CN104546933A - Application of bacteroides caccae in treatment or prevention of rheumatoid arthritis or related diseases thereof - Google Patents
Application of bacteroides caccae in treatment or prevention of rheumatoid arthritis or related diseases thereof Download PDFInfo
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Abstract
The invention provides an application of bacteroides caccae in treatment or prevention of rheumatoid arthritis or related diseases thereof, and also provides bacteroides caccae containing pharmaceutical compositions, medicaments, foods and feeds. By providing bacteroides caccae for animals, an anti-inflammatory effect can be effectively played, the symptoms such as redness and swelling of joints are effectively improved, and the symptoms of arthritis are obviously relieved, and therefore, the bacteroides caccae can be effectively used for treating or preventing rheumatoid arthritis or related diseases thereof.
Description
Technical field
The present invention relates to microbiological art, particularly, relate to the purposes of excrement bacteroid in treatment or prevention rheumatoid arthritis or its relevant disease, also relate to the pharmaceutical composition, medicine, the food and feed that comprise excrement bacteroid.
Background technology
Rheumatoid arthritis (rheumatoid arthritis, RA) is called for short rheumatoid disease, is a kind of systemic autoimmune disease, mainly involves synovium of joint, is secondly the connective tissues such as serous coat, the heart, lung, blood vessel, nerve.Acute phase inflammatory main manifestations is synovial membrane angioedema, synovitis, if not by timely Diagnosis and Treat, acute inflammatory reaction disappears, and oozes out and absorbs gradually, and synovial membrane medium vessels screen is formed, the remarkable hyperplasia of synovial cell.Then articular cartilage damage is caused, bone tissue inflammation, necrosis and fibrous connective tissue hyperplasia.Calcification then occurs and occurs fibroid and bone arthrosclerosis, articular cavity is significantly narrow or disappear completely.The joint function disturbance that this phase chronic inflammation processes causes, is difficult to a great extent recover, can causes permanent disability.Just have 1 people to suffer from RA in every 100 ~ 150 people in the whole world, China's illness rate is 0.32% ~ 0.36%.RA all can fall ill at each age, was mainly in female middle-aged in adult, and the ratio of men and women is about 1:3.Within 2003, according to WHO, under good medical condition, medical expense is for each person every year about 6000 dollars, and the indirect loss caused by this disease also can not be ignored.
At present, doctor trained in Western medicine mainly adopts the method such as drug therapy and gene therapy.Conventional Western medicine mainly contains NSAIDs (NSAIDs), glucocorticoid, makes medication, immunodepressant and biologic product etc. slowly.But price is high, toxic and side effect is larger shortcoming that Western medicine generally has, so limit their application.The selective height of gene therapy, it can be treated from molecular level for disease, simultaneously can by the long-term high-level local expression of repressor gene, and the treatment for RA patient opens new approach.But current gene therapy is also in the starting stage, still there is more problem.As lacked desirable carrier, different hosts produces different immune responses to carrier, whether the gene of importing stably express etc. can all need further research and inquirement in body.In addition, the security of gene therapy, medical expense and ethnics Problem etc. are also the problems that this research needs to solve.
Evidence suggests, enteric microorganism and systemic immunity are replied and RA exists certain contacting.Lactic acid bacteria (lactic acid bacteria, LAB) can reduce pro-inflammatory cytokines level under the prerequisite not affecting regulating cell cytokines level, thus plays antiinflammatory action, alleviates RA symptom.Therefore can inferring, some treatment means that intestinal microecology is returned to normal, while recovery enteron aisle and function of immune system, also may play certain effect to alleviating RA symptom.Research confirms, a kind of LAB (Bacillus coagulans GBI-30,6086) may become a kind of ancillary drug alleviating RA symptom safely and efficiently
Because cause and onset of disease mechanism is not yet completely clear, though the treatment of RA obtains certain progress, be still in control or relief of symptoms stage so far, there is no effectively treatment or cure method.Therefore this area is a kind of effectively new in the urgent need to developing, and has no side effect, is used for the treatment of and prevents the medicine of rheumatoid arthritis and relevant disease thereof.
Summary of the invention
The present invention is intended to solve one of technical problem in correlation technique at least to a certain extent.For this reason, one object of the present invention is to propose the purposes of excrement bacteroid in treatment or prevention rheumatoid arthritis or its relevant disease.
