acid (for example, containing 40% or more of methacrylic acid and containing methylcellulose phthalic acid) Preparation of a copolymer of hydroxypropyl acrylate or its ester derivative of methacrylic acid).
  • the cellulose acetate phthalate used in the casing of the present invention has a viscosity of about 45 to 90 cp, an acetyl content of 17 to 26%, and a phthalic acid content of 30 to 40%.
  • the cellulose acetate trimellitate used in the casing has a viscosity of about 5-21 cp and an acetaminophen content of 17-26%.
  • Cellulose acetate trimellitate is produced by Eastman Kodak Company and can be used in the casing material of the present invention.
  • the hydroxypropyl methylcellulose phthalate used in the casing of the present invention has a molecular weight of generally 20,000 to 130,000 Daltons, an ideal molecular weight of 80,000 to 100,000 Daltons, and a hydroxypropyl content of 5 to 10%.
  • the methoxy group content is 18-24%, and the phthaloyl group content is 21-35%.
  • HP50 The hydroxypropylmethylcellulose phthalate used in the casing of the present invention is HP50, which is produced by Shin-Etsu Chemidnl Co. Ltd., Japan. HP50 contains 6-10% hydroxypropyl, 20-24% methoxy, 21-27% propyl and has a molecular weight of 84,000 Daltons.
  • Another casing material is HP55, HP55 contains 5-9% hydroxypropyl methylcellulose phthalate, 18-22% methoxy, 27-35% phthalic acid, and its molecular weight is 78,000 Daltons.
  • the casing of the present invention is prepared by spraying a casing solution onto the core using conventional methods. All solvents in the enteric coating process are alcohols (e.g., ethanol), ketones (e.g., acetone), halogenated hydrocarbon compounds (e.g., dichloromethane), or combinations thereof. Softeners such as di-n-butyl phthalate and triacetin are added to the casing solution in a ratio of about 1 part to about 0.05 part or about 0.3 parts of softener.
  • the spraying method is preferably carried out continuously, and the amount of the sprayed material can be controlled according to the conditions employed for the coating.
  • the spray pressure can be adjusted at will, and in general, the desired result can be obtained at an average pressure of 1-1.5 bar.
  • “Pharmaceutically effective amount” in the specification means an amount which can exert a function or activity on a human and/or animal and which can be accepted by humans and/or animals.
  • it may be prepared to contain 1 ⁇ 10 -1 ⁇ 10 15 cfu / ml or cfu / g (particularly, may contain 1 ⁇ 10 4 - 1 ⁇ 10 10 cfu / ml or cfu / g; more special
  • the formulation may contain 1 x 10 6 - 1 x 10 10 cfu/ml or cfu/g) of anaerobic bacteria and/or metabolites thereof.
  • the effective dosage of the anaerobic bacterium or its metabolites used may vary depending on the mode of administration and the severity of the condition to be treated.
  • a dosage form suitable for internal administration comprising about 1 x 10-1 x 10 15 cfu/ml or cfu/g intimately mixed with a solid or liquid pharmaceutically acceptable carrier (preferably, may contain 1 x 10 4 -1) ⁇ 10 10 cfu/ml or cfu/g; more preferably, 1 ⁇ 10 6 - 1 ⁇ 10 10 cfu/ml or cfu/g) of active anaerobic bacterium or fermentatively produced active ingredient may be contained.
  • This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as is critical to the condition of the treatment.
  • the anaerobic bacteria of the genus anaerobic or the metabolite thereof may be administered orally or the like.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: medium, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, peanut oil). And sesame oil), as long as it is suitable for the characteristics of the anaerobic bacterium or its metabolites and the specific mode of administration required.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives, and antioxidants such as vitamin E, vitamin C, BHT, and BHA.
  • compositions are solid compositions, especially tablets and/or solid filled or liquid filled capsules. Oral administration is preferred.
  • composition of the invention is administered to the individual for one or more administrations per day.
  • Dosage unit of administration means a dose that is formally separable and suitable for use in humans or all other mammalian individuals.
  • Each unit contains a pharmaceutically acceptable carrier and a therapeutically effective amount of a microorganism of the invention.
  • the amount administered depends on the patient's body weight and the severity of the inflammation-related diseases (such as inflammatory bowel disease (such as ulcerative enteritis, gastritis, common enteritis), rheumatoid arthritis), the supplementary active components included, and the Changes in microorganisms. Further, if possible, it can be administered separately and can be administered continuously if necessary. Therefore, the amount administered does not limit the invention.
  • the "composition" in the present invention means not only a medicine but also a functional food and a health supplement.
  • the composition comprises: a beverage, a food, a pharmaceutical, an animal feed, and the like.
