CN106389478A - Applications of Bacteroides fragilis in treatment and/or prevention of obesity or diabetes mellitus - Google Patents
Applications of Bacteroides fragilis in treatment and/or prevention of obesity or diabetes mellitus Download PDFInfo
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- CN106389478A CN106389478A CN201510459406.0A CN201510459406A CN106389478A CN 106389478 A CN106389478 A CN 106389478A CN 201510459406 A CN201510459406 A CN 201510459406A CN 106389478 A CN106389478 A CN 106389478A
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- bacteroides fragilis
- diabetes
- obesity
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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
- A61K35/741—Probiotics
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention relates to applications of Bacteroides fragilis in treatment and/or prevention of obesity or diabetes mellitus, particularly to applications of Bacteroides fragilis in preparation of pharmaceutical compositions, foods, health products and food additives for treatment and/or prevention of obesity or diabetes mellitus, wherein the Bacteroides fragilis is ZY-312, is preserved in the China general microbiological culture collection center on April 2, 2015, and has the preservation number of CGMCC No.10685. According to the present invention, the Bacteroides fragilis provides good effects for treatment and/or prevention of obesity or diabetes mellitus, has characteristics of no drug resistance generation, safety, no toxicity, no enterotoxin gene bft and broad application prospects, and further has beneficial characteristics of cholate resistance, gastric acid resistance and the like compared with the existing strains.
Description
Technical field
The present invention relates to microorganism, medicine, health products, food and daily chemical products technical field, particularly
It is related to bacteroides fragilis treating and/or preventing the application in obesity or diabetes.
Background technology
Diabetes (Diabetes Mellitus) are a kind of metabolic diseases of multi-pathogenesis, are due to insulin
Secretion or effect produce defect and cause popularity dysbolism, caused disease.Diabetes are to continue
Property chronic hyperglycemia be the disease of principal character, and also result in vivo protein, fat, water, electrolyte
Etc. metabolism disorder.
The diabetes cause of disease is divided into inherent cause and environmental factor two aspect at present.Inherent cause：1 type or 2 types
All there is obvious genetic heterogeneity in diabetes.There is family morbidity tendency in diabetes, 1/4～1/2 patient
There is Diabetes family history.Clinically at least more than 60 kinds of genetic syndrome can be with diabetes.1 type
Diabetes have multiple DNA sites to participate in morbidity, wherein with DQ loci polymorphism relation in HLA antigen gene
The closest.Have been found that multiple clear and definite gene mutations in diabetes B, such as insulin gene, insulin
Acceptor gene, glucokinase gene, chondriogen etc..Environmental factor：Feed is excessive, physical exertion
Reducing the obesity leading to is the topmost environmental factor of diabetes B, makes with diabetes B inheritance susceptible
Property individual easily fall ill.There is immune system abnormality in type 1 diabetes patient, in some viruses such as COxsackie
Lead to autoimmune response after the infection such as virus, rubella virus, parotid gland virus, destroy insulin β cell.
Diabetes have become the third-largest NCD, the World Health Organization after angiocardiopathy and tumour
(WHO) predict：The year two thousand thirty whole world diabetic will exceed 3.6 hundred million, and wherein diabetes B accounts for 90
More than %.Diabetes B is Non-Insulin Dependent Diabetes Mellitus, be a kind of incidence of disease raise year by year common
Disease.
Clinically diabetes are largely divided into two classes：
First type：Insulin-dependent diabetes mellitus (Insulin-dependent diabetic mellitus,
IDDM), general age of onset is in the majority with less than 30 years old person, and therefore past attempts are referred to as " blue or green juvenile onset
Diabetes ", in fact any age all it may happen that.First patients with type Ⅰ DM is a kind of self immune system pair
The β cell of pancreas Lan Shi island (Islet of Langerhans) carries out attacking the autoimmunity disease destroyed
Sick (Autoimmune Disease).Virus infection in reason and personal gene genetic, environmental factor,
Or toxicant destroys the β cell of pancreas and autoimmunity forms antibody and the cellular immunity of anti-β cell
It is relevant that β cell is attacked in effect.Finally result in patient pancreas cannot normal secretions insulin, and easily occur
DKA, therefore needs insulin injection to treat.
Second-Type：Non-Insulin Dependent Diabetes Mellitus (non-insulin dependent diabetic
Mellitus, NIDDM), after mostly betiding 40 years old, patient mostly is build compared with overweight people, and the past claims
For " maturity-onset diabetes ", but also it may happen that in young man, being fallen ill with familial form relatively conventional, such
Patients with type Ⅰ DM accounts for more than the 95% of diabetes total number of people in Taiwan.Such patients with type Ⅰ DM is due to insulin
Hyposecretion, and caused by insulin resistance (insulin resistance)；Though there being some patientss
The secretion of insulin reduces, but the ability of Most patients excreting insulin is still, therefore, mostly leans on diet
Control and oral hypoglycaemic medicine controls blood sugar, without the treatment of insulin injection immediately.Additionally, patient is big
How can be with the symptom of insulin resistance (insulin resistance).The formation of insulin resistance
Mainly because of β cell transition ground excreting insulin (hyperinsulinamia) of pancreas Lan Shi island,
Cause the sensitiveness (insulin to insulin for the perienchymas such as skeletal muscle, adipose tissue and liver
Sensitivity) reduce.Thus reduce the utilization rate to glucose for the tissue, and cause showing of hyperglycaemia
As.This type course advancement is slow, therefore, has no typical diabetic symptom in early days, is difficult to discover.But often
With the big blood vessel of diabetic keratopathy (as miocardial infarction, headstroke), thin vessels (as kidney, eye nethike embrane and god
Through pathology) etc. chronic complicating diseases.
Additionally, being often accompanied with the situation of abnormalities of sugar/lipid metabolism with Second-Type diabetic patients, such as blood plasma
Middle triglyceride (triglyceride, TG) concentration rises, HDL-C (HDL-C)
Concentration declines and LDL-C (LDL-C) concentration rises.These symptoms can lead to second
The risk of diabetes mellitus type angiocardiopathy.Pointed out according to research, the liver blood fat of severe diabetes mellitus patient
Value Scavenging activity can decline.When in liver, triglyceride and LDL-C are constantly accumulated
Afterwards, liver cell will occur pathology to form NASH and then have a strong impact on liver function.