In a first aspect of the present invention, the invention provides excrement bacteroid and preparing the purposes in medicine, described medicine is used for the treatment of or prevents rheumatoid arthritis or its relevant disease.Inventor finds, by providing this medicine to animal, effectively can play effect of anti-inflammatory, the symptom of joint redness and swelling is effectively improved, and arthritic symptom obviously alleviates, and namely can effectively treat or prevent rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
In a second aspect of the present invention, the invention provides a kind of pharmaceutical composition.According to embodiments of the invention, this pharmaceutical composition comprises: excrement bacteroid; And pharmaceutically acceptable auxiliary material.Inventor surprisingly finds, by providing this pharmaceutical composition to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, arthritic symptom obviously alleviates, animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this pharmaceutical composition.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/g, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/mL.Thus, suppress arthritis to occur and improve the successful of arthritic symptom, if excrement bacteroid content is too low, the effect for the treatment of or prevention rheumatoid arthritis is undesirable, if excrement bacteroid too high levels, then treatment or prevention rheumatoid arthritis effect without significantly improving, cause waste.
According to a preferred embodiment of the present invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/g, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/mL.
According to a further advantageous embodiment of the invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
According to embodiments of the invention, described pharmaceutically acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices.
According to embodiments of the invention, described pharmaceutically acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil.
In a third aspect of the present invention, the invention provides a kind of medicine.According to embodiments of the invention, this medicine comprises: foregoing pharmaceutical composition.By providing this medicine to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, and arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this medicine.
According to embodiments of the invention, described medicine is at least one dosage form be selected from granule, capsule, tablet, powder agent, oral liquid, suspension and emulsion.Thus, be easy to carry out administration.
In a fourth aspect of the present invention, the invention provides a kind of food.According to embodiments of the invention, this food comprises: excrement bacteroid; And acceptable auxiliary material in bromatology.Inventor finds, by providing this food to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this food.
It should be noted that, the kind of term used in the present invention " food " is not particularly limited, and can be any known food, include but not limited to dairy produce, biscuit, cake, beverage, health products etc.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, when described food is solid-state, described food product packets is containing 1 × 10-1 × 10
20the described excrement bacteroid of cfu/g, when described food is in a liquid state, described food product packets is containing 1 × 10-1 × 10
20the described excrement bacteroid of cfu/mL.Thus, suppress arthritis to occur and improve the successful of arthritic symptom, if excrement bacteroid content is too low, the effect for the treatment of or prevention rheumatoid arthritis is undesirable, if excrement bacteroid too high levels, then treatment or prevention rheumatoid arthritis effect without significantly improving, cause waste.
According to a preferred embodiment of the present invention, when described food is solid-state, described food product packets is containing 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/g, when described food is in a liquid state, described food product packets is containing 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/mL.
According to a further advantageous embodiment of the invention, when described food is solid-state, described food product packets is containing 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid, when described food is in a liquid state, described food product packets is containing 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
According to embodiments of the invention, in described bromatology, acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices.
According to embodiments of the invention, in described bromatology, acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil.
According to embodiments of the invention, described food is at least one dosage form be selected from solid, dairy products, solution product, pulverulent product and suspension goods.
In a fifth aspect of the present invention, the invention provides a kind of feed.According to embodiments of the invention, this feed comprises: excrement bacteroid.Inventor finds, by providing this feed to animal, can obviously suppress arthritic generation, joint of animal is rubescent obviously to go down with swelling, arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this feed.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 shows according to one embodiment of the invention, and what microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 were fallen ill on mouse arthritis affects Macroscopic score result;
Fig. 2 shows according to one embodiment of the invention, and microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 affect result to arthritic mice splenocyte in-vitro multiplication; And
Fig. 3 shows according to one embodiment of the invention, and microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 affect result to arthritic mice cell factor.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usual conveniently condition is as people such as Sambrook, molecular cloning: laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989) condition described in, or (James Cappuccino and Natalie Sherman compiles according to " microorganism: laboratory manual ", Pearson Education publishing house) described in condition, or according to the condition that manufacturer advises.
