连胆消炎方通过FXR-FGF15信号通路调控胆汁酸代谢改善DSS诱导溃疡性结肠炎

Abstract

Background Ulcerative colitis (UC) is a chronic, non-specific inflammatory disorder that primarily affects the rectal and colonic mucosa and submucosa, and its pathogenesis is closely related to the dysregulation of bile acid (BA) metabolism. Liandan Xiaoyan Formula (LDXYF), a classic Traditional Chinese medicine formula composed of Herba andrographis and Ramulus et folium, widely used for enteritis treatment in China, and its mechanism has not been clarified. Purpose To clarify the effects and mechanism of LDXYF on UC treatment via serum metabolomics and experimental verification. Methods The effects of LDXYF on UC was investigated in 3.5 % dextran sulfate sodium (DSS)-induced UC mice. Serum metabolomics strategy was applied for exploring the core mechanism of LDXYF. The regulation of LDXYF on BA metabolism and FXR-FGF15 signaling pathway were further verified by fluorescence reaction, PCR and WB technology. The critical role of FXR for UC treatment of LDXYF was studied via molecular docking, molecular dynamics simulation and FXR knockout (FXR -/- ) mice. Results LDXYF treatment alleviated UC via alleviating body weight loss, reducing disease activity index and the levels of inflammatory factors (TNF-α, MPO), and protecting intestinal barrier. Serum metabolomics revealed that LDXYF notably modulated the levels of 35 metabolites in UC mice, which mainly involved in primary bile acid synthesis, arachidonic acid metabolism, and energy metabolism, hinted the potential mechanism of LDXYF related to regulate BA metabolism by FXR-FGF15 signaling pathway. Bile acid profile showed that LDXYF altered the disorder of BA metabolism. Molecular docking and molecular dynamics simulation presented that a high affinity between active ingredients of LDXYF and FXR protein. We further demonstrated that LDXYF could increase FXR expression in both liver and colon tissues, and then subsequently regulate BA enterohepatic circulation via FXR-FGF15 axis and its target genes for cholesterol