Currently used for the mode for the treatment of diabetes, except can separately be divided into non-drug therapy and medicine in addition to administration of insulin
Thing treats two kinds.In terms of non-drug therapy, mainly to be controlled by way of diet regulation and control and motion
Treat.And in drug treatment, main purpose is that the insulin making deficiency rises, downgrades the high blood after feed
Sugar and improve insulin resistance etc..Medicine currently used for treatment diabetes can be divided into：
(1) sulphonyl urea class (Sulfonylurea)：Such medicine main mechanism is to promote pancreas
The secretion of insulin, particularly strengthening pancreatic beta cell stimulates and the effect of uelralante to glucose；Often
Sulphonyl urea class hypoglycemic drug is You Erkang (glibenclamide, trade name：Euglucon),
Gram pyrrole thiophene (glipizide, trade name：Minidiab) and Mount Tai honey cron (gliclazide, trade name：
diamicron).However, such medicine is except the side effect having been found that, such as fash, scratch where it itches outer, its
Subject also has its limitation, if any serious Liver and kidney function obstacle person, pregnant woman and lactation person, to sulphonyl
Urea class medicine occurs severe allergy, and person all should not use this kind of hypoglycemic drug.
(2) alpha-glucosidase (α-Glucosidase) inhibitor：Such medicine main mechanism
For suppression pancreas AMS (α-amylase) and enteral alpha-glucosidase (α-glucosidase)
Activity, and then suppress carbohydrate in the decomposition of enteron aisle and absorption, such medicine can be effectively reduced meal
Blood sugar and insulin concentration afterwards, but side effect is abdominal distension or suffers from diarrhoea once in a while, suffers from abdominal pain and exert one's utmost effort.
(3) thiazolidinediones (Thiazolidinedione) derivative：Such medicine primarily serves the purpose of
Increase nucleus endoperoxides corpusculum hyperplasia activated receptor-γ (peroxisome
Proliferator-activated receptor (PPAR)-gamma) activity, and then strengthen pancreas islet
The effect of element, makes glucose inside cells transfer protein GLUT2 and GLUT4 increase, by glucose transport to thin
Intracellular utilizes.Clinically often using troglitazone (troglitazone, trade name：Rezulin), sieve
Lattice row ketone (rosiglitazone, trade name：Avandia), Pioglitazone (pioglitazone, business
The name of an article：Actos) etc.；But it should be noted that troglitazone (troglitazone) once caused cause
The hepatotoxicity wind agitation of life, therefore, the listing in Britain is just prohibited from using for latter two months.Additionally, thiazolidinediones
(Thiazolidinedione) the derivative Ye Zao U.S. orders to reclaim comprehensively and disable.
(4) biguanides (Biguanides)：Biguanides are the derivative of guanidine (guanidine),
At present, biguanides hypoglycemic drug is how based on metformin.Such medicine itself will not stimulate pancreas islet
The secretion of element, it controls blood sugar mechanism of action to be at following 5 points：A. appetite-suppressing, is therefore preferentially used in
With fat Second-Type diabetes patient so as to feed reduce, Body weight loss and improve insulin effect,
B. delay intestinal absorption glucose, c. to promote glucose in the anaerobic decomposition of enteron aisle, and then increase
Utilization in enteron aisle for the glucose, but excessive lactate (lactate) may be produced, easily cause breast
The effect in liver for the insulin, the therefore gluconeogenesis effect of suppression liver are strengthened in acid poisoning, d., subtract
Few glucose disengages from liver, e. promotes to be stored in intracellular suction pressure Protein G LUT4 to cell
Surface, to participate in transportation work, makes the suction pressure protein content of cell surface dramatically increase.Additionally, it is this kind of
The side effect of hypoglycemic drug, takes as before and may have the discomfort of intestines and stomach, such as apocleisis, Nausea and vomiting or abdomen
Rush down, a few peoples all might have inactivation phenomenon after being likely to occur fash, and Long-Time Service occurs.
As described above, up to the present, existing multiple researchs and make great efforts to develop treatment or prevention obesity and
The medicine of diabetes, but result is also less than satisfactory.Above-mentioned multiple chemical substances have been developed that as treatment
Obesity and the medicine of diabetes, but have side effect.These medicines make body fat and valuable protein
Run off together.As a result, any medicine is not had can individually to treat or suppression obesity and diabetes from source.
Bacteroides fragilis (Bacteroides fragilis) be a kind of Gram-negative, shaft-like, two
End blunt circle and dense dye, have pod membrane, no brood cell, motorless obligate anaerobes, its be divided into product enterotoxin type
With non-product enterotoxin type.Bacteroides fragilis, as the part of people and animal intestinal normal flora, is mainly stored in
In colon, additionally, respiratory tract intestines and stomach and urogenital tract also can be colonized growth.At present, research is more
Be bacteroides fragilis as a kind of conditioned pathogen, when host mucosal is impaired, submucosa can be invaded, draw
Play infection, also can cause its organ of body such as enteron aisle, abdominal cavity, liver, lung, brain tissue through blood flow
Pyogenic infection simultaneously occurs together abscess and causes the symptoms such as acute and chronic diarrhea；Additionally, bacteroides fragilis is to colon, straight
The generation of intestinal cancer also has facilitation.
This area has carried out numerous studies to bacteroides fragilis.For example, from well-developed baby or low
Isolate a kind of bacteroid bacterial strain BF839 in age animal intestinal, can increase after being made into active bacteria formulation
Child grows, to tools such as preventing and treating acute chronic enteritis, flora imbalance, the infection of the upper respiratory tract and neurosiss
There is good therapeutic effect (referring to Application No. " 90102847.9 ", entitled " one plant of beneficial bacterial strain and its application "
Chinese invention patent application；Zhang Jijie, etc. the clinical application research of bacteroides fragilis (BF839) bacterium solution.
