CN116855418B - Coliform bacteria capable of producing gas and having effect of preventing and/or treating inflammatory bowel disease and application thereof - Google Patents
Coliform bacteria capable of producing gas and having effect of preventing and/or treating inflammatory bowel disease and application thereof Download PDFInfo
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- CN116855418B CN116855418B CN202310941647.3A CN202310941647A CN116855418B CN 116855418 B CN116855418 B CN 116855418B CN 202310941647 A CN202310941647 A CN 202310941647A CN 116855418 B CN116855418 B CN 116855418B
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Abstract
The invention belongs to the technical field of biology, and particularly relates to coliform bacteria capable of regulating autoimmune reaction and application thereof in the field of immunotherapy of inflammatory bowel diseases. The coliform bacteria can strengthen the immune regulation function of organisms by enhancing the differentiation of Treg cells, achieves the purpose of relieving the occurrence and development of inflammatory enteritis diseases, and has wide prospect in clinical application.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to coliform bacteria capable of regulating autoimmune reaction and application thereof in the field of immunotherapy of inflammatory bowel diseases.
Background
Inflammatory bowel disease (Inflammatory bowel disease, IBD) is a chronic, inflammatory and autoimmune disease, including two diseases-Crohn's Disease (CD) and ulcerative colitis (Ulcerative colitis, UC), characterized by chronic inflammation of the gastrointestinal tract (GI), but its pathogenesis is unknown. Prolonged inflammation can lead to gastrointestinal damage.
Inflammatory Bowel Disease (IBD) develops through fusion of environmental, microbial, immune and genetic factors, possibly in individuals with genetic predisposition. Many clinical studies have investigated the role of infection in the development of inflammatory diseases of the gastrointestinal tract; furthermore, the possible role of some pathogens in the development and exacerbation of inflammatory diseases of the gastrointestinal tract has been described. Alterations in intestinal microbiota are associated with the development and progression of IBD, but it is not clear which microbiota are involved in or how they contribute to or inhibit the development of IBD.
Foxp3 expressing regulatory T (Treg) cells are a subset of CD4+ T cells, have an immunomodulatory effect, play an important role in maintaining immune tolerance and balance, and are essential for the prevention of autoimmunity. Therefore, the specific strain capable of enhancing the differentiation of Treg cells has wide application prospect in the field of treatment of inflammatory bowel diseases.
In the prior art, the mouse inflammatory enteritis model mainly comprises two types of DSS and TNBS. By using both models, relevant actionable materials can be screened initially.
DSS is a polyanionic derivative of dextran formed by esterification of dextran with chlorosulfonic acid and has the formula (C6H 7Na3O14S 3) n, MW: 36000-50000 are different, and the sulfur content is generally 17-20%. Although the mechanism of induction is not clear, current studies mainly consider that DSS increases intestinal permeability, breaks intestinal mucosal barrier, upregulates certain cytokines (tumor necrosis factor, interleukin, interferon, IL-10 and IL-12), activates certain pathways (NF- κb pathway and TRPV1 pathway) or is associated with dysbacteriosis of the intestinal tract, etc.
The 2,4, 6-trinitrobenzenesulfonic acid (TNBS) colitis model is one of the major models of experimental research in Inflammatory Bowel Disease (IBD) because TNBS-induced inflammation mimics several of the features of crohn's disease. TNBS is a small molecule that is not antigenic in itself, but that, when bound to host proteins, causes an immune response and is therefore a hapten. TNBS-treated mice can establish a preclinical model mimicking clinical Crohn's Disease (CD), characterized by infiltration of cd4+ T cells, neutrophils and macrophages, forming inflammation that progresses laterally, resulting in transmural colitis.
The inflammatory bowel disease is not currently treated effectively, and the therapeutic drugs comprise the following classes:
(1) Aminosalicylic acid formulations
Sulfasalazine (SASP) has been an effective drug for the treatment of IBD since the 30s of the 20 th century, but its metabolite sulfapyridine produces adverse effects. Novel formulations such as sustained-release formulations and topical therapeutic formulations have been studied to increase the concentration in the colon, thereby maximizing efficacy and reducing the toxic side effects of the drug.
(2) Adrenoglucocorticoid (GCS)
GCS is the most effective drug for inhibiting acute active inflammation by single application, has good recent curative effect, has the effective rate of 90 percent, and can control inflammation, inhibit autoimmune reaction and relieve poisoning symptoms. The common medicines include hydrocortisone, dexamethasone, prednisone and the like, but the medicines are easy to produce adverse reactions after long-term use. At present, a new generation of GCS preparations such as Budesonide, beclomethasone dipropionate, hydrocortisone and the like have been developed, and the medicines have strong anti-inflammatory effect and less systemic side reactions. In addition, the treatment of IBD has been the treatment of a variety of topical therapeutic agents, such as enemas, foams and suppositories, which greatly reduce systemic side effects.