In a first aspect of the present invention, the invention provides excrement bacteroid and preparing the purposes in medicine, described medicine is used for the treatment of or prevents rheumatoid arthritis or its relevant disease.Inventor finds, by providing this medicine to animal, effectively can play effect of anti-inflammatory, the symptom of joint redness and swelling is effectively improved, and arthritic symptom obviously alleviates, and namely can effectively treat or prevent rheumatoid arthritis or its relevant disease.
It should be noted that, term used herein " animal " is not particularly limited, and can be any animal with enteron aisle, preferred mammal, more preferably people, Lagomorpha or muroid.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, animal subject forms arthritis model animal through modeling, animal pattern takes in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI4227, all obviously can improve the rubescent and swelling situation of joint of animal, ameliorate osteoarthritis symptom.According to embodiments of the invention, respectively through arthritis DBA/1J mouse that bacterial strain Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227 treat, with do not connect compared with subject control group, joint redness and swelling are obviously disappeared, and arthritic symptom obviously alleviates.Thus, show that described bacterial strain can in order to prevention and therapy rheumatoid arthritis or its relevant disease.
In a second aspect of the present invention, the invention provides a kind of pharmaceutical composition.According to embodiments of the invention, this pharmaceutical composition comprises: excrement bacteroid; And pharmaceutically acceptable auxiliary material.Inventor surprisingly finds, by providing this pharmaceutical composition to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, arthritic symptom obviously alleviates, animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this pharmaceutical composition.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/g, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/mL.Thus, suppress arthritis to occur and improve the successful of arthritic symptom, if excrement bacteroid content is too low, the effect for the treatment of or prevention rheumatoid arthritis is undesirable, if excrement bacteroid too high levels, then treatment or prevention rheumatoid arthritis effect without significantly improving, cause waste.
According to a preferred embodiment of the present invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/g, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/mL.
According to a further advantageous embodiment of the invention, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid, when described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
According to embodiments of the invention, described pharmaceutically acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices.
According to embodiments of the invention, described pharmaceutically acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil.
In a third aspect of the present invention, the invention provides a kind of medicine.According to embodiments of the invention, this medicine comprises: foregoing pharmaceutical composition.By providing this medicine to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, and arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this medicine.
According to embodiments of the invention, described medicine is at least one dosage form be selected from granule, capsule, tablet, powder agent, oral liquid, suspension and emulsion.Thus, be easy to carry out administration.
In a fourth aspect of the present invention, the invention provides a kind of food.According to embodiments of the invention, this food comprises: excrement bacteroid; And acceptable auxiliary material in bromatology.Inventor finds, by providing this food to animal, can obviously suppress arthritic generation, joint redness and swelling are obviously gone down, arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this food.
It should be noted that, the kind of term used in the present invention " food " is not particularly limited, and can be any known food, include but not limited to dairy produce, biscuit, cake, beverage, health products etc.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, when described food is solid-state, described food product packets is containing 1 × 10-1 × 10
20the described excrement bacteroid of cfu/g, when described food is in a liquid state, described food product packets is containing 1 × 10-1 × 10
20the described excrement bacteroid of cfu/mL.Thus, suppress arthritis to occur and improve the successful of arthritic symptom, if excrement bacteroid content is too low, the effect for the treatment of or prevention rheumatoid arthritis is undesirable, if excrement bacteroid too high levels, then treatment or prevention rheumatoid arthritis effect without significantly improving, cause waste.
According to a preferred embodiment of the present invention, when described food is solid-state, described food product packets is containing 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/g, when described food is in a liquid state, described food product packets is containing 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/mL.
According to a further advantageous embodiment of the invention, when described food is solid-state, described food product packets is containing 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid, when described food is in a liquid state, described food product packets is containing 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
According to embodiments of the invention, in described bromatology, acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices.
According to embodiments of the invention, in described bromatology, acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil.
According to embodiments of the invention, described food is at least one dosage form be selected from solid, dairy products, solution product, pulverulent product and suspension goods.
In a fifth aspect of the present invention, the invention provides a kind of feed.According to embodiments of the invention, this feed comprises: excrement bacteroid.Inventor finds, by providing this feed to animal, can obviously suppress arthritic generation, joint of animal is rubescent obviously to go down with swelling, arthritic symptom obviously alleviates, and animal action is flexible, shows that rheumatoid arthritis or its relevant disease can effectively be treated or prevent to this feed.