Products in China magazine, nineteen ninety-five, volume 8, the 2nd phase, the 63-65 page)).
For another example, Application No. " 201310095126.7 ", entitled " have the fragile plan of probiotic properties
Bacillus "；Application No. " 201310085744.3 ", entitled " bacteroides fragilis is acute in preparation treatment
Application in radiation enteritis composition "；Application No. " 201310085716.1 " is entitled " fragile
Disclosed in the Chinese invention patent application of application in preparation treatment IBD composition for the bacteroid "
Bacteroides fragilis, was to isolate a kind of fragile plan with probiotic properties from infant faeces in 2012
Bacillus strain (deposit number is CGMCC NO.7280), can be used for treating IBD, diarrhoea etc..
Additionally, by the identification further to this bacterial strain, finding this bacterial strain (Bd312) in ne ar, culture
Characteristic, biochemical reactions result are similar to bacteroides fragilis, through BLASTN sequence alignment, separated bacterium
Strain and bacteroides fragilis type strain ATCC25285 homology reach 99%, and drug sensitive experiment is pointed out, bacterial strain Bd312
Insensitive to Cefradine, Amoxicillin, gentamicin, sulfalene uh azoles, TMP, acute and chronic poison
Property test prompting non-toxic (Liu Yangyang, etc. the separation of the nontoxic bacteroides fragilis in healthy babies body and mirror
Fixed. Chinese Medical Journal, 2014, volume 94, the 30th phase, the 2372-2374 page).However,
There is presently no the document record with regard to treating obesity and diabetes and its complication using bacteroides fragilis.
Content of the invention
The technical problem to be solved be provide a kind of bacteroides fragilis bacterial strain and its treatment and/or
Application in prevention obesity or diabetes.
To achieve these goals, the invention provides bacteroides fragilis treat and/or prevention obesity or
Application in diabetes.
Above-mentioned bacteroides fragilis application, wherein, described bacteroides fragilis is bacteroides fragilis ZY-312,
Preserving number is CGMCC No.10685.
In order to above-mentioned purpose is better achieved, present invention also offers a kind of be used for treatment and/or pre- preventing obesity
Disease or the pharmaceutical composition of diabetes, wherein, described pharmaceutical composition includes the fragile plan of pharmacy effective dose
Bacillus ZY-312 and pharmaceutically acceptable carrier, described bacteroides fragilis ZY-312 preserving number is CGMCC
No.10685.
Above-mentioned pharmaceutical composition, wherein, described pharmaceutical composition is tablet, capsule, oral liquid or jelly
Dry powder doses.
Above-mentioned pharmaceutical composition, wherein, described pharmaceutically acceptable carrier is defatted milk, lactose, Portugal
Grape sugar, sucrose, D-sorbite, mannose, trehalose, starch, Arabic gum, calcium phosphate, alginates,
Gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl are fine
One of dimension element, methyl hydroxybenzoate, nipasol, talcum, magnesium stearate or mineral oil
Or many of composition.
In order to above-mentioned purpose is better achieved, present invention also offers a kind of be used for treatment and/or pre- preventing obesity
Disease or the food of diabetes, wherein, described food contains the fragile plan that preserving number is CGMCC No.10685
Bacillus ZY-312.
In order to above-mentioned purpose is better achieved, present invention also offers a kind of be used for treatment and/or pre- preventing obesity
Disease or the health products of diabetes, wherein, it is the crisp of CGMCC No.10685 that described health products contain preserving number
Weak bacteroid ZY-312.
In order to above-mentioned purpose is better achieved, present invention also offers a kind of be used for treatment and/or pre- preventing obesity
Disease or the food additives of diabetes, wherein, it is CGMCC that described food additives contain preserving number
The bacteroides fragilis ZY-312 of No.10685.
The method have technical effect that：
The present invention passes through experiment to be proved for the first time, and bacteroides fragilis ZY-312 is for treatment and/or pre- preventing obesity
Disease or diabetes have good effect, do not produce drug resistance, and safety non-toxic, for treating and/or preventing
Obesity or diabetes provide new selection.Additionally, the bacteroides fragilis ZY-312 of the present invention is one plant
New bacteroides fragilis, this bacterial strain isolates and purifies from well-developed infant faeces and obtains, and is to have
The bacteroides fragilis new strains of probiotic properties, experiment shows the separated bacteroides fragilis ZY-312 arriving not
Bft containing enterotoxin genes (Bacteroides fragilis toxin), compared with existing bacterial strain, has
The probiotic properties such as bile tolerance, stomach juice-resistant, have broad application prospects.
Describe the present invention below in conjunction with the drawings and specific embodiments, but not as to the present invention's
Limit.
Brief description
Fig. 1 is colonial morphology figure after the bacteroides fragilis ZY-312 Anaerobic culturel of the present invention；
Fig. 2 is bacteroides fragilis ZY-312 gram stain microscopy figure (1000 ×) of the present invention；
Fig. 3 is bacteroides fragilis ZY-312 scanning electron microscopic observation figure (30000 ×) of the present invention；
Fig. 4 is the PCR primer Gel electrophoresis results comparison diagram of the present invention；
Fig. 5 is the PCR primer Gel electrophoresis results comparison diagram of the present invention；
Fig. 6 is the phylogenetic tree comparing foundation according to whole genome sequence；
Fig. 7 be the present invention test during mouse average blood sugar situation of change comparison diagram；
Fig. 8 is the 1st week sugar tolerance experimental comparison figure of the present invention；
Fig. 9 is the 7th week sugar tolerance experimental comparison figure of the present invention；
Figure 10 be the present invention test during Mouse Weight change comparison diagram.
The bacteroides fragilis (Bacteroides fragilis) of the present invention, is named as ZY-312, in 2015
On April 2, in is preserved in China General Microbiological culture presevation administrative center (CGMCC), its deposit number
For CGMCC No.10685, preservation address is Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3.