(3) Immunosuppressant
Traditional immunosuppressants include: azathioprine (AZA), 6-mercaptopurine (6-MP), and Methotrexate (MTX). These immunosuppressants are also useful in the treatment of IBD and are generally effective, but are not effective in all IBD patients and have a high number of adverse effects. Novel immunosuppressants, such as cyclosporin a (CsA), tacrolimus (FK 506), and mycophenol (MMF), are effective against IBD, but their efficacy and safety have yet to be further evaluated.
(4) Monoclonal antibodies
Although aminosalicylic acid preparations, adrenoglucocorticoid and immunosuppressant have better curative effects on most cases, the effectiveness and safety of the drugs have a certain limit, and with the deep research on IBD pathogenesis, monoclonal antibody treatment becomes a new direction of research.
Infiniximab (IFX) -human mouse chimeric TNF-alpha monoclonal antibody of the 90 th century of the 20 th century appears, and clinical application for more than 10 years proves that the antibody has excellent curative effects on active or remission CD in clinical symptoms, improvement of endoscopic lesions, ulcer, fistula healing and the like. Since IFX has a short domestic market time, its application indication is only CD and its complications, but has been used in foreign patients with moderate and severe UC where hormone and immunosuppressant are ineffective or intolerant. With the continuous accumulation of clinical application experience of IFX and the appearance of new generation medicines such as pure humanized anti-TNF-alpha IgG monoclonal antibody adam (Adaliumab), humanized anti-alpha 24 Integrin (Integrin) IgG4 monoclonal antibody Natalizumab, polyethylene glycol human anti-TNF-alpha antibody Fab fragment product cetuzu (Certolizumab Pegol) and the like, the curative effect of monoclonal antibodies is increasingly accepted by people. Many large clinical control studies have demonstrated that monoclonal antibodies have significant efficacy over traditional drugs in inducing remission, but also have great advantages in maintenance therapy (Colombel JF, kammMA, schwartz, et al Sustainability of adalimumab in fistula healing and respons: 2 year data from CHARM and 12-montan-label extension follow-up study [ J ]. Am J Gastroenterol, 2007, 102 (11): 2541-2550.). The current common practice is: for moderate, severe IBD and high risk patients, immediate induction of remission with monoclonal antibodies is provided if traditional drugs are ineffective.
The reasons for limiting the use of monoclonal antibodies are, apart from their high price, also the potential risk. The likelihood of a patient suffering from tuberculosis or histoplasmosis, etc., is significantly increased if IFX is used. In addition, the prevalence of diseases such as demyelinating lesions of the nervous system, congestive heart failure, and lymphomas has increased.
(5) Antibiotics
Antibiotics, penicillins, tobramycin, novel cephalosporins and cephalosporins are selected as appropriate for patients suffering from bacterial infections and severe patients. In recent years, metronidazole has been widely used for the treatment of IBD, and metronidazole can inhibit intestinal anaerobic bacteria, has the effects of immunosuppression, influencing leukocyte chemotaxis and the like, has good effects on UC and CD, can promote fistula healing and prevent recurrence, has adverse reactions such as nausea, vomiting, acroparesthesia and the like, and can be considered for use as a second-line medicament when GCS or SASP is ineffective.
(6) Microecological preparation
Since dysbacteriosis and intracavity antigen stimulation of intestinal tract are important reasons for IBD triggering and recurrence, the application of microecologics to improve intestinal microenvironment, restore normal flora and down regulate immune response of the organism has been started for about 10 years, so as to achieve the purposes of controlling intestinal inflammation and maintaining remission. The microecological preparation comprises probiotics, prebiotics and synbiotics. Probiotics are preparations containing a specific sufficient number of living bacteria; the prebiotics are functional oligosaccharides which are not easy to be digested and absorbed by human bodies, but can be absorbed and utilized by beneficial bifidobacteria in intestinal tracts to play a role in promoting bifidobacteria; the synbiotics are mixed preparations of probiotics and prebiotics, or vitamins, microelements and the like are added.
Human probiotics have a history of centuries, but their actual use in the clinic has begun in the last decades. Kruis et al (Kruis W, fric P, pokrotonieks J, et al Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle1917 is as effective as with standard mwsalazine. Gut, 2004.53:1617-1623.) compared the therapeutic effects of mesalamine and probiotics in 327 UC patients in maintenance therapy. Two groups of patients were orally administered 50mg (3 times/d) of mesalamine and 1 time/d of escherichia coli Nissle1917, respectively. The recurrence rate, the remission days and the disease activity index of the two groups are similar, which indicates that the probiotic treatment can achieve similar curative effect with the anti-inflammatory drug and has no drug side effect. After 18 active UC patients were given bifidobacterium longum and inulin, oligofructose for one treatment course, the sigmoidoscope score was reduced in the treatment group, whereas there was no improvement in the placebo group, treatment group clinical symptoms were improved (Furrie E, macfarlane S, kennedy A, et al Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflamation in patients with active ulcerative colitis: a randomised controlled pilot three. Gut, 2005.54:242-249.). 34 patients with light and medium active stage UC who do not respond to the traditional drug treatment receive a probiotic preparation VSL3 treatment, the remission rate is 53%, and 24% of patients respond. It is shown that VSL3 has a therapeutic effect on UC (Bibiloni R, fedorak RN, tannock GW, et al VSL#3procyanic-mixture induces remission in patients with active ulcerative colitis, am J Gastroenterol, 2005.100:1539-1546.).