  • a food composition comprising an effective amount of C. sphaeroides and/or a metabolite thereof, and a balance of a food acceptable carrier,
  • the dosage form of the food composition is selected from the group consisting of a solid, a dairy, a solution, a powder, or a suspension.
  • the food composition may further comprise a growth factor (such as milk growth factor).
  • the composition further comprises a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof; and/or a prebiotic selected from the group consisting of oligofructose (FOS), oligomeric half Lactose (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligosaccharide (SOS), inulin, oligosaccharides, or combinations thereof.
  • a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof
  • prebiotic selected from the group consisting of oligofructose (FOS), oligomeric half Lactose (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligosaccharide
  • the composition further comprises a substance (such as a protective agent) selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • a substance such as a protective agent selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • composition of the composition is as follows:
  • composition of the composition is as follows:
  • the microecological preparation is a biological preparation containing probiotics and metabolites or a dietary supplement which can increase probiotics, and can achieve the purpose of improving human health by regulating and maintaining the micro-ecological balance in the intestinal tract. It mainly includes probiotics, prebiotics and synbiotics.
  • the microecological preparation comprises (a) a safe and effective amount of C. faecalis and/or a metabolite thereof; and (b) a food acceptable carrier or a pharmaceutically acceptable carrier.
  • the formulation further comprises a growth factor (such as milk growth factor, preferably including a vitamin, an anthraquinone, and/or a pyrimidine).
  • the formulation further comprises a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof; and/or a prebiotic selected from the group consisting of oligofructose (FOS) ), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligosaccharide (SOS), inulin, oligosaccharides, or combinations thereof.
  • a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof
  • prebiotic selected from the group consisting of oligofructose (FOS) ), galactooligosaccharide (GOS), xylooligosaccharide (XOS), oligofructose (LACT), soy oligo
  • the composition further comprises a substance (such as a protective agent) selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • a substance such as a protective agent selected from the group consisting of cysteine, glutathione, butylated hydroxy anise to help maintain the activity of the anaerobic bacterium Ether, dibutylmethyltoluene, tocopherol, bamboo leaf antioxidant, D-isoascorbic acid and its sodium salt, sodium ascorbate, calcium ascorbate, phospholipid, vitamin C (ascorbic acid), vitamin E, or a combination thereof.
  • the anaerobic bacterium of the genus anaerobic can be produced by a conventional method.
  • a method for producing a large scale anaerobic bacterium of the genus comprising the following steps:
  • the conditions suitable for culture refer to any conditions suitable for cultivating the fecal anaerobic baseball of the present invention.
  • the conditions suitable for culture refer to anaerobic culture at 37 ° C using PYG medium. 24h-72h.
  • the method comprises ingesting a pharmaceutical composition, a food composition, a beverage composition, or a combination thereof of the present invention.
  • the subject includes mammals such as humans.
  • the method comprises: ingesting a pharmaceutical composition, a food composition, or an animal feed of the invention, or a combination thereof.
  • the subject is an animal, preferably a mouse, a rabbit.
  • the method comprises ingesting a pharmaceutical composition, a food composition, a beverage composition, or a combination thereof of the present invention.
  • the subject includes mammals such as humans.
  • the method comprises: ingesting a pharmaceutical composition, a food composition, or an animal feed of the invention, or a combination thereof.
  • the subject is an animal, preferably a mouse, a rabbit.
  • the method comprises ingesting a pharmaceutical composition, a food composition, a beverage composition, or a combination thereof of the present invention.
  • the subject includes mammals such as humans.
  • the method comprises: ingesting a pharmaceutical composition, a food composition, or an animal feed of the invention, or a combination thereof.
  • the subject is an animal, preferably a mouse, a rabbit.
  • Anaerofustis stercorihominis AM25-6 (same name as the preservation name) of the strain of the present invention has been deposited with the Guangdong Provincial Collection of Microorganisms and Culture Collections (GDMCC) on October 13, 2016, at the address of 100, Xianlie Middle Road, Guangzhou. No. 59, Building 5, Building No. 5, Deposit No.: GDMCC 60087.
  • the anaerobic bacterium of the present invention can significantly improve indicators associated with inflammation-related diseases such as inflammatory bowel diseases (such as ulcerative enteritis, gastritis, common enteritis), rheumatoid arthritis (such as weight control) Decrease, improve the degree of intestinal lesions (including slowing the length of the colon, reducing the inflammation of the colon, etc.), reducing the disease activity index (DAI), etc.).
  • inflammation-related diseases such as ulcerative enteritis, gastritis, common enteritis
  • rheumatoid arthritis such as weight control
  • DAI disease activity index
  • the treatment of UC mice by the anaerobic bacterium of the present invention can effectively control the decrease of body weight of UC mice induced by DSS, inhibit the increase of disease activity index (DAI) in mice, and improve mice. Changes in the colon.