Specific embodiment
Below in conjunction with the accompanying drawings the structural principle and operation principle of the present invention is described in detail：
Embodiments of the present invention include：The present invention is by sieving to the excrement being derived from healthy babies in a large number
Choosing, filters out a large amount of bacteroides fragilis bacterial strains, is identified by physical and chemical experiment it was found that a kind of new fragility is intended
Bacillus (Bacteroides fragilis), is named as ZY-312 it turned out that not containing enterotoxin genes bft
(Bacteroides fragilis toxin), is one plant of avirulent strain, by fermentation culture, dyeing microscopic examination
And Analysis of The Physiological And Biochemical Properties and zoopery find：Compared with existing bacteroides fragilis bacterial strain, it has
The probiotic properties such as prominent bile tolerance, stomach juice-resistant, can make up some defects of original probio, in digestion
Road containing remaining in that under cholate, acid condition compared with high bioactivity, can effectively overcome and existing fragile intend bar
The shortcomings of bacterium easily inactivates in alimentary canal, and can effectively treat and/or prevent obesity or diabetes,
It is the preferred strain of probiotic composition.This bacteroides fragilis (Bacteroides fragilis) ZY-312
It is preserved in China General Microbiological culture presevation administrative center (CGMCC) on April 2nd, 2015, its guarantor
Hiding numbering is CGMCC No.10685, and preservation address is Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3.
Pharmaceutical composition can be prepared into using bacteroides fragilis ZY-312.This pharmaceutical composition includes pharmacy
The bacteroides fragilis ZY-312 of effective dose and pharmaceutically acceptable carrier, described bacteroides fragilis
ZY-312 preserving number is CGMCC No.10685.Described pharmaceutical composition is tablet, capsule, oral liquid
Or freeze dried powder.Described pharmaceutically acceptable carrier is defatted milk, lactose, glucose, sucrose, sorb
Sugar alcohol, mannose, trehalose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates,
Fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, hydroxy benzenes first
One of sour methyl esters, nipasol, talcum, magnesium stearate or mineral oil or many of combination
Thing.
The bacteroides fragilis ZY-312 of the present invention can also make food, health products or food additives etc..
Described food, the health products or food additives fragile plan bar for CGMCC No.10685 all containing preserving number
Bacterium ZY-312.These food, health products or food additives be used equally to treat and/or prevent obesity or
Diabetes.
Below in conjunction with specific embodiment, the invention will be further described.It is pointed out that by the present invention
In the bacteroides fragilis for treating and/or preventing obesity or diabetes or containing the present invention fragility plan
The pharmaceutical composition of bacillus, food, health products and food additives, after being applied to experimenter, can be answered
For indication mentioned above and show function described above, all formulations within the scope of the present invention
All test, hereinafter, only for illustrating, only describe wherein one small part in an embodiment, but
Should not be construed as limitation of the present invention.
Unless specifically indicated, otherwise the reagent used in the present invention is all commercially available commercially available.
Embodiment 1
The separation of bacteroides fragilis ZY-312, purifying
Reagent and instrument
(1) culture medium A：(the rich biotechnology in Qingdao sea has bacteroid-bile-aesculin (BBE) agar
Limit company, article No.：HB7028 improved formulations, concrete composition such as table 1 below are added on the basis of)：
Table 1 is cultivated and composition
(2) culture medium B：(the rich biotechnology in Qingdao sea has bacteroid-bile-aesculin (BBE) agar
Limit company, article No.：HB7028 improved formulations, concrete composition such as table 2 below are added on the basis of)：
Table 2 is cultivated and composition
(3) culture medium C：Brucella broth (Qingdao Hai Bo bio tech ltd, article No.：HB0241)
Middle addition hyclone, addition is 5% (v/v) (Zhejiang Tian Hang biotech inc, product
Board：Chinese holly, article No.：HB0205).
(4) laboratory apparatus
2.5L sealing culture tank (Mitsubishi Gas Chemical Co., Ltd, C-31)
Constant incubator (Shanghai Yiheng Scientific Instruments Co., Ltd, model：DHP-9082)
Microscope (Nikon instrument (Shanghai) Co., Ltd., model：E100)
PCR instrument (Thermo Fischer Scient Inc., model：AppliedPCR
System 9700)
Electrophoresis apparatus (Beijing Liuyi Instrument Factory, model：DYCP-32B)
(5) reagent
Anaerobic gas generation bag (Mitsubishi Gas Chemical Co., Ltd, article No.：C-1)
DNA of bacteria extracts kit (Bacterial DNA Kit (DNA of bacteria extracts kit) OMEGA,
Article No.：D3350-01)
Taq enzyme (bioengineering (Dalian) Co., Ltd, article No.：DR100A)
Agarose (brand：Biowest, article No.：91622)
Sulfamethoxazole (Sigma-Aldrich (sigma), article No.：S7507-10G)
TMP (Sigma-Aldrich (sigma), article No.：T7883-5G)
Vitamin K1 (Qingdao day aquatic organism Science and Technology Ltd., article No.：21005)
DL1000 DNA Marker (precious bioengineering (Dalian) Co., Ltd, article No.：D526A)
Bacteroides fragilis produces enterotoxin strain, and (Gastroenterology dept. of Nanfang Hospital teacher Sun Yong provides, and is isolatable from clinical diarrhoea
Patient)
Bacteroides fragilis type strain ATCC25285 (purchased from Guangdong Microbes Inst)
(preserving number is CGMCC No.7280 to bacteroides fragilis bacterial strain Bd312, knows photo-biological science and technology by Guangzhou
Co., Ltd provides)
BF839 bacterial strain (is isolatable from the prebiotic liquid of totem).
(6) culture medium configuration
Culture medium A configures：Weigh 61.5 grams of BBE culture medium, heating for dissolving in 1000mL distilled water,
121 DEG C of autoclavings 15 minutes, when being cooled to 50 DEG C about, add filtration sterilization sulfalene uh azoles 1g,
TMP 4g and aseptic de-fiber sheep blood 50mL, mix, are poured into sterilized petri dishes, standby.
Culture medium B configures：Weigh 61.5 grams of BBE culture medium, heating for dissolving in 1000mL distilled water,
121 DEG C of autoclavings 15 minutes, when being cooled to 50 DEG C about, add filtration sterilization sulfalene uh azoles 1g,
TMP 4g, mixes, is poured into sterilized petri dishes, standby.