Rembacken et al (Rembackers BJ. Non-pathogenic escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomized trial [ J ]. Lancet, 1999, 354 (9): 635-639.) compared the efficacy and maintenance of remission of mesalamine and Escherichia coli in 116 active UC patients using a random control double simulation. As a result, the remission rate of the mesalamine group was 75% and the escherichia coli group was 68%; the number of days to achieve remission was 44 days for mesalamine group and 42 days for escherichia coli group; the recurrence rate of mesalamine group is 73% and the escherichia coli group is 67%; the average day of remission was 206 days (median 175 days) for mesalamine and 221 days (median 185 days) for escherichia coli, suggesting that non-pathogenic escherichia coli was as effective as mesalamine in maintaining remission.
Taken together, several clinical studies are demonstrated to demonstrate the efficacy of probiotics in treating IBD. Intestinal flora is closely related to the onset of IBD, and with the continuous perfection of the intestinal mucosal immune system and the research on genetic susceptibility of IBD, the microecologics will be very promising for the treatment of IBD.
Disclosure of Invention
The invention aims to provide an intestinal tract bacterium which can strengthen the immunoregulation function of an organism by enhancing the differentiation of Treg cells so as to achieve the aim of relieving the occurrence and development of inflammatory enteritis diseases.
The invention is realized by the following technical scheme:
coliform bacteria producing gasCollinsella aerofaciens）ibiome002 the material is preserved in China center for type culture collection, the address is eight ways of China center for type culture collection of university of Wuhan in Wuhan, hubei province, and the preservation date is 2022, 9 and 27 days, and the preservation number is CCTCC NO: M20221518.
The invention also protects a pharmaceutical composition comprising the coliform bacteria producing gasCollinsella aerofaciens) iriome 002 or a culture supernatant thereof, and/or a pharmaceutically acceptable carrier.
The invention also protects the coliform bacteria producing gasCollinsella aerofaciens) Use of ibiome002 or a culture supernatant thereof, or a pharmaceutical composition as described above, for the manufacture of a medicament for the alleviation, treatment or co-treatment of inflammatory bowel disease.
Further, the pharmaceutical composition may further comprise other substances for preventing, treating or assisting in treating inflammatory bowel disease, or for modulating immune response of an organism (such as folic acid, vitamin B12 and other vitamins, and drugs such as sulfasalazine, olsalazine, balsalazide, hydrocortisone, methylprednisolone, oral prednisone, prednisolone, hydrocortisone, budesonide, mesalazine, azathioprine, methotrexate, cyclosporine, tacrolimus, infliximab, adalimumab, cetuximab, golimumab, vedolizumab, natalizumab, usitaglab, tofacitinib, oznimod, metronidazole, ciprofloxacin and the like).
Further, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
Still further, the inflammatory bowel disease is DSS or TNBS induced enteritis.
The invention also protects the coliform bacteria producing gasCollinsella aerofaciens) The application of ibiome002 or culture supernatant thereof or the pharmaceutical composition in preparing Treg agonist, which is an agent or drug for improving differentiation efficiency of Treg cells in CD4T cells.
The pharmaceutical composition of the present invention may contain pharmaceutically acceptable solvents, emulsifiers, suspending agents, preservatives, lubricants, etc. commonly used in the art, but is not limited thereto.
The pharmaceutical composition of the present invention can be prepared into commonly used dosage forms, such as tablets, granules, capsules, suspensions, freeze-dried preparations, and the like. The dosage of the medicine is 10 6 ~10 10 CFU, once daily, lasts for more than 1-2 weeks.
The invention has the beneficial effects that:
the invention clearly shows that the human intestinal bacteria (coliform bacteria) which play a therapeutic role in inflammatory bowel diseases can strengthen the immunoregulatory function of organisms by enhancing the differentiation of Treg cells, achieves the purpose of relieving the occurrence and development of inflammatory enteritis diseases, and has wide prospect in clinical application.
Preservation of organisms
Collinsella aerofaciensibiome002 is preserved in China center for type culture collection, with the address being eight ways of China center for type culture collection of university of Wuhan, hubei province, and the preservation date being 2022, 9 months and 27 days, and the preservation number being CCTCC NO: M20221518.
Drawings
Fig. 1 shows the 16S sequencing results of multiple FMT donor stool samples obtained from kunming hospital, wherein: the abscissa indicates the number of stool samples of different FMT donors and the ordinate indicates the relative content of species.
Fig. 2 shows a schematic diagram of the experimental design of DSS model detection of FMT donor samples, wherein: HC was healthy, CTRL was DSS modeling control, and FMT was experimental.
