Altered profiles of fecal bile acids correlate with gut microbiota and inflammatory responses in patients with ulcerative colitis

摘要

BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.