Culture medium C configures：Weigh brucella broth culture medium 28.1g, heating stirring is dissolved in 1000mL and steams
In distilled water, dispense triangular flask, 121 DEG C of autoclavings 15 minutes, standby.Using front, add 5% tire
Cow's serum.
Brucella broth configures：Weigh brucella broth culture medium 28.1g, heating stirring is dissolved in 1000mL and steams
In distilled water, dispense triangular flask, 121 DEG C of autoclavings 15 minutes, standby.
Method：
1st, isolate and purify
Take fresh infant faeces 0.5g, be placed in the triangular flask filling 4.5mL brucella broth, vibrate 1
Minute.Take 0.1mL to drip on brucella broth culture medium, after line, be placed in anaerobic jar, 37 DEG C, culture
48 hours.Picking colonies typical, in fluid nutrient medium 24h, carries out Gram's staining.Basis of microscopic observation shape
State, chooses the bacterium solution of Gram-negative bacteria, streak inoculation is in blood plate, Anaerobic culturel 48h.According to flat board
The dyeing property of upper colony morphology characteristic and Microscopic observation thalline, size, club shape and distribution situation, judge
Whether purify.As bacterium is impure, then continue above step, repeated multiple times separation is passed on, until being purified
Bacterial strain.
2nd, colony characteristicses
After bacteroides fragilis ZY-312 cultivates 48h on blood plate, assume circular dimpling, translucent, white
Color, smooth surface, not haemolysis, colony diameter in 1-3mm, referring to Fig. 1.
3rd, form under microscope
Bacteroides fragilis ZY-312 carries out gram stain microscopy, is gram-negative bacteria, presents typical
Shaft-like, two ends blunt circle and dense dye, not colored part shape such as cavity in the middle of thalline, referring to Fig. 2.
4th, form under Electronic Speculum
Fixer is fixed, scanning electron microscopic observation.Visible under mirror, bacteroides fragilis ZY-312 size 0.5～
0.8 × 1～4.5 μm, atrichia, no gemma, referring to Fig. 3.
5th, biochemical identification
Biochemical identification result such as table 3 below (in table ,+represent positive ,-represent negative)
Table 3 biochemical identification result
| Measure reaction substrate | Result |
| Tryptophan | - |
| Urea element | - |
| Glucose | + |
| Mannitol | - |
| Lactose | + |
| Sucrose | + |
| Maltose | + |
| Salicin | - |
| Wood sugar | + |
| Arabinose | - |
| Gelatin | - |
| Aesculin | + |
| Glycerine | - |
| Cellobiose | -/+ |
| Mannose | + |
| Pine three sugar | - |
| Gossypose | + |
| Sorbierite | - |
| Rhamnose | - |
| Trehalose | - |
API20A (biochemical reaction identification plate, French Biomerieux SA) biochemical reactions
Result shows：Bacteroides fragilis ZY-312 can glucose fermentation, lactose, sucrose, maltose, wood sugar,
Aesculin, mannose, gossypose, meet the feature of bacteroides fragilis.
Embodiment 2
Bacteroides fragilis ZY-312 identifies
PCR (PCR) primer (being synthesized by Invitrogen (Shanghai) trade Co., Ltd) sequence
Row are as follows：
Primer pair 1：
Forward primer：5’-ACGCTTGCACCCTCCGTATTA-3’
Reverse primer：5’-GCTTAGAGTTTGATCCTGGCTCAG-3’
Primer pair 2：
Forward primer：5’-TGGGTGGTTGCTGCCTGGACACA-3’
Reverse primer：5’-CATCCGGGTATGGATATGAA-3’
Primer pair 3：
Forward primer：5’-GATGCTCCAGTTACAGCTTCCATTG-3’
Reverse primer：5’-CGCCCAGTATATGACCTAGTTCGTG-3’
Bft gene primer pair：
Forward primer：5’-GACGGTGTATGTGATTTGTCTGAGAGA-3’
Reverse primer：5’-ATCCCTAAGATTTATTATCCCAAGTA-3’
1st, PCR identification (PCR is PCR, is the method for conventional rapid amplifying gene)
(1) 16S rRNA sequencing
Above-mentioned bacterial strains are taken to be inoculated in culture medium A, 37 DEG C, Anaerobic culturel 48h.Single bacterium is taken to be inoculated in liquid
In body culture medium, 37 DEG C, Anaerobic culturel 48h.DNA extraction kit extracts DNA of bacteria, and (Tiangeng is biochemical
Scientific and technological (Beijing) Co., Ltd, article No.：DP302-02), as pcr template DNA.
The amplification of 16S rRNA gene order：Primer pair 1 amplified fragments size is about 531bp；Primer pair 2
Amplified fragments size is 518bp；Primer pair 3 amplified fragments size is about 970bp.
Using 20 μ L PCR reaction systems：Taq enzyme 10 μ L, template DNA 2 μ L, Direct/Reverse primer
Each 1 μ L, aseptic deionized water 6 μ L.
PCR reaction condition is：95 DEG C of denaturations 5min, 95 DEG C of denaturation 30s, 55 DEG C of annealing 30s, 72 DEG C
Extend 45s, 30 circulations, 72 DEG C of extension 10min.
PCR primer carries out electrophoresis in 2% Ago-Gel, and deposition condition is 100V, 15min.
PCR primer Gel electrophoresis results are as shown in figure 4, wherein 1,2 swimming lanes are respectively primer pair 1, primer
To 2 amplified productions；4th, 5 swimming lanes are respectively primer pair 1, primer pair 2 amplified production (repeats the knot of PCR
Really)；3rd, 6 swimming lanes are primer pair 3 amplified production；7 swimming lanes are DNA molecular amount reference material (DL1000 DNA
marker).It is 531bp that isolated strains DNA enters primer size after performing PCR amplification using primer pair 1, adopts
Entering primer size after performing PCR amplification with primer pair 2 is 518bp, is entered after performing PCR amplification using primer pair 3
Primer size is 970bp, meets expection, and separated bacterial strain is bacteroides fragilis.