Figure 3 shows the relative change in mouse body weight throughout DSS modeling, wherein: HC is a healthy group, CTRL is a DSS modeling control group, FMT is an experimental group, and numbers marked among the groups represent the space between the two groupsPValues.
Fig. 4 shows that at the time of sacrificing mice, the large intestine of the mice was taken out for photographing recording (fig. 4A), and the large intestine length was counted (fig. 4B), wherein: HC is a healthy group, CTRL is a DSS modeling control group, FMT is an experimental group, and numbers marked among the groups represent the space between the two groupsPValues.
FIG. 5 shows a flow-through analysis of in vitro treatment of nadir ve CD4T with bacterial supernatants isolated from FMT fecal samples, FIGS. 5A through 5E are lymphocyte- & gt single cell- & gt living cell- & gt CD4T cell- & gt Foxp3+CD4T, respectively.
FIG. 6 shows the in vitro stimulation results of isolated bacterial culture supernatants showing the ratio of Foxp3 positive CD4T cells to CD4T cells.
Fig. 7 shows the experimental design of Treg cell effect in CD4 cells of the mouse intestinal lamina propria after the mice were subjected to bacterial i.e. ibiome002 culture supernatant for gastric lavage.
Fig. 8 shows the flow gate strategy of Treg cell effect in CD4 cells of the mouse intestinal lamina propria after ibiome002 culture supernatant lavage of the mouse, fig. 8A to 8F are lymphocyte → single cell → living cell → cd4 cd4+cd3+ cell → cd4T cell → foxp3+cd4t, respectively.
FIG. 9 shows the ratio of Foxp3+CD4T cells in the mouse intestinal lamina propria after the mice were perfused with the ibiome002 culture supernatant, wherein: CTRL is a medium lavage control group, ibiome002 is an ibiome002 culture supernatant lavage experimental group.
FIG. 10 shows a graph of experimental design for exploring the effect of ibiome002 bacterial culture supernatant on DSS model mice.
FIG. 11 shows the relative change in body weight of mice throughout DSS molding after the gastric ibiome002 bacterial culture supernatant or medium has been perfused, wherein: CTRL is a medium lavage control group, ibiome002 is an ibiome002 culture supernatant lavage experimental group, and numbers marked between groups represent the space between the two groupsPValues.
Fig. 12 shows that at the sacrifice of DSS model mice after lavage of ibiome002 bacterial culture supernatant or medium, the rat large intestine of the mice was removed for photographic recording (fig. 12A) and the large intestine length was counted (fig. 12B), wherein: CTRL is a medium lavage control group, ibiome002 is an ibiome002 culture supernatant lavage experimental group, and numbers marked between groups represent the space between the two groupsPValues.
FIG. 13 shows a graph of experimental design for exploring the effect of ibiome002 bacterial culture supernatant on TNBS-model mice.
FIG. 14 shows mice throughout TNBS molding after the gastric ibiome002 bacterial culture supernatant or medium has been perfusedRelative change in body weight, wherein: CTRL is a medium lavage control group, ibiome002 is an ibiome002 culture supernatant lavage experimental group, and numbers marked between groups represent the space between the two groupsPValues.
FIG. 15 shows that at the sacrifice of TNBS model mice after lavage of ibiome002 bacterial culture supernatant or medium, the large intestine of the mice was removed for photographic recording (FIG. 15A) and the large intestine length was counted (FIG. 15B), wherein: CTRL is a medium lavage control group, ibiome002 is an ibiome002 culture supernatant lavage experimental group, and numbers marked between groups represent the space between the two groupsPValues.
Description of the embodiments
For a better understanding of the present invention, reference will now be made to the following examples, which are intended to illustrate, but not to limit the present invention, with reference to the accompanying drawings.
The temperature of the strain culture in the solid medium and the liquid medium was 37℃unless otherwise indicated. The centrifugation conditions for collecting the bacterial culture supernatant were room temperature and centrifugation at 3000rpm for 10min, unless otherwise indicated. Unless otherwise indicated, all materials used in the experiments were conventional commercial products.
Example 1: fungus library establishment
1. Establishing an intestinal bacteria library serving as a donor volunteer for fecal bacteria transplantation in clinic:
firstly, extracting DNA from feces provided by 45 fecal transplant donors from Kunming hospital, picking 100 mu L of fecal sample, respectively adding 200 mu L of SDS, 200 mu L of broken beads, 400 mu L of DNA binding solution PCR-A (AxyPrep AP-PCR-250) and 400 mu L of phenol chloroform into the feces, fully mixing uniformly by using a tissue breaker, centrifuging at 12000rpm for 5min, transferring supernatant into a preparation tube (provided in AxyPrep kit), placing the preparation tube into a 2mL centrifuge tube (provided in AxyPrep kit), centrifuging at 12000 Xg for 1 min, and discarding filtrate. The preparation tube was placed back into a 2mL centrifuge tube, 700. Mu.L Buffer W2 (desalted solution, provided in the kit) was added, and 12000 Xg was centrifuged for 1 min, and the filtrate was discarded. The preparation tube was placed in a clean 1.5 mL centrifuge tube (provided in the kit), 25-30 μl deionized water was added to the center of the preparation tube membrane, and the tube was allowed to stand at room temperature for 1 min. DNA was eluted by centrifugation at 12000 Xg for 1 min, and diluted to 2 ng/. Mu.L to obtain fecal flora DNA of each group. A portion was subjected to 16S rDNA sequencing (attorney docket Jin Weizhi Co.) and the sequencing results are shown in FIG. 1.