  • DAI disease activity index
  • the isolated sample was obtained from a healthy male feces, and the feces were collected into sterile sample tubes and brought back to the laboratory for sorting within 1 h.
  • the collected fresh samples were immediately transferred to an anaerobic operation box, and 0.2 g of the sample was suspended in 1 ml of sterile PBS (phosphate buffer), and shaken well.
  • the strain was isolated by a gradient dilution plating method using PYG medium (purchased from Huanqi Microbiology Technology Co., Ltd.).
  • the obtained pure culture strain was cultured to a concentration of about 10 9 cfu/ml, and 400 ul of the bacterial solution was added to add 40% glycerol to 400 ul to achieve a glycerol concentration of 20%, and then subjected to -80 ° C cryopreservation.
  • the genomic DNA of the isolated strain was extracted and PCR amplified using 16S rDNA universal primers.
  • the primer sequences were 27f (5'-AGAGTTTGATCATGGCTCAG-3' (SEQ ID NO.: 2) and 1492r (5'-TAGGGTTACCTTGTTACGACTT-3' ( SEQ ID NO.: 3)), the amplification system is: 10 ⁇ PCR buffer, 3 uL; dNTP, 2.5 uL; 27F, 0.5 uL; 1492R, 0.5 uL; Taq enzyme, 0.3 uL; genomic template, 1 uL; ddH2O, 18.2 uL.
  • the PCR amplification conditions were: pre-denaturation at 95 ° C for 4 min, followed by 30 cycles, including denaturation at 95 ° C for 30 s, annealing at 57 ° C for 40 s, extension at 72 ° C for 1 min 30 s.
  • the obtained 16S rDNA amplification products were detected by electrophoresis, purified, 3730 sequencing, obtaining a 1625 rDNA sequence of length 1425 bp (SEQ ID NO.: 1), and aligning the 16S rNDA sequence of AM25-6 in the EzBioCloud database ( http://www.ezbiocloud.net/identify)
  • the most homologous to AM25-6 was Anaerofustis stercorihominis DSM 17244 (purchased from the German Collection of Cultures).
  • the isolated colonies of AM25-6 cultured in PYG medium for 72 hours were characterized by: light yellow, colony Smaller, needle-like, translucent, about 0.2 mm in diameter ( Figure 1).
  • the microscopic morphology of the cells of AM26-6 was found to be short rod-shaped, Gram-positive, non-spore-forming and flagella by Gram staining and spore flagella staining (Fig. 2).
  • the test results of catalase and oxidase were negative, and the utilization of carbon source by AM25-6 was detected by API 20A (Mérieux, France). The results are shown in Table 1, where + indicates a positive reaction and - indicates a negative reaction. , w represents a weak positive reaction.
  • the drug sensitivity paper method was used to test the sensitivity of AM25-6 to 20 common antibiotics. 100ul of the bacterial solution cultured to the log phase of AM25-6 was plated, and the antibiotic drug-sensitive tablets (purchased from Hangzhou microorganisms) were used. Reagent Co., Ltd.) was applied to the surface of the plate and cultured at 37 ° C for 48 hours to measure the size of the inhibition zone. The results are shown in Table 2.
  • SCFA short-chain fatty acids
  • organic acids include 3-methylbutyric acid, quinic acid, lactic acid, oxalic acid, malonic acid, benzoic acid, maleic acid, succinic acid, fufuic acid, malic acid, adipic acid, tartaric acid, shikimic acid, Citric acid, isocitric acid and L-ascorbic acid, standard for each SCFA and organic acid were purchased from Sigma.
  • the detection process is as follows:
  • the SCFA was tested by Agilent Meteorological Chromatograph (GC-7890B, Agilent) using HP-INNOWax (Cross-Linked PEG), 30m ⁇ 0.25mm ⁇ 0.25um capillary column.
  • the detector is a hydrogen flame ion detector, GC.
  • the parameters are set to column temperature: 180 ⁇ 200°C; gasification chamber temperature: 240°C; detection temperature: 210°C; injection volume: 2 ⁇ L; carrier gas flow rate: N 2 , 50mL/min; hydrogen flow rate: 50mL/min; air Flow rate: 600 ⁇ 700ml / min.
  • the organic acid was also detected by Agilent Meteorological Chromatograph (GC-7890B, Agilent).
  • the column was selected from 122-5532G DB-5ms (40m ⁇ 0.25mm ⁇ 0.25um), column temperature: 270 ⁇ 290°C; inlet temperature: 250 ° C; gas flow rate: 0.86 ml / min.
  • AM25-6 has the ability to produce acetic acid, butyric acid, isovaleric acid, benzoic acid and lactic acid, and can produce isobutyric acid, valeric acid, 3-methylbutyric acid, succinic acid, adipic acid and lemon in small amounts. acid.