PCR primer is carried out nucleotide sequencing (surveyed by Shenzhen Huada Genetic Technology Co., Ltd
Fixed).Sequencing result is in the Genbank (DNA sequence data that American National Biotechnology Information center is set up
Storehouse) on carry out BLAST comparison (http：//www.ncbi.nlm.nih.gov/BLAST/), it is shown in Table 4.
Result shows to be separated to for one plant of bacteroides fragilis.
Table 4 16S rRNA sequence B LAST comparison result (part)
(2) PCR detection bft gene
Will the inoculation that screens of sequencing in culture medium C, 37 DEG C, Anaerobic culturel 48 hours.Take training
Bacteria liquid 2mL, extracts DNA with DNA of bacteria extracts kit, as pcr template DNA.Bft gene
Amplification adopts bft gene primer, and amplified fragments size should be 294bp.
Using 20 μ L PCR reaction systems：Taq enzyme 10 μ L, template DNA 2 μ L, each 1 μ L of upper and lower primer,
Aseptic deionized water 6 μ L.
PCR reaction condition is：95 DEG C of denaturations 5min, 95 DEG C of denaturation 30s, 55 DEG C annealing 30s, 72 DEG C
Extend 45s, totally 30 circulations, 72 DEG C of extension 10min.PCR primer carries out 2% agarose gel electrophoresis,
Deposition condition is 100V, 15min.
Result referring to Fig. 5, wherein 1,2,3,4 swimming lanes be ZY-312 isolated strains electrophoresis result；5、6、
7 is to produce enterotoxin strain bacteroides fragilis electrophoresis result；8 swimming lanes are DL1000 DNA marker.4th, 5 swimming
Road is bft gene primer to amplified production；1st, 7 swimming lanes are primer pair 2 amplified production；2nd, 6 is primer
To 1 amplified production；3 swimming lanes are primer pair 3 amplified production.
Result shows, ZY-312 is one plant of bacteroides fragilis, and does not contain enterotoxin bft gene, is one
The new avirulent strain of strain.
2nd, genome sequencing analyzes and identifies
Bacteroides fragilis ZY-312 is carried out with genome sequencing (Shenzhen Huada Genetic Technology Co., Ltd),
Sequencing result is mutually compared with the strain sequence delivered, (can be using treebest software
Freely download on sourceforge website
http：//treesoft.svn.sourceforge.net/viewrc/treesoft/) built using adjacent method
NJ-tree or using software PhyML adopt maximum likelihood method build maximum likelihood tree.Phylogenetic tree shows
(referring to Fig. 6), bacteroides fragilis ZY-312 and bacteroides fragilis type strain ATCC25285 is (i.e.
NCTC9343) in same branch, show that examining bacteroides fragilis ZY-312 is one plant of new bacteroides fragilis,
With ATCC25285 homology.
Virulence genes are carried out to genome sequencing result, to verify its whether base of bft containing toxin producing
Cause.Result shows, does not contain bft gene, be one plant and do not produce intestines in bacteroides fragilis ZY-312 full-length genome
The new bacteroides fragilis of toxin.
Embodiment 3
The tolerance to hydrochloric acid in gastric juice for the bacteroides fragilis ZY-312
1st, simulated gastric fluid is prepared (according to 2010《Chinese Pharmacopoeia》Simulated gastric fluid compound method)
The dense HCl of 23.4mL is dissolved in 100mL purified water, obtains final product watery hydrochloric acid.Take 8.2mL watery hydrochloric acid,
Add 400mL purified water and 5g pepsin (Pig source, 1: 15000), constant volume to 500mL.
In 37 DEG C, magnetic stirrer over night, obtain final product simulated gastric fluid.
2nd, thalline prepares
Collect bacterium solution, centrifugation, abandon supernatant, after physiological saline is resuspended, be centrifuged again, abandon supernatant, thalline is standby
With.
3rd, simulated gastric fluid is added to measure viable count
To thalline add simulated gastric fluid, resuspended, respectively measure 0,1,2,3h viable count.
Count plate adopts 10 times of serial dilutions：100 μ L bacterium solution are taken to add 900 μ L brucella broth trainings
In foster base, progressively gradient dilution is to suitable concn.Each 4 concentration gradient of flat board point, each gradient repeats
Point sample 3 times, each point sample 20 μ L.37 DEG C, Anaerobic culturel 48h, number clump count (takes clump count to be 3-30
Concentration gradient count).
Viable count (CFU/mL)=tri- point sample bacterium colony summation/3 × 50 × dilution factor
Table 5 different strains hydrochloric acid in gastric juice tolerance experimental results (data is viable bacteria concentration log value, and h is hour)
Probio has to enter into the intestines and stomach of human body and reaches its function of finite concentration competence exertion.From oral cavity to
During enteron aisle, probio must be possible to enter enteron aisle by stomach with viable bacteria state first.Food is (outstanding
It is fluid) 1-2h is generally by the time of stomach.According to the difference of dietary structure, the pH value of human gastric juice
Fluctuation is very big, generally in pH3.0 about, up to pH1.5, dietary alkali when empty stomach or edible acid food
Propepsin can be activated up to pH 4-5, this sour environment of gastric juice, thus killing during property food
Enter the bacterium in stomach with food.If probio will play prebiotic effect in human body, it is necessary for thering is one
Fixed acid-fast ability and resistance to pepsic ability.
Result shows (table 5), and compared with other bacterial strains of bacteroides fragilis, bacteroides fragilis ZY-312 exists
After 3h, viable bacteria concentration is still higher, and the viable bacteria concentration of other bacterial strains reduces quickly in time, and ZY-312 is described
To hydrochloric acid in gastric juice tolerance preferably, there is prebiotic potentiality and application prospect well.