Single colonies were isolated from 10 volunteers FMT (numbers 2646, 2696, 2701, 2800, 2815, 2819, 2820, 2824, 2848, 2904) in which 16S sequencing showed high bacterial diversity: the volunteer faeces samples were stored in 20% glycerophosphate buffer and diluted to 10 gradient respectively -5 ，10 -6 ，10 -7 Each concentration was plated on GAM broth (Solarbio LA 4450), BBE (pseudo-bile esculin solid medium, solarbio LA 7310), RCM (Clostridium enrichment medium, qingdao sea Bob HB 0316), MRS broth (Solarbio cat#M 8540), TSA (tryptone soy agar, OXOID, CM 1065), BHI (brain heart extract medium, OXOID, CM 1136), columbia blood plates (Bickmann organism). The monoclonal was picked up to the corresponding liquid medium, and the species were determined by sequencing (amplification procedure: 94℃for 3min, 94℃for 30s,65 ℃ (-1 ℃ C./cycle) for 30s,72℃for 30s (1 kb/30 s), step2-4 10 cycles, 94℃for 30s,55℃for 30s,72℃for 30s, step5-7 for 30-35 cycles, 72℃for 5min, 12℃for 5 min) with 16s rRNA universal primer (upstream primer sequence 27F, downstream primer sequence 1492R) and stored at-80 ℃. Shaking the bacteria at 37deg.C to OD 600 At=0.8, the bacterial culture supernatant was collected by centrifugation at 3000rpm for 10min and frozen at-40 ℃ for future use. Together, a pool of 5 phylum, 12 class, 15 order, 25 family 1000 strains was established, containing the major group of human intestinal microorganisms.
DSS model detection of FMT donor samples
SPFC57/B6j mice (SPF grade, 6-8 weeks old, purchased from Xuezhikang) were used and were divided into healthy groups (HC, 4), DSS model control groups (CTRL, 5) and experimental groups (FMT, 5).
Preparing a tetrad antibiotic solution: to 250mL of mouse drinking water were added 0.25g ampicillin, 0.25g neomycin, 0.25g metronidazole and 0.125g vancomycin hydrochloride.
Fecal samples (FMT, run in biosafety cabinet) required for fecal transplantation were prepared: 1mL (about 1 g) of the fecal sample was sucked up by using a 1mL range pipette, diluted and mixed uniformly with 10mL of a sterile phosphate buffer solution, the suspension was filtered through a 200. Mu.L filter screen to remove residues in the fecal sample, the filtrate was collected, sub-packaged, and placed in a-80℃refrigerator for frozen storage.
Preparing a DSS solution: a sample of 5g dextran sodium sulfate (Dextran Sulphate Sodium, DSS, source MP Biomedicals CAT NO. 1601110) was weighed out and 1000mL of sterile water was added to it to make a 2.5% DSS solution.
As shown in fig. 2, the mice were treated as follows:
mice entered the mouse house to adapt to the environment on day-13, and healthy mice provided regular drinking water and food for free feeding without additional treatment. The mice in the DSS molding control group and the mice in the experimental group are respectively perfused with the four-linked antibiotic solution on the-12 th day, -10 th day and-8 th day, and the volume of each perfusing is 200 mu L/mouse; the FMT and sterile phosphate buffer solutions were infused on days-6, -4, -2, each with a volume of 200 μl/mouse and a CFU of about 2 x 10 8 The method comprises the steps of carrying out a first treatment on the surface of the Starting on day 0, mice of group 2 were DSS-modeled using DSS solution, and mice were weight-tested daily during DSS modeling. By day 11, the mice were sacrificed, and the large intestine was surgically removed from the abdominal cavity of the mice for photographing, and the results are shown in fig. 4.
The results of fig. 3 and 4 show that, compared with the DSS molding control group (CTRL), after fecal bacteria transplantation (FMT) of the fecal bacteria transplanted donor, the weight of the mice is reduced slowly with time, and the length of the large intestine is longer on day 11, so that the mice have a certain effect of relieving inflammatory enteritis.
Example 2: screening of target strains
Na d ve CD4T cells were isolated from spleens of 6-8 week Foxp3 fluorescent reporter mice (insertion of IRES sequences and the phycoerythhrin fluorescent protein sequence following Foxp3 protein transcription sequences, allowing simultaneous expression of Foxp3 by cells expressing phycoerythhrin fluorescence).
