BACKGROUND Fecal microbiota transplantation(FMT)has shown promising therapeutic effects on mice with experimental colitis and patients with ulcerative colitis(UC).FMT modulates the Toll-like receptor 4(TLR4)signaling ...BACKGROUND Fecal microbiota transplantation(FMT)has shown promising therapeutic effects on mice with experimental colitis and patients with ulcerative colitis(UC).FMT modulates the Toll-like receptor 4(TLR4)signaling pathway to treat some other diseases.However,it remains unknown whether this modulation is also involved in the treatment of UC.AIM To clarify the necessity of TLR4 signaling pathway in FMT on dextran sodium sulphate(DSS)-induced mice and explain the mechanism of FMT on UC,through association analysis of gut microbiota with colon transcriptome in mice.METHODS A mouse colitis model was constructed with wild-type(WT)and TLR4-knockout(KO)mice.Fecal microbiota was transplanted by gavage.Colon inflammation severity was measured by disease activity index(DAI)scoring and hematoxylin and eosin staining.Gut microbiota structure was analyzed through 16S ribosomal RNA sequencing.Gene expression in the mouse colon was obtained by transcriptome sequencing.RESULTS The KO(DSS+Water)and KO(DSS+FMT)groups displayed indistinguishable body weight loss,colon length,DAI score,and histology score,which showed that FMT could not inhibit the disease in KO mice.In mice treated with FMT,the relative abundance of Akkermansia decreased,and Lactobacillus became dominant.In particular,compared with those in WT mice,the scores of DAI and colon histology were clearly decreased in the KO-DSS group.Microbiota structure showed a significant difference between KO and WT mice.Akkermansia were the dominant genus in healthy KO mice.The ineffectiveness of FMT in KO mice was related to the decreased abundance of Akkermansia.Gene Ontology enrichment analysis showed that differentially expressed genes between each group were mainly involved in cytoplasmic translation and cellular response to DNA damage stimulus.The top nine genes correlating with Akkermansia included Aqp4,Clca4a,Dpm3,Fau,Mcrip1,Meis3,Nupr1 L,Pank3,and Rps13(|R|>0.9,P<0.01).CONCLUSION FMT may ameliorate DSS-induced colitis by regulating the TLR4 signaling pathway.TLR4 modulates the composition of gut microbiota and the expression of related genes to ameliorate colitis and maintain the stability of the intestinal environment.Akkermansia bear great therapeutic potential for colitis.展开更多
BACKGROUND Emerging evidence has demonstrated that fecal microbiota transplantation(FMT)has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis(UC),although the mechan...BACKGROUND Emerging evidence has demonstrated that fecal microbiota transplantation(FMT)has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis(UC),although the mechanism of FMT is unclear.AIM To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota,through association analysis of gut microbiota with colon transcriptome in mice.METHODS Dextran sodium sulfate(DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage.Severity of colon inflammation was measured by body weight,disease activity index,colon length and histological score.Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing.The differentially expressed genes(DEGs)in the colon were obtained by transcriptome sequencing.The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry.RESULTS Compared with the DSS group,the weight loss,colon length shortening and inflammation were significantly alleviated in the FMT group.The scores of disease activity index and colon histology decreased obviously after FMT.FMT restored the balance of gut microbiota,especially by upregulating the relative abundance of Lactobacillus and downregulating the relative abundance of Clostridium_sensu_stricto_1 and Turicibacter.In the transcriptomic analysis,128 DEGs intersected after DSS treatment and FMT.Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation.In the DSS group,there was an increase in colonic T helper CD4^(+)and T cytotoxic CD8^(+)cells by flow cytometry.FMT selectively downregulated the ratio of colonic CD4^(+)and CD8^(+)T cells to maintain intestinal homeostasis.Furthermore,Clostri dium_sensu_stricto_1 was significantly related to inflammation-related genes including REG3G,CCL8 and IDO1.CONCLUSION FMT ameliorated DSS-induced colitis in mice via regulating the gut microbiota and T-cell modulation.展开更多
基金the Scientific Research Project of Jiangsu Provincial Health Commission,No.H2018082Huai’an Natural Science Research Project Project,No.HAB201926Scientific Research Project of Translational Medicine Innovation Team of Huai’an First People’s Hospital,No.YZHT201905.