Embodiment 4
Bacteroides fragilis ZY-312 is to cholate tolerance test
1st, experiment material
Pancreas peptone soybean broth (abbreviation TSB, brand：OXOID, article No.：CM0129B)
Tryptose soya agar (abbreviation TSA, brand：OXOID, article No.：CM0131B)
Bilein (precious bioengineering Shanghai (share) Co., Ltd, article No.：ON1210)
Hyclone (MP Biomedicais company of the U.S., article No.：2916754)
2nd, the preparation of bacterial strain and reagent
Courage powder solution：Add bilein in TSB, three final concentrations, (1% N of respectively 10g/L are set
Courage powder), 20g/L (2% bilein) and 40g/L (4% bilein).Add serum (dense eventually after sterilizing
Degree 50mL/L) stand-by.Meanwhile, to be not added with the TSB of courage powder as comparison.
Strain culturing and collection：Bacterial strain (ZY-312, Bd312, BF839, ATCC25285) in 37 DEG C,
Anaerobic liquid static culture, to logarithmic growth later stage (about 14-16 hour), dispenses to centrifuge tube, often manages
Packing 3ml bacterium solution, room temperature, 4000rpm are centrifuged 5 minutes.Wash 1 (room of bacterium with 0.01M PBS again
Temperature, 4000rpm are centrifuged 5 minutes), abandon supernatant, precipitation is stand-by.
3rd, cultivate in artificial courage powder culture medium
Will be resuspended for the bacterium after washing with above-mentioned courage powder solution, adjusting initial bacterial concentration with the solution of powder containing courage is
1×108CFU/mL.And in 37 DEG C, Anaerobic culturel 1,2,4 hours, coated plate counts viable count purpose and becomes
Change, number of bacteria is as comparison within 0 hour.Experiment is parallel to do 3 times.
4th, calculate bacteria resistant courage powder situation
By above three time point coated plate result, it is compared with corresponding 0 hour result, you can obtain bacterium
Strain acts on the result of its tolerance courage powder after different time in artificial courage powder solution, with mean ± standard deviation and system
Meter result explanation.
The table 6 SK08 bacterial strain powder of resistance to courage experimental result (n=3)
As shown in table 6,0-4h observes result, and ZY-312 all can be normal in 1%, 2%, 4% concentration courage powder
Growth, raises with courage powder concentration that its viable count is higher, and ZY-312 viable count is significantly higher than other bacterial strain groups.
Result shows ZY-312 tolerance cholate, and is significantly better than other bacterial strains.
Cholate is the sodium salt or sylvite that the bile acid of hepatocytes secrete is combined to form with glycine or taurine, it
It is that bile participates in digestion and the main component absorbing.After cholate is discharged to small intestine, major part is absorbed by small intestinal mucosa
Enter blood, reenter liver composition bile.In human small intestine, the mass concentration of cholate is 0.03～0.3g/100mL's
Scope fluctuates.
For living cells, cholate can destroy cell membrane, is therefore to evaluate probio to the tolerance of cholate
One of important indicator.Probio can produce bile salt hydrolase, and glycine and taurine can be combined by this enzyme
Cholate catalyzing hydrolysis are amino acid residue and free cholate.The bacterial strain with bile salt dissociation capability can reduce
The serum cholesterol level of high cholesterol crowd and the generation preventing normal person's hypercholesterolemia.In alimentary canal
The concentration of cholate is not changeless, the beginning 1h digesting on the feed, and its mass concentration is 15～20
G/L, afterwards its mass concentration be reduced to 3g/L.Probio must be during by stomach and intestine, Ke Yi
Survive under normal gallbladder salinity, such as will colonize in small intestine it is necessary to tolerate the inhibitory action of cholate.Therefore,
With respect to other bacterial strains of bacteroides fragilis, ZY-312 has more preferable application prospect.
Embodiment 5
Bacteroides fragilis ZY-312 acts on to obesity and diabetic mice
Experiment material
Db/db mouse (Nanjing Ai Ermaite bio tech ltd), glucose (1.6g/Kg), SPF
(three promises are biological to be passed for grade particles feed (Guangdong Province's Experimental Animal Center), stable blood glucose meter and test strip
Sense limited company).
Db/db mouse, by C57BL/KsJ inbred strain autosomal recessive inheritance derivation, belongs to II type
Diabetes model.Animal started voracity and gets fat when one month, then produced hyperglycaemia, high blood insulin,
Hyperglycemic factor also raises.General dead in 10 months.Db/db (C57BL/KsJ) mouse is Leptin
Acceptor point mutation leads to leptin signal path obstacle, thus lead to mouse occur obesity, insulin resistance,
The symptoms such as hyperglycaemia, fatty liver.Significantly fat and fasting blood is may occur in which within 6 weeks after the birth of db/db mouse
Sugar increases, and amount of drinking water, urine volume increase, and 8-12 is the most obvious when all, and may occur in which that diabetic nephropathy etc. is concurrent
Disease.Db/db mouse is frequently as obesity, diabetes B, fatty liver research model.
Bacteroides fragilis ZY-312 fermented and cultured：The ZY-312 of activation is inoculated in pancreas casein peptone soybean meat
In soup culture medium, Anaerobic culturel 12h at 37 DEG C.The using method of bacteroides fragilis ZY-312：To send out
Yeast-like fungi body be lyophilized, pulverize after obtain bacterium powder, be dissolved according to quantity in PBS before gavage, gavage mouse.
Experiment packet
Db/db mouse is randomly divided into 4 groups, every group 10,4 groups be respectively control group, low dose group,
Middle dose group, high dose group.
Experimentation and result
Daily to db/db mouse morning and evening gavage 2 times, mouse continuous gavage 7 weeks, daily mensure dietary amount,
Body weight.Shown in each group given low design table 7.
Table 7 given low designs
(1) mouse average blood sugar situation of change during testing
Mouse measures blood sugar after gavage on every Mondays, carries out tail vein blood to mouse, with blood glucose meter and blood sugar examination
Paper measures blood glucose value.
Referring to Fig. 7, Fig. 7 result shows, during test, control group mice blood sugar is stepped up, diabetes
Shape increases, gavage bacteroides fragilis ZY-312 each group, blood sugar do not continue raise, and in, low dosage
Group blood sugar downward trend substantially, has significant difference with control group.Show that bacteroides fragilis ZY-312 can
To reduce blood sugar, improve diabetic symptom.