According to embodiments of the invention, described excrement bacteroid is Bacteroides caccae.Thereby, it is possible to effectively play effect for the treatment of or prevention rheumatoid arthritis or its relevant disease.
According to embodiments of the invention, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.Thus, the effect for the treatment of or prevention rheumatoid arthritis or its relevant disease is better.
According to embodiments of the invention, when described feed is solid-state, described feed comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/g, when described feed is in a liquid state, described feed comprises 1 × 10-1 × 10
20the described excrement bacteroid of cfu/mL.Thus, suppress arthritis to occur and improve the successful of arthritic symptom, if excrement bacteroid content is too low, the effect for the treatment of or prevention rheumatoid arthritis is undesirable, if excrement bacteroid too high levels, then treatment or prevention rheumatoid arthritis effect without significantly improving, cause waste.
According to a preferred embodiment of the present invention, when described feed is solid-state, described feed comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/g, when described feed is in a liquid state, described feed comprises 1 × 10
4-1 × 10
15the described excrement bacteroid of cfu/mL.
According to a further advantageous embodiment of the invention, when described feed is solid-state, described feed comprises 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid, when described feed is in a liquid state, described feed comprises 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
Embodiment 1 determines the beneficial bacterium treating or prevent rheumatoid arthritis
1.1 sample collections and DNA extract
Collect the ight soil of 212 volunteers, tartar and saliva sample altogether from BJ Union Hospital, sample message, in table 1, wherein, is divided into training group and test group.Training group comprises 157 volunteers, and wherein 77 is the RA case of not treating, and 80 is healthy person (contrast).In test group, wherein 34 volunteers to form 17 " case-health " right, wherein have 8 to having relationship by blood, other 9 to not having genetic connection; Other 21 volunteers are that DMARD (disease-modifying antirheumatic drugs) treats RA case.
Refrigeration transportation after gathering fecal specimens also transfers to rapidly-80 DEG C of preservations, carry out DNA extraction (with reference to Qin, J.et al.A metagenome-wide association study of gut microbiota in type 2diabetes.Nature 490,55 – 60 (2012)).When gathering tartar sample, utilize medical calm from the tartar of dental surface scraping 3 μ l, be transferred to 200 μ l 1x lysis buffer (10mM Tris, 1mM EDTA, 0.5% polysorbas20,200 μ g/ml Proteinase Ks) in, cultivate 2 hours at 55 DEG C, then cultivate 10 minutes at 95 DEG C, stop cracking reaction, finally in-80 DEG C of preservations.When gathering saliva sample, get 100 μ l samples in the collecting pipe containing 100 μ l 2x lysis buffers, meanwhile, scraping posterior phraynx surface sample also adds in this pipe, and follow-up cleavage step is identical with tartar sample, equally in-80 DEG C of preservations.Tartar sample and saliva sample to BGI-Shenzhen, carry out DNA extraction with reference to fecal specimens through refrigeration transportation.
When volunteer is admitted to hospital first, collect phenotypic information according to standardization program.The fecal specimens of 21 DMARD treatment cases is only included among 212 fecal specimens for building enteric microorganism gene set, no longer analyzes herein.This research obtains BJ Union Hospital and BGI-Shenzhen's Institutional Review Board approval.
Table 1 sample message
1.2 grand gene order-checking and assemblings
Utilize the DNA sample extracted to build sequencing library, on Illumina checks order platform, carry out two-way (Paired-end) grand gene order-checking (Insert Fragment 350bp reads long 100bp).(quality-controlled is filtered to the data that order-checking produces, remove adapter polluted sequence, go low quality sequence and remove host genome polluted sequence), and utilize SOAPdenovo software (v2.04) to carry out accent assembling.
It is 0.37%, 5.55% and 40.85% respectively that the average host genome of ight soil, tartar and saliva sample is polluted.