Specifically, surface fat was removed from spleen tissue, phosphate buffer saline was added, ground into a cell suspension, and the residual tissue was filtered with a steel mesh. The cells were collected at the bottom of the tube by centrifugation at 500g at 4℃for 5min, and the erythrocytes were removed by addition of erythrocyte lysate. The remaining cells were isolated by CD4T cell magnetic bead sorting kit (Biolegend 480035) to give nameive CD4T cells.
1.5X10 s obtained above 5 CD4T cells were activated in vitro by adding anti-CD3 antibody (final concentration 5. Mu.g/mL) and anti-CD28 antibody (final concentration 2. Mu.g/mL) (Biolegend 100223,Biolegend 102112) to CD4T cells at 1.5X10 5 96-well plates were plated per well. To the wells, 20. Mu.L of culture supernatant of the single strain isolated from the sample No. 2815FMT was added for stimulation, and the culture was continued for 4d (i.e., stimulation time 4 d).
The above cells were collected (about 1X 10) 6 Tube) was added with 60. Mu.L of a mixture containing a specific surface-labeled fluorescent antibody (KO 525-dye Biolegend 0.05. Mu.L/well, FITC-CD 4 Biolegend 0.2. Mu.g/well) and left at 4℃for 15-20min in the absence of light. The 1 XPBS was topped up and washed once (6000 rpm. Times.2 min).
Resuspending the cells with 200-300 mu L of 1 XPBS at a loading concentration of 3-5X 10 6 /mL. The cell suspension was filtered through a 200 mesh nylon mesh to remove impurities, transferred to an Ep tube, checked on-machine, and analyzed with Flowjo software. Taking Foxp3 as an example, single cells are encircled by FSC-H and FSC-A on the horizontal axis and the vertical axis, and se:Sub>A viable cell negative to dye is encircled in se:Sub>A single cell gate, then CD4 positive is encircled, and the positive condition of the Foxp3 of the CD4T cell is detected, so that the results of each group are shown in FIGS. 5-6. FIG. 5 shows the strategy described above for the flow gate and FIG. 6 shows the results of in vitro stimulation of bacterial culture supernatants.
In FIG. 6, strain 238 was isolated on a GAM plate and allowed to grow on BBE plates as an off-white colony by anaerobic culture in GAM broth. The results of 16s rRNA obtained by the 16s sequencing method of example 1 are shown in SEQ ID NO. 1. The strain 16s rRNA gene analysis was performed by submitting to NCBI blast website (https:// blast. NCBI. Nlm. Nih. Gov/blast. Cgi). The comparison result shows that the strain with highest similarity isCollinsella aerofaciensStrain JCM 10188 (similarity 99.56%), therefore the strain belongs toCollinsella aerofaciensSeed, number it asCollinsella aerofaciensibiome002。
The results show that, as can be seen from FIG. 6, the metabolite produced by strain 238 (Klebsiella aerogenes) identified in the figure promotes the differentiation of naend CD4T cells into Treg cells most strongly among the different strains of volunteer origin.
Example 3: coliform bacteria culture supernatant lavage mice in vivo field planting condition and safety
As in the previous experimental procedure, as in FIG. 7, the culture supernatant of the ibiome002 bacteria was perfused daily, 200. Mu.L/mouse, 2X 10 10 CFU, and the weight of the mice is detected every two days in the process of stomach irrigation, and the organs of the mice are weighed when the mice are sacrificed, so that the safety of the strain is evaluated.
By comparing the weight detection of mice and the weight of each organ, no obvious difference is observed in each group, and no swelling and weight gain of liver, kidney and intestines are observed, so that the safety of the strain ibiome002 is proved to be better.
Intestinal lamina propria lymphocyte separation instant flow detection
On day 14, each group of mice was euthanized, the intestinal contents were rinsed with PBS and the intestinal canal was dissected, the intestines were cut into 1-2cm pieces and placed in 25mL of predigested liquid (RPMI 65mL, sieve G4530-500ML; fetal bovine serum 1.2mL,Clark,FB15011;EDTA 120. Mu.L, bio-technology, B540625-0500), and shaken at 37℃for 20min at 220 rpm. Filtering the obtained culture medium through a 200-mesh steel net, adding a predigested liquid into the intestinal section for subsequent treatment, and centrifuging the filtered culture medium to obtain intestinal epithelial cells and intraepithelial lymphocytes. Repeating the above steps for 2 times, adding the rest tissue into digestive juice (RPMI 10mL, saiweier G4530-500ML; DNase I20 μL Roche 11284932001; type II collagenase 5mg sigma SCR103; fetal bovine serum 0.2mL,Clark FB15011) containing collagenase and DNase, and filtering to obtain intestinal lamina propria lymphocyte.
