胆汁酸代谢紊乱和肠道微生态失衡与肠道炎症发生关系密切。研究表明炎症相关性肠病个体肠腔中胆汁酸池（pool）增加可能是由肠道FXR负反馈作用减弱所致，且肠道某些产胆盐水解酶（BSH）菌可影响胆汁酸代谢及抑制肠道FXR表达。我们发现脱氧胆酸（DCA）可显著促进肠上皮细胞炎症因子分泌，且体内研究证明DCA可使肠道产BSH菌群（产乳酸菌及双歧杆菌属）丰度减少，肠道Fxr表达下降并伴随肠炎发生。故我们推测“DCA诱导肠道微生态失衡，并协同抑制肠道FXR反馈作用加重结肠炎”。本研究首先评价DCA介导的肠炎发生过程中肠腔胆汁酸组成、肠道菌群组成改变、FXR及其下游分子表达变化；采用抗生素整体调控肠道菌群探讨DCA诱导肠炎进展情况、肠道菌群及胆汁酸变化；最后探讨产BSH菌及肠道特异性FXR激动剂对DCA介导的肠炎小鼠肠FXR-FGF15轴及肠道炎症的影响。预期成果将为胆汁酸相关性肠炎的防治提供一种新思路。

Bile acid dysmetabolism and intestinal dysbiosis are associated with development of intestinal inflammation. Studies have revealed that increased bile acids pool was found in the intestinal lumen of individuals with intestinal inflammation, which might through the negative activity of intestinal FXR feedback signaling. It was also demonstrated that some strains of probiotics could express the bile salt hydrolase (BSH), thus modulates the bile acid metabolism and intestinal FXR signaling. Our preliminary results have demonstrated that deoxycholic acid (DCA), a secondary bile acid, could significantly upregulated the level of intestinal inflammatory cytokines. In vivo, we found the abundance of BSH-producing bacteria (Lactobacillus and Bifidobacterium) were decreased and the expression of intestinal Fxr was repressed during the progression of colitis mediated by DCA. Based on these preliminary studies, we hypothesize that DCA induces intestinal dysbiosis, and collectively repressed the intestinal FXR feedback signaling, which contributes to the aggravation of intestinal inflammation. Our proposal is firstly to determine how DCA induces changes of bile acid composition and intestinal microbiota during the development of intestinal inflammation. We also analyze the intestinal FXR signaling and the downstream targets in this process. Secondly, we will use antibiotics cocktail to modulate the intestinal microbiota generally to explore its effects on the intestinal inflammation development, changes of gut microbiota and bile acid metabolism. Lastly, we will evaluate the effects of BSH- producing bacteria and the gut-restricted FXR agonist fexaramine (Fex) on the intestinal inflammation mediated by DCA and activation of bile acid-related FXR signaling. Results from our project will provide new insights in the prevention and treatment of bile acid related intestinal inflammatory diseases.