朝药草芍药基于肠肝轴对肝纤维化肠道稳态失衡-炎症通路的调控作用研究

肝纤维化是慢性肝病向终末期肝病发展的关键环节，多数肝纤维化由炎症发展，甚至来自机体内循环炎症，均可诱发肝脏内微循环的紊乱。前期研究发现朝药草芍药及抗肝纤维化活性成分激活肝脏LXRs和FXR抑制肝纤维化及炎症，并缓解肝纤维化小鼠结肠组织炎性浸润。肠道FXR是胆汁酸受体，对胆汁酸转运、肠道菌群以及肠道炎症至关重要。据此，本课题提出草芍药基于肠肝轴调控肠道稳态失衡-炎症通路进而改善肝纤维化的相关假说。体内研究从肝纤维化小鼠肝脏组织、肠道组织，探讨草芍药逆转肝纤维化、调控肝纤维化过程中肠道稳态失衡作用；体外从肝星状细胞、肝细胞、肠上皮细胞、以及巨噬细胞各层面，探讨草芍药逆转活化HSCs、调控细胞炎性因子释放、介导肠道核受体调控胆汁酸转运；明确草芍药对关键靶位肠肝轴以及信号转导的调控，最终阐明草芍药基于肠肝轴抗肝纤维化的作用机制，为民族药治疗肝纤维化提供新的思路和理论依据。

Hepatic fibrosis is a necessary station in the development of chronic liver diseases to end-stage liver diseases. Most liver fibrosis develops from inflammation, and even inflammation of internal circulation, which result in hepatic microcirculation disturbance. Our previous study found that Korean medicine Paeonia obovate Maxim and its anti-hepatic fibrosis active ingredients could activate liver LXRs and FXR to inhibit hepatic fibrosis and inflammation, and alleviate colonic inflammatory infiltration in mice with hepatic fibrosis. FXR exists in liver and intestine, a bile acid receptor, and is essential for bile acid transport, intestinal flora and intestinal inflammation. Accordingly, our project propose the hypothesis that Korean medicine Paeonia obovate Maxim regulates intestinal homeostasis dysregulation-inflammatory pathway in hepatic fibrosis based on gut-liver axis. In vivo, we would study the effect of Paeonia obovate Maxim on reversing hepatic fibrosis and regulating intestinal homeostasis imbalance in the process of hepatic fibrosis in mice. In vitro, we would explore the reversal of activated HSCs, regulation of inflammatory cytokines release, and regulation of bile acid transport via intestinal nuclear receptors by Paeonia obovate Maxim, in hepatic stellate cells, hepatocytes, intestinal epithelial cells, and macrophages. The study would clarify that Paeonia obovate Maxim regulates gut-liver axis and relative signal transduction, further clarify anti-hepatic fibrosis mechanism of Paeonia obovate Maxim based on gut-liver axis, to provide new ideas and theoretical basis for the treatment of hepatic fibrosis by ethnic medicine.