文摘BACKGROUND Fecal microbiota transplantation(FMT)has shown promising therapeutic effects on mice with experimental colitis and patients with ulcerative colitis(UC).FMT modulates the Toll-like receptor 4(TLR4)signaling pathway to treat some other diseases.However,it remains unknown whether this modulation is also involved in the treatment of UC.AIM To clarify the necessity of TLR4 signaling pathway in FMT on dextran sodium sulphate(DSS)-induced mice and explain the mechanism of FMT on UC,through association analysis of gut microbiota with colon transcriptome in mice.METHODS A mouse colitis model was constructed with wild-type(WT)and TLR4-knockout(KO)mice.Fecal microbiota was transplanted by gavage.Colon inflammation severity was measured by disease activity index(DAI)scoring and hematoxylin and eosin staining.Gut microbiota structure was analyzed through 16S ribosomal RNA sequencing.Gene expression in the mouse colon was obtained by transcriptome sequencing.RESULTS The KO(DSS+Water)and KO(DSS+FMT)groups displayed indistinguishable body weight loss,colon length,DAI score,and histology score,which showed that FMT could not inhibit the disease in KO mice.In mice treated with FMT,the relative abundance of Akkermansia decreased,and Lactobacillus became dominant.In particular,compared with those in WT mice,the scores of DAI and colon histology were clearly decreased in the KO-DSS group.Microbiota structure showed a significant difference between KO and WT mice.Akkermansia were the dominant genus in healthy KO mice.The ineffectiveness of FMT in KO mice was related to the decreased abundance of Akkermansia.Gene Ontology enrichment analysis showed that differentially expressed genes between each group were mainly involved in cytoplasmic translation and cellular response to DNA damage stimulus.The top nine genes correlating with Akkermansia included Aqp4,Clca4a,Dpm3,Fau,Mcrip1,Meis3,Nupr1 L,Pank3,and Rps13(|R|>0.9,P<0.01).CONCLUSION FMT may ameliorate DSS-induced colitis by regulating the TLR4 signaling pathway.TLR4 modulates the composition of gut microbiota and the expression of related genes to ameliorate colitis and maintain the stability of the intestinal environment.Akkermansia bear great therapeutic potential for colitis.
基金Scientific Research Project of Jiangsu Provincial Health Commission,No.H2018082Huai'an Natural Science Research Project,No.HAB201926Scientific Research Project of Translational Medicine Innovation Team of Huai'an First People's Hospital,No.YZHT201905。
文摘BACKGROUND Emerging evidence has demonstrated that fecal microbiota transplantation(FMT)has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis(UC),although the mechanism of FMT is unclear.AIM To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota,through association analysis of gut microbiota with colon transcriptome in mice.METHODS Dextran sodium sulfate(DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage.Severity of colon inflammation was measured by body weight,disease activity index,colon length and histological score.Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing.The differentially expressed genes(DEGs)in the colon were obtained by transcriptome sequencing.The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry.RESULTS Compared with the DSS group,the weight loss,colon length shortening and inflammation were significantly alleviated in the FMT group.The scores of disease activity index and colon histology decreased obviously after FMT.FMT restored the balance of gut microbiota,especially by upregulating the relative abundance of Lactobacillus and downregulating the relative abundance of Clostridium_sensu_stricto_1 and Turicibacter.In the transcriptomic analysis,128 DEGs intersected after DSS treatment and FMT.Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation.In the DSS group,there was an increase in colonic T helper CD4^(+)and T cytotoxic CD8^(+)cells by flow cytometry.FMT selectively downregulated the ratio of colonic CD4^(+)and CD8^(+)T cells to maintain intestinal homeostasis.Furthermore,Clostri dium_sensu_stricto_1 was significantly related to inflammation-related genes including REG3G,CCL8 and IDO1.CONCLUSION FMT ameliorated DSS-induced colitis in mice via regulating the gut microbiota and T-cell modulation.