(2) sugar tolerance experiment
The Sunday of the 1st, 7 weeks carries out sugar tolerance experiment：Water 14h is can't help in the fasting of evening Saturday, and the morning on Sunday surveys
Determine mouse fasting blood-glucose gastric infusion, after 30 minutes fill sugar and be designated as 0min, respectively at 10min, 20min,
30min, 60min, 120min carry out tail vein blood to mouse, measure blood with blood glucose meter and blood sugar test paper
Sugar value.
Referring to Fig. 8, Fig. 8 result shows, after 1 week, glucose load tests each group blood glucose value to mouse continuous gavage
Difference is inconspicuous, and during 120min, high dose group blood glucose value is substantially less than control group.
Referring to Fig. 9, Fig. 9 result shows, mouse continuous gavage is after 7 weeks, gavage bacteroides fragilis ZY-312
Each group fasting blood sugar is all substantially less than control group, and high dose group fasting blood sugar recovers normal.Sugar tolerance is real
During testing, gavage bacteroides fragilis ZY-312 each group blood glucose value is below control group, and has conspicuousness
Difference.
(3) Mouse Weight change during testing
Table 8 Mouse Weight is advanced the speed
Figure 10, table 8 result show, after testing 7 weeks, gavage bacteroides fragilis ZY-312 each group Mice Body
Weight average is substantially less than control group, reduces diabetic mice body weight increase speed, and body weight increase speed is less than comparison
Group, shows obesity symptom mitigation.
The present invention has good effect for treatment and/or prevention obesity or diabetes, does not produce resistance
Property, and safety non-toxic, for treating and/or preventing obesity or diabetes to provide new selection.Experiment table
The bacteroides fragilis ZY-312 of the bright present invention does not contain enterotoxin genes bft (Bacteroides fragilis
Toxin), compared with existing bacterial strain, there are the probiotic properties such as bile tolerance, stomach juice-resistant, there is wide answering
Use prospect.
Certainly, the present invention also can have other various embodiments, in the feelings spiritual and its substantive without departing substantially from the present invention
Under condition, those of ordinary skill in the art work as and can make various corresponding changes and deformation according to the present invention, but
These change accordingly and deform the protection domain that all should belong to appended claims of the invention.
Claims (8)
1. bacteroides fragilis is being treated and/or is preventing the application in obesity or diabetes.
2. bacteroides fragilis as claimed in claim 1 application is it is characterised in that described bacteroides fragilis
For bacteroides fragilis ZY-312, preserving number is CGMCC No.10685.
3. a kind of pharmaceutical composition for treating and/or preventing obesity or diabetes it is characterised in that
Described pharmaceutical composition includes the bacteroides fragilis ZY-312 of pharmacy effective dose and pharmaceutically acceptable load
Body, described bacteroides fragilis ZY-312 preserving number is CGMCC No.10685.
4. pharmaceutical composition as claimed in claim 3 is it is characterised in that described pharmaceutical composition is piece
Agent, capsule, oral liquid or freeze dried powder.
5. the pharmaceutical composition as described in claim 3 or 4 is it is characterised in that described pharmaceutically can connect
The carrier being subject to be defatted milk, lactose, glucose, sucrose, D-sorbite, mannose, trehalose, starch,
Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone,
Cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum,
One of magnesium stearate or mineral oil or many of composition.
6. a kind of food for treating and/or preventing obesity or diabetes is it is characterised in that described food
Product contain the bacteroides fragilis ZY-312 that preserving number is CGMCC No.10685.
7. a kind of health products for treating and/or preventing obesity or diabetes are it is characterised in that described
Health products contain the bacteroides fragilis ZY-312 that preserving number is CGMCC No.10685.
8. a kind of food additives for treating and/or preventing obesity or diabetes it is characterised in that
Described food additives contain the bacteroides fragilis ZY-312 that preserving number is CGMCC No.10685.
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| CN105434476A (en) * | 2015-10-29 | 2016-03-30 | 广州知易生物科技有限公司 | Application of bacteroides fragilis to prevention and/or treatment of inflammatory bowel diseases (IBDs) |
| TWI640313B (en) * | 2017-08-18 | 2018-11-11 | 長庚生物科技股份有限公司 | Anti-obesity properties of parabacteroides goldsteinii |
| CN110870876A (en) * | 2018-09-04 | 2020-03-10 | 星聚樊生物科技有限公司 | Parabacteroides gomerdae and use thereof for preparing composition for preventing or treating obesity |
| CN111714522A (en) * | 2019-03-04 | 2020-09-29 | 中国科学院微生物研究所 | Bacteroides and application thereof |
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| CN101125151A (en) * | 2006-08-16 | 2008-02-20 | 大连森佰澳科技有限公司 | Bacteroides signal molecule microecological preparation and its preparation method |
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| CN102947441A (en) * | 2010-06-01 | 2013-02-27 | 穆尔研究企业有限责任公司 | Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105434476A (en) * | 2015-10-29 | 2016-03-30 | 广州知易生物科技有限公司 | Application of bacteroides fragilis to prevention and/or treatment of inflammatory bowel diseases (IBDs) |
| CN105434476B (en) * | 2015-10-29 | 2019-02-15 | 广州知易生物科技有限公司 | A kind of application of bacteroides fragilis in prevention and or treatment inflammation enteropathy |
| TWI640313B (en) * | 2017-08-18 | 2018-11-11 | 長庚生物科技股份有限公司 | Anti-obesity properties of parabacteroides goldsteinii |
| CN110870876A (en) * | 2018-09-04 | 2020-03-10 | 星聚樊生物科技有限公司 | Parabacteroides gomerdae and use thereof for preparing composition for preventing or treating obesity |
| CN110870876B (en) * | 2018-09-04 | 2021-08-20 | 星聚樊生物科技有限公司 | Parabacteroides gomerdae and use thereof for preparing composition for preventing or treating obesity |
| CN111714522A (en) * | 2019-03-04 | 2020-09-29 | 中国科学院微生物研究所 | Bacteroides and application thereof |
| CN111714522B (en) * | 2019-03-04 | 2022-07-15 | 中国科学院微生物研究所 | Bacteroides and application thereof |
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