  • the mouse model selected in this example is: a mouse model of ulcerative enteritis induced by DSS (Dextran Sulfate, Na), and the mice are continued to drink 0.15% DSS (sodium dextran sulfate).
  • DSS Dense Sulfate, Na
  • mice A total of 48 experimental mice were randomly divided into 4 groups, 12 in each group, including:
  • control group feeding with normal feed
  • AM25-6 treatment group - DSS modeling each mouse perfused with 0.2ml of AM25-6 bacteria solution;
  • VSL # 3 treatment group - DSS modeling each mouse was given 0.2ml VSL # 3 per day (purchased from Alfasigma, USA, clinically used for the treatment of probiotics for UC);
  • the treatment process of AM25-6 was as follows: the AM25-6 bacterial solution was cultured for 24 hours, the cells were collected by centrifugation, suspended in PBS (phosphate buffer), and the concentration of the bacteria was adjusted to 109 cfu/ml, and each mouse was perfused with 200 ul per day. AM25-6. VSL # 3 was also suspended in PBS, and the concentration was adjusted to 10 9 cfu/ml, and each mouse was given 200 ul per day.
  • AM25-6 and VSL # 3 were administered in the first 3 days of DSS modeling.
  • DSS was added to the drinking water of mice, and UC was modeled by free drinking for 7 days.
  • the body weight, diet and drinking water were recorded daily.
  • the fecal traits and fecal occult blood of the mice were observed, and the disease activity index (DAI) of the mice was calculated on the first day, the third day, the fifth day, and the seventh day, respectively.
  • the DAI scoring standards are shown in Table 4.
  • the mice were sacrificed. All mice were bled, necked, colonic, photographed, weighed, and the length of the colon was measured. Colon tissue was stored in a -80 ° C refrigerator and paraformaldehyde.
  • Stool characteristics in the table normal stool - forming stool; loose stool - paste-like, semi-formed stool that does not adhere to the anus; loose stool - a thin watery stool that can adhere to the anus.
  • blood in the stool normal mice have positive blood in the stool; the blood in the naked eye is red or brown; the occult blood is positive in the blood of the naked eye, and the test is performed using tetramethylbenzidine.
  • the DAI index is equal to three points of weight loss, stool traits, and fecal occult blood. with.
  • mice The changes in body weight of mice before and after treatment are shown in Table 5 and Figure 3 below:
  • the intervention of the bacteria of the present invention can control the increase of DAI, and the DAI of the AM25-6 group was significantly controlled on the 5th day relative to the model group ( ⁇ P ⁇ 0.1), and on the 7th day AM25-6 and VSL
  • the DAI of the # 3 group of mice was also significantly lower than that of the model group ( ⁇ P ⁇ 0.05), and the DAI of the AM25-6 group was slightly lower than VSL # 3, indicating that AM25-6 is controlling the increase of DAI in UC mice.
  • the effect is comparable to VSL # 3, even slightly better than VSL # 3.
  • the colon tissue of the UC model mice changes, as the ulcer tissue and inflammation cause the colon tissue to shorten. After the end of the treatment, the colon length of the mouse is measured by anatomy as shown in Table 7.
  • Example 4 Food composition containing E. anaerobic bacteria Anaerofustis stercorihominis AM25-6
  • Example 5 Pharmaceutical composition containing E. anaerobic bacteria Anaerofustis stercorihominis AM25-6
  • the raw material ratio is shown in Table 9.
  • lactose, yeast powder and peptone are mixed uniformly with purified water, preheated to 60-65 ° C, homogenized at 20 Mpa, sterilized at 90 ° C for 20-30 minutes, cooled to 36-38 ° C, mixed with vitamin C, and connected.
  • Example 6 A method for preparing a medicament for treating an inflammation-related disease such as ulcerative enteritis (UC)
  • UC ulcerative enteritis
  • Preparation of drug or pharmaceutical dosage form 5 volumes (ml) of growth factor and 1 volume (ml) of a protective agent (such as vitamin C, cysteine) are added to 100 volumes (ml) of Anaerofustis stercorihominis AM25-6 fermented The bacterial solution is thoroughly stirred and mixed, and then a starch adjuvant such as maltodextrin is added to prepare a pharmaceutical or pharmaceutical dosage form containing Anaerofustis stercorihominis AM25-6.
  • a protective agent such as vitamin C, cysteine

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Abstract

L'invention concerne anaerofustis stercorihominis et ses applications. L'anaerofustis stercorihominis a pour effets de prévenir et/ou de traiter des maladies liées à une inflammation, telles que des maladies intestinales inflammatoires (telles que l'entérite ulcéreuse, la gastrite, et l'entérite générale) et la polyarthrite rhumatoïde.
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