1.3 gene sets build
For the assembling fragment (contigs) assembled, GeneMark software (v2.7d) is utilized to carry out predictive genes, then (alignment similarity (identity) is more than 95% to utilize BLAT software to carry out de-redundancy, the coverage (overlap) of comparison is more than 90%, there is no breach (gaps)), for 212 fecal specimens (treating sample comprising 21 DMARD), obtain and comprise 3, the nonredundancy gene set of 800,011 gene; For 203 buccal sample (comprising 105 tartar samples and 98 saliva samples), obtain and comprise 3,234, the nonredundancy gene set of 997 genes.(alignment similarity is more than 95% with reference in gene set to utilize BLAT software fecal specimens gene set to be added to further the published enteric microorganism comprising more than 430 ten thousand genes, comparison coverage is more than 90%, with reference to above-mentioned document Qin, J.et al.2012), finally obtain the new gene collection comprising more than 590 ten thousand genes.
High-quality sequenced fragments (reads) and enteron aisle or oral cavity are compared with reference to gene set, thus obtains the relative abundance (with reference to above-mentioned document Qin, J.et al.2012) of gene.
1.4 species taxonomy annotations calculate with abundance
By comparing with IMG (v400) database, species taxonomy is carried out (with reference to above-mentioned document Qin to the gene of prediction, J.et al.2012), (alignment similarity is more than 65% to obtain the species taxonomy of a level respectively, comparison coverage is more than 70%), belong to the species taxonomy (alignment similarity is more than 85%) of level and the species taxonomy (alignment similarity is more than 95%) of the level of kind.The relative abundance of gene is utilized to calculate the relative abundance of these species (with reference to above-mentioned document Qin, J.et al.2012), and carry out statistical check (p<0.05) with rank test (Wilcoxon rank-sum test), there are the species of significant difference in the relative abundance between determining case and contrasting.
1.5 grand genome association analyses
By comparing case and the fecal microorganism gene set (microbiome) contrasted, 3, (each gene at least appears in 6 samples 110,085 gene, sample n=157, case is not treated containing 21 DMARD described in table 1) in, find that the relative abundance of 83,858 genes has significant difference (p<0.01, rank test, FDR=0.3285), these genes are marker gene.According to these marker gene relative abundance difference in the sample to which, further cluster, obtains grand genome linkage group (the Metagenomic Linkage Group of ight soil, MLG, a MLG is similar to species, and clustering method is with reference to above-mentioned document Qin, J.et al.2012).Same method, from 2 of tartar, in 247,835 genes (each gene at least appears in 6 samples, sample n=105), filter out 209,820 marker gene (p<0.01, rank test, FDR=0.072), cluster, obtains the MLG of tartar.From 2,404 of saliva, in 726 genes (each gene at least appears in 6 samples, sample n=98), filter out 206,399 marker gene (p<0.01, rank tests, FDR=0.088), cluster, obtains saliva MLG.In addition, by comparing the fecal microorganism gene before and after DMARD treatment, from 1, in 538,688 genes (each gene at least appears in 6 samples, sample n=64), filter out 86158 marker gene (p<0.05, paired Wilcoxon rank-sum test, FDR=0.912), cluster is treated in the ight soil MLGs of case to DMARD.
According to classification and the relative abundance of MLGs constitutivegene, carry out MLGs species taxonomy and build MLGs relative abundance spectrum (with reference to above-mentioned document Qin, J.et al.2012).To the level to be categorized into kind, in demand fulfillment MLGs 90% gene can comparison to (, more than 95%, comparison coverage is more than 70% for alignment similarity) on the genome of these species.To be categorized into genus level, then needing the gene of in MLGs 80%, no matter being at DNA sequence dna or protein sequence, being all higher than 80% with the similarity of this genus.According to Kendall ' the s correlation (regardless of case-control status) between all samples abundance, MLGs can be carried out cluster further.Enteron aisle MLG, saliva MLG, tartar MLG with DMARD treat the species taxonomy result of relevant MLG respectively in table 2, table 3, table 4, table 5.
The species taxonomy information of table 2 enteron aisle MLG
The species taxonomy information of table 3 saliva MLG
The species taxonomy information of table 4 tartar MLG
Table 5 DMARD treats the species taxonomy information of relevant MLG
Embodiment 2 zoopery is verified
In order to verify that embodiment 1 is determined treatment at table 2, table 3, table 4, table 5 or prevented the beneficial bacterium of rheumatoid arthritis, inventor carries out zoopery to each bacterial classification, utilizes its effect of the obtainable host strains of this bacterial classification.