The lamina propria lymphocytes were labeled with Biolegend-specific fluorescent antibodies (KO 525 dyne, FITC CD45.2, APC-A750 CD3, perCP CD 4), the blocking of the external standard was stimulated normally, the supernatant was aspirated after centrifugation, 20. Mu.L of supernatant was left, after resuspension, 250. Mu.L of Fixation/Permeabilization solution was added per tube, mixed well and labeled at 4℃for 20min. 500. Mu.L of 1 XPerm/Wash ™ buffer was added to each tube, 10000rpm X3 min, the supernatant was aspirated twice for the last time, 30. Mu.L of an internal standard antibody (PE Foxp3 bioleged) prepared with 1 XPerm buffer was added after resuspension of the cells, and after mixing, the cells were labeled at 4℃for 30min in the absence of light. The antibody was washed by centrifugation at 500. Mu.l of 1 XPerm buffer at 10000rpm X3 min, resuspended in an appropriate volume of PBS and filtered before being transferred to the tube for detection. And (3) detecting the secretion of Foxp3 on the flow cytometry. The streaming gate-dividing strategy is shown in fig. 8: after separating the intestinal epithelial cells of the mice, the living cells are circled out, the CD45+ lymphocytes are circled out, the CD3+ T cells are circled out, the CD4 is further distinguished, and finally the differentiation of the Foxp3 positive CD4T cells is detected. The streaming results are shown in fig. 9.
The results showed that, as seen from fig. 9, the positive ratio of Foxp3 in the group of lavage phosphate buffer CD4T cells was lower than that of the iriome 002 culture supernatant for the group of lavage, confirming the effect of the intestinal flora on CD4T cell differentiation into Treg. This demonstrates that lavage via the ibiome002 culture supernatant can improve the immunomodulatory capacity of mice, especially in terms of cell effects in tregs in Lamina Propria Lymphocyte (LPL) CD4T.
Example 4: therapeutic effect of strain ibiome002 culture supernatant on inflammatory enteritis mouse model
The currently most widely used preclinical mouse models of IBD are chemically induced disease models, such as Dextran Sodium Sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), oxazolone, and the like. The main advantages of chemically induced IBD models are relatively low molding costs and ease of development. The experiment constructs a mouse inflammatory enteritis model by using DSS and TNBS respectively.
1. DSS mouse inflammatory enteritis model
DSS is a negatively charged sulfated polysaccharide that when administered to mice destroys epithelial cells. Then, nonspecific immune cells release cytokines, leading to inflammation of the colon, characterized by ulcers and granulocyte infiltration. Common uses of DSS-induced colitis models include studying how the innate immune system participates in intestinal inflammation, and finding important links to maintaining or reestablishing epithelial integrity during/after injury.
As previously shown in figure 10Mice of the experimental group were subjected to gastric lavage treatment for two weeks on the culture supernatant of ibiome002, 200. Mu.L/mouse, 2X 10 6 CFU; for the control group, control gavage treatment was performed using GAM medium used for the ibiome002 culture at a concentration of od=1 at 200 μl/mouse. On day 1 during DSS modeling, the labeled mice were identified and their body weights were determined. DSS solution was administered to the drinking bottles of the cages. Each mouse used 5mL of DSS solution per day. On day 3, the bottles were emptied and the remaining DSS solution was measured. The bottles were filled with fresh DSS solution (5 per day mL per mouse). Mice were fed with 2.5% DSS solution. Each mouse had about 5-8 mL of DSS solution per day. Mice were weighed daily (fig. 11) and observed for fecal status. The sacrificial mice were treated on day 10, and the large intestine was surgically removed from the abdominal cavity of the mice for photographing, and the results are shown in fig. 12.
The results show that compared with the control group, after the ibiome002 culture supernatant is used for lavaging, the weight of the mice is slowly reduced along with time, and the length of the large intestine is longer on day 10 of DSS treatment, so that the mice have a certain effect of relieving inflammatory enteritis.
2. TNBS (tumor-associated bs) model for simulating enteritis of mice
TNBS is a small molecule that is not antigenic in itself, but that, when bound to host proteins, causes an immune response and is therefore a hapten. TNBS-treated mice can establish a preclinical model mimicking clinical Crohn's Disease (CD) in which the immune response generated is Th 1-mediated, characterized by infiltration of cd4+ T cells, neutrophils and macrophages. A laterally progressing inflammation is formed, leading to transmural colitis. The TNBS-induced colitis model is very suitable for studying CD immunology and can also be used to test the efficacy of new immunotherapy.
