The Role And Mechanisms Of Dysregulated Bile Acid-gut Microbiota Metabolic Axis In Obesity Susceptibility

ObjectiveIn recent years,bile acids(BAs)have been recognized as important signaling molecules to modulate metabolism,which are closely associated with obesity and are modified by gut microbiota.The effects and mechanism of the changes of bile acid(BA)composition mediated by the gut microbiota on the metabolic status of obesity and the susceptibility to obesity remain poorly understood.In this study we aimed to investigate the changes of bile acid and gut microbiota under different obesity status,interactive association between gut microbiota and bile acid,and effects of the changes of BA profile mediated by gut microbiota on the susceptibility to obesity.MethodsThe serum bile acid profiles of 183 case-control subjects(including 121 metabolically healthy overweight / obese subjects and 62 metabolically unhealthy overweight / obese subjects)were measured and analyzed using targeted metabolomic method.Metabolomics and metagenomics analysis were performed to analyze the changes of BA and gut microbiota of high fat diet obesity prone(HF-OP)and high fat diet obesity resistant(HF-OR)mice.The gene expression and related regulating factors involved in bile acid synthesis were analyzed.In addition,the expressions of glucagon-like peptide-1(GLP-1)in ileum and thermogenic genes in brown adipose tissue were detected.In vitro,different bile acids were used to stimulate GLP-1 secretion from intestinal endocrine cells.Furthermore,the mice were colonized with Clostridium scindens to observe changes of BA profile.Finally,BA profiles and effects of ursodeoxycholic acid(UDCA)on obesity were analyzed after UDCA administration in HFD mice.Results1.In case-control study,the proportions of non-12-OH bile acids in serum were significantly increased in metabolically healthy overweight / obese subjects,and had negative correlation with serum glucose,total cholesterol,triglyceride,and insulin resistance index.The proportion of non-12-OH BAs had good performance in predicting metabolically healthy overweight / obesity subjects.2.Compared with HF-OP mice,the levels of non-12-OH bile acid were significantly increased in HF-OR mice.The levels of UDCA,chenodeoxycholic acid(CDCA)and lithocholic acid(LCA)were significantly decreased in HF-OP mice,whereas the levels of TCA were increased.Compared with HF-OP mice,hepatic sterol-12a-hydroxylase(CYP8B1)expression levels were significantly lower in HF-OR mice,while oxysterol7?-hydroxylase(CYP7B1)expression levels were higher.3.Metagenomic data suggested that gut microbiota in HF-OP and HF-OR mice were significantly different.Clostridium scindens was significantly decreased in HF-OP mice,and was closely associated with the levels of UDCA and LCA in stool.In vivo,serum C4 levels and hepatic non-12-OH bile acid levels were significantly elevated in mice after Clostridium scindens colonization.4.Compared with HF-OR mice,the expression levels of GLP-1 and Glucagon(the precursor of GLP-1)in ileum of HF-OP mice were significantly reduced.The expression levels of PGC-1a and UCP1 in brown adipose tissue of HF-OP mice were obviously downregulated.In vitro,bile acid,especially non-12-OH bile acid,displayed a stronger potential to enhance GLP-1 secretion in the enteroendocrine cell lines.5.UDCA was the most decreased bile acid in HF-OP group.We identified that treatment with UDCA in HFD mice enhanced the non-12-OH BA%,and attenuated the HFDinduced obesity phenotype.ConclusionsThis study demonstrates that the non-12-OH BA% is closely with metabolically healthy overweight / obesity.Compared with high fat diet obesity prone mice,the levels of non-12-OH bile acid are significantly increased in high fat diet obesity resistant mice.Dysregulated BA signaling mediated by gut microbiota alters host metabolism and contributes to host metabolism and obesity susceptibility.The balance of BA synthesis(between the classical and alternative pathways)may be an important target for regulating metabolism in obesity,suggesting modulation of BA composition could be a promising strategy for obesity therapy.