Experimental technique
1, modeling and administration
The male DBA/1J mouse of SPF (Specific pathogen free) level in 6 ~ 8 week age, be purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center, raise in IVC (individual ventilated cage) mouse cage system (purchased from Suzhou Feng Shi animal used as test equipment Co., Ltd), indoor maintenance temperature 22 ~ 24 DEG C, humidity 40% ~ 60%, illumination every day 12h, ad lib and drinking-water.Adaptability is divided into after raising 2 weeks 5 groups (model control group, microbial inoculum 1 group, microbial inoculum 2 groups, microbial inoculum 3 groups, Normal groups) at random, often organizes 12.Bacteroides caccae ATCC 43185 (microbial inoculum 1) is purchased from ATCC (American Type Culture Collection), Bacteroides caccae VPI 2308 (microbial inoculum 2) and Bacteroides caccae VPI4227 (microbial inoculum 3) derives from Virginia, US Polytechnics anaerobic bacteria laboratory (Virginia Polytechnic Institute and State University Anaerobe Laboratory Collection) (Johnson, J.L. (1978) .Taxonomy of the Bacteroides I.Deoxyribonucleic acid homologies among Bacteroides fragilis and other saccharolytic Bacteroides species.International journal of systematic bacteriology, 28 (2), 245-256.).In improvement kitchen meat nutrient solution (ATCC Medium 1490), 37 DEG C of Anaerobic culturel 48-72h, start experiment after 16S rDNA order-checking qualification is errorless.Bacterial strain information is in table 6.
Table 6 bacterial strain information
| Numbering | Bacterial classification name |
| Microbial inoculum 1 | Bacteroides caccae ATCC 43185 |
| Microbial inoculum 2 | Bacteroides caccae VPI 2308 |
| Microbial inoculum 3 | Bacteroides caccae VPI 4227 |
With reference to the method (S.Yoshino of S.Yoshino, E.Sasatomi, M.Ohsawa, Bacterial lipopolysaccharide acts as an adjuvant to induce autoimmune arthritis in mice, 2000) modeling method, in brief:
From experiment the 1st day, microbial inoculum 1 group (microbial inoculum 1+CIA/LPS), microbial inoculum 2 groups (microbial inoculum 2+CIA/LPS), microbial inoculum 3 groups (microbial inoculum 3+CIA/LPS) respectively with 500 μ l/50g.BW dosage, gavage bacterium 1, bacterium 2, bacterium 3 fresh medium (10
9-10
10cfu/ml), model control group (M+CIA/LPS) and Normal group (M+AA+PBS) be gavage equal-volume aseptic culture fluid respectively, administration every other day 28 days.At the 1st day, the 21st day, II Collagen Type VI (CIA) is utilized to induce the generation of 3 model group (microbial inoculum 1 group, microbial inoculum 2 groups and microbial inoculum 3 groups) and model control group mouse arthritis in conjunction with lipopolysaccharides (LPS).Concrete operations are: 100mg II collagen type (taking from calf articular cartilage, Funakoshi Co) is dissolved in 100ml 5mM acetic acid (AA), and 4 DEG C of stirrings are spent the night, intraperitoneal injection of mice.Get lipopolysaccharides (Shanghai Vaccine and Serum Institute) the 1 μ g of E.coli 011:B4 subsequently, be dissolved in 0.1ml phosphate buffer (PBS), equally through intraperitoneal injection.Normal group selects 5mM acetic acid through same volume and PBS buffer solution lumbar injection at same time.Observe mouse foot claw-like state every day, weekly arthritis index is marked.Start latter 35 days in experiment, often organize random selecting 6 execution, get spleen cell and carry out subsequent experimental.Residue mouse continues to observe course of arthritis progress and 50 days cervical dislocation are put to death after experiment starts.
2, arthritis evaluations
Utilize naked eyes to carry out Macroscopic score according to the increase of erythema and periarticular tissue edema situation to the arthritic order of severity and obtain arthritis index, concrete standards of grading are described below: 0: do not have arthritic sign; 1:1 arthroncus and/or rubescent; 2:2 arthroncus and/or rubescent; 3: be greater than 2 arthroncus and/or rubescent; 4: whole sufficient pawl generation severe joint inflammation.Every mouse arthritis index is every animal 4 pawl score sum.
3, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact of Collagen-Induced Arthritis mouse boosting cell in-vitro multiplication
Random selecting model group (microbial inoculum 1 group, microbial inoculum 2 groups and microbial inoculum 3 groups), model control group and Normal group often organize each 6 mouse, conventional separating Morr. cell.(Sailongbone extracts is to the therapeutic action of the mouse arthritis that ox II Collagen Type VI is induced and Mechanism Study for the method for subsequent operation reference Zhao Xiaohui etc., Zhao Xiaohui, Yue Huilan, Mei Lijuan, Shao Zan, Tao Yanduo, in May, 2008): with the RPMI RPMI-1640 containing 10% calf serum by cell concentration furnishing 4 × 10
6cell/ml.In 96 orifice plates, every hole adds 100 μ l cell suspensions, 100 μ l collagen antigens.Cell is in containing 5%CO
237 DEG C of incubators in cultivate, cultivate and terminate the every hole of front 8h and add 25 μ l
3h-thymidylic acid.Continue to be cultured to experiment to terminate.With cell collector by cell harvesting on glass fibre membrane, read in cell DNA on β calculating instrument after adding scintillation solution
3h-thymidylic acid amount, represents cell proliferative conditions with umber of pulse per minute (counts per minute, cpm).
4, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact of arthritic mice inflammatory cytokine
Conventional method separating Morr. cell, with the RPMI RPMI-1640 containing 10% calf serum by cell concentration furnishing 4 × 10
6cell/ml, is inoculated in 24 hole tissue culturing plates with splenocyte suspension 1ml/ hole, wherein containing 1mM glutamine, and 100U/ml penicillin, 100mg/ml streptomysin, 5 × 10
-5m 2 mercapto ethanol and 1% hot deactivation autoserum.After 48h, collect supernatant in-70 DEG C of preservations, utilize ELISA kit (being purchased from Mei Lian bio tech ltd, Shanghai) to detect wherein cell factor IL-12, IFN-γ, TNF-α and IL-10 level.
Experimental result
1, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 impact that mouse arthritis is fallen ill.
Microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 Macroscopic score on the impact that mouse arthritis is fallen ill the results are shown in Table 7 and Fig. 1.From experimental result, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 administration, after 4 weeks, compare model control group, and obviously can suppress the generation of CIA mouse arthritis, mouse foot swelling is obviously gone down, and arthritic symptom obviously alleviates, and mouse action is more flexible.
What table 7 microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 were fallen ill on mouse arthritis affects result (often organizing 6 mouse)
2, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact of arthritic mice splenocyte in-vitro multiplication
The impact on arthritic mice splenocyte in-vitro multiplication of microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 the results are shown in Table 8 and Fig. 2, wherein, represent that between two groups, numerical value is not through Tukey ' s Test checkout discrepancy significantly (p>0.05) with same letter mark.As seen from the experiment, by gavaging microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3, when adding antigen, the external breeder reaction after antigenic stimulus of arthritic mice splenocyte obvious reduction compared with model control group, under the condition not adding antigen, each model group also show Spleen cell proliferation inhibitory action in various degree.
Table 8 microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact (often organizing 6 mouse) of arthritic mice splenocyte in-vitro multiplication
3, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact of arthritic mice cell factor
Microbial inoculum 1, microbial inoculum 2 and the impact of microbial inoculum 3 on arthritic mice cell factor the results are shown in Table 9 and Fig. 3, and wherein, between the expression two groups of same letter mark, numerical value is not through Tukey ' s Test checkout discrepancy significantly (p>0.05).From experimental result, detect can find by ELISA, compare with Normal group, 3 model group mouse cells press down scorching factor IL-10 and secrete significantly minimizing (p<0.05), and inflammatory factor IL-12, TNF-α and IFN-γ secretion significantly increases (p<0.05); Compare with model control group, model group mouse cell IL-10 secretion significantly increases (p<0.05), IL-12, IFN-γ, TNF-α secretes and significantly reduces (p<0.05), and without significant difference (p>0.05) between 3 model group.Illustrate that microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 gavage can suppress the secretion of inflammatory factor IL-12, IFN-γ, TNF-α in spleen cell cultures supernatant, and improving the secretion pressing down scorching factor IL-10, display microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 pairs of arthritic mice cell immunity of spleen hyperfunctions have obvious inhibitory action.