As previously shown in FIG. 13, mice of the experimental group were subjected to gastric lavage treatment of the ibiome002 culture supernatant for two weeks, 200. Mu.L/mouse, 2X 10 8 CFU; for the control group, control gavage treatment was performed using GAM medium used for the ibiome002 culture at a concentration of od=1 at 200 μl/mouse. Following the pre-sensitization of the mice, fresh acetone and olive oil were mixed by vigorous vortexing at a volume ratio of 4:1 on the day of pre-sensitization. Mixing 4 volumes of acetone/olive oil with1 volume of 5% (wt/vol) TNBS solution was mixed to obtain 1% (wt/vol) TNBS. The solution was mixed by rigorous vortexing. The mouse was weighed and marked for identification throughout the experiment (day 1). The mouse was gently anesthetized with 1.5% isoflurane mixture while the mouse was placed on an isothermal heating pad. An electric razor was used to shave a 1.5 x 1.5 cm area of skin between the shoulders of the mouse back to prevent the animal from licking the area. Licking may induce oral tolerance. mu.L of 1% (wt/vol) TNBS pre-sensitization solution was applied to the shaved skin area with a pipette. The solution should be absorbed rapidly by the skin. The mouse was replaced with a cage and monitored for good recovery. Hold until day 8. Mice were treated on day 8, at which time the body weight of the experimental mice should not change much from the initial body weight and they should have no obvious signs of distress. If the body weight is less than 95% of the initial body weight, the mice should be removed from the rest of the experiment. The mouse was anesthetized by ip administration of 80 μl/10 g body weight of a 2mg/kg ketamine/xylazine solution and placed on an isothermal heating pad. A 1ml syringe was connected to the 3.5F catheter and filled with 2.5% (w/v) TNBS solution. The catheter was passed through the anus into the colon approximately 4 cm. Progress is very slow to avoid damage or perforation of the colon wall. If any resistance is sensed during catheterization, the catheter is removed and gentle reinsertion is attempted. mu.L of 2.5% (wt/vol) TNBS solution was slowly injected into the colon lumen. The catheter was slowly removed from the intestine and the mouse head was left down for 1 minute. In order to obtain reproducible results, it must be ensured that the TNBS solution remains completely in the colon. The mouse is put back into the cage. At selected time points (typically at day 1, 2 or 3 after intrarectal TNBS administration). The treatment of the sacrificial mice was performed on day 12, and the large intestine was surgically removed from the abdominal cavity of the mice for photographing, and the results are shown in fig. 14 to 15.
The results show that compared with the control group, after the ibiome002 culture supernatant is used for lavaging, the weight of the mice is slowly reduced with time, and the length of the large intestine is longer on the 12 th day of TNBS treatment, so that the mice have a certain effect of relieving inflammatory enteritis.
Example 5: containingCollinsella aerofaciensDrug of ibiome002
Will beCollinsella aerofaciensibiome002（2*10 10 CFU/mL) is subjected to anaerobic culture with GAM culture medium, culturing at 37deg.C for 24-36 hr, centrifuging, cooling and drying until water content is less than 3%, to obtain the final productCollinsella aerofaciensThe medicine bacterial powder of the ibiome 002.
Example 6: containingCollinsella aerofaciensPharmaceutical composition of ibiome002
0.5g of the product prepared in example 6 is weighedCollinsella aerofaciensMixing iriome 002 bacteria powder, folic acid 0.4mg, vitamin B12 0.2 μg, maltodextrin 0.5g, and encapsulatingCollinsella aerofaciensA pharmaceutical composition of ibiome002 bacteria.
Example 7: pharmaceutical composition for treating inflammatory bowel disease
The pharmaceutical composition prepared in example 7 was taken orally in 2 capsules/day in combination with hydrocortisone 300 mg/day orally for 1-2 weeks.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solution of the present invention should fall within the scope of protection defined by the claims of the present invention without departing from the spirit of the present invention.
Claims (7)
1. Coliform bacteria producing gasCollinsella aerofaciens) ibiome002, its characterized in that: the coliform bacteria strain is preserved in China center for type culture collection, the address is eight paths of China center for type culture collection of Wuhan university in Wuhan district of Wuhan, hubei province, the preservation date is 2022, 9 and 27 days, and the preservation number is CCTCC NO: m20221518.
2. A pharmaceutical composition characterized by: comprising the coliform bacteria of claim 1Collinsella aerofaciens) ibiome002 or culture supernatant thereof, and a pharmaceutically acceptable carrier.
3. The coliform bacteria of claim 1Collinsella aerofaciens) Use of ibiome002 or a culture supernatant thereof, or a pharmaceutical composition according to claim 2, for the manufacture of a medicament for alleviating, treating or co-treating inflammatory bowel disease.
4. A use according to claim 3, characterized in that: the pharmaceutical composition also includes other substances for preventing, treating or assisting in the treatment of inflammatory bowel disease.
5. Use according to claim 3 or 4, characterized in that: the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
6. Use according to claim 3 or 4, characterized in that: the inflammatory bowel disease is DSS or TNBS induced enteritis.
7. The coliform bacteria of claim 1Collinsella aerofaciens) Use of ibiome002 or a culture supernatant thereof, or a pharmaceutical composition according to claim 2, for the preparation of a Treg agonist, which is an agent or drug that increases the efficiency of Treg cell differentiation in CD4T cells.
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| Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD;Thomas Lee等;《Gut》;参见全文 * |
| 炎症性肠病和结直肠癌患者肠道细菌宏基因组分析;马永顺;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;参见全文 * |
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