Table 9 microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 are on the impact (often organizing 6 mouse) of arthritic mice cell factor
Conclusion
The above results shows, on CIA mouse model of rheumatoid arthritis, microbial inoculum 1, microbial inoculum 2 and microbial inoculum 3 obviously can suppress the morbidity of mouse arthritis, alleviate the related symptoms of CIA mouse, demonstrate good antiinflammatory action.
In the description of this description, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this description or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (10)
1. excrement bacteroid is preparing the purposes in medicine, and described medicine is used for the treatment of or prevents rheumatoid arthritis or its relevant disease,
Optionally, described excrement bacteroid is Bacteroides caccae,
Optionally, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.
2. a pharmaceutical composition, is characterized in that, comprising:
Excrement bacteroid; And
Pharmaceutically acceptable auxiliary material,
Optionally, described excrement bacteroid is Bacteroides caccae,
Optionally, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.
3. pharmaceutical composition according to claim 2, is characterized in that, when described pharmaceutical composition is solid-state, described pharmaceutical composition comprises 1 × 10-1 × 10
20cfu/g, preferably 1 × 10
4-1 × 10
15cfu/g, more preferably 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/g,
When described pharmaceutical composition is in a liquid state, described pharmaceutical composition comprises 1 × 10-1 × 10
20cfu/mL, preferably 1 × 10
4-1 × 10
15cfu/mL, more preferably 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
4. pharmaceutical composition according to claim 2, it is characterized in that, described pharmaceutically acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices
Optionally, described pharmaceutically acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil.
5. a medicine, is characterized in that, comprising:
Pharmaceutical composition according to any one of claim 2-4.
6. medicine according to claim 5, is characterized in that, described medicine is at least one dosage form be selected from granule, capsule, tablet, powder agent, oral liquid, suspension and emulsion.
7. a food, is characterized in that, comprising:
Excrement bacteroid; And
Acceptable auxiliary material in bromatology,
Optionally, described excrement bacteroid is Bacteroides caccae,
Optionally, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.
8. food according to claim 7, is characterized in that, when described food is solid-state, described food product packets is containing 1 × 10-1 × 10
20cfu/g, preferably 1 × 10
4-1 × 10
15cfu/g, more preferably 1 × 10
6-1 × 10
11cfu/g, described excrement bacteroid,
When described food is in a liquid state, described food product packets is containing 1 × 10-1 × 10
20cfu/mL, preferably 1 × 10
4-1 × 10
15cfu/mL, more preferably 1 × 10
6-1 × 10
11the described excrement bacteroid of cfu/mL.
9. food according to claim 7, it is characterized in that, in described bromatology, acceptable auxiliary material is be selected from least one in carrier, excipient, diluent, lubricant, wetting agent, emulsifying agent, suspension stabiliser, anticorrisive agent, sweetener and spices
Optionally, in described bromatology, acceptable auxiliary material is be selected from least one in lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, alginates, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, dolomol and mineral oil
Optionally, described food is at least one dosage form be selected from solid, dairy products, solution product, pulverulent product and suspension goods.
10. a feed, is characterized in that, comprising: excrement bacteroid,
Optionally, described excrement bacteroid is Bacteroides caccae,
Optionally, described excrement bacteroid is be selected from least one in Bacteroides caccae ATCC 43185, Bacteroides caccae VPI 2308 and Bacteroides caccae VPI 4227.
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| CN201410522408.5A CN104546933A (en) | 2014-09-30 | 2014-09-30 | Application of bacteroides caccae in treatment or prevention of rheumatoid arthritis or related diseases thereof |
| HK15110144.7A HK1209350A1 (en) | 2014-09-30 | 2015-10-15 | Use of bacteroides caccae in the treatment or prevention of rheumatoid arthritis or related diseases |
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| CN201410522408.5A CN104546933A (en) | 2014-09-30 | 2014-09-30 | Application of bacteroides caccae in treatment or prevention of rheumatoid arthritis or related diseases thereof |
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| US11779613B2 (en) | 2017-06-14 | 2023-10-10 | Cj Bioscience, Inc. | Compositions comprising a bacterial strain of the genus Megasphera and uses thereof |
| US12048720B2 (en) | 2017-06-14 | 2024-07-30 | Cj Bioscience, Inc. | Compositions comprising bacterial strains |
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