基于“肠-肝轴”研究绿原酸-栀子苷组合调控枯否细胞极化治疗非酒精性脂肪性肝炎的作用机制

The treatment for Nonalcoholic steatohepatitis (NASH) is very important because NASH is a key phase for the development of liver fibrosis, cirrhosis, liver cancer and other chronic liver disease. Combination or compound of effective component of Traditional Chinese Medicine (TCM) has become the focus research of integrated Traditional and Western medicine， which are characterized by clear material basis and maintain the disciplines of overall compatibility according to theory of TCM. It is reported that uniform design is a good method for chlorogenic acid and geniposide to form the optimization dosage for NASH. Combination of chlorogenic acid and geniposide had remarkable curative effect for NASH, with decreasing portal vein endotoxin (LPS) content and inhibiting the expression of kupffer cells M1 polarization. Results indicated that the mechanism of combination of chlorogenic acid and geniposide for NASH is involved in the regulation of gut-liver axis.A scientific hypothesis has been proposed: the mechanism of combination of chlorogenic acid and geniposide for regulation of kupffer cells polarization signal pathway induced by LPS is based on the gut-liver axis. To verify the hypothesis, rat NASH model induced by high fat diet in vivo and M1 Kupffer cells polarization induced by LPS in vitro will be established; changes of the intestinal bacteria, intestinal permeability, endotoxemia and kupffer cells polarization will be observed. The aim of research is to reveal the mechanism of combination of chlorogenic acid and geniposide to regulate the Kupffer cells polarization by LPS signal pathway based on gut-liver axis theory.

非酒精性脂肪性肝炎（NASH）作为肝纤维化、肝硬化、肝癌等慢性肝病发生、发展的重要阶段，截断其发展已成为肝病防治的焦点。中药有效成分组合或复方在实现中药复方“去粗取精”基础上，回归中医方剂“整体配伍”学科特色，是中医药创新发展的方向。研究证实，剂量配比优化的绿原酸-栀子苷组合治疗NASH疗效显著，具有降低门静脉内毒素（LPS）含量、抑制枯否细胞M1极化的作用特点，或参与调控“肠-肝轴”作用机制。课题组提出科学假说：绿原酸-栀子苷组合调控“LPS-枯否细胞M1极化”信号通路治疗NASH是基于“肠-肝轴”学说。为验证该假说，拟采用高脂饮食诱导的大鼠NASH模型以及LPS诱导枯否细胞M1极化与肝细胞共培养的体外模型，基于“肠-肝轴”学说，剖析肠道菌群结构、肠壁通透性、内毒素含量以及枯否细胞极化状态变化，同时围绕“LPS-枯否细胞M1极化”信号通路，揭示绿原酸-栀子苷组合治疗NASH的作用机理。

非酒精性脂肪性肝炎(NASH)作为肝纤维化、肝硬化、肝癌等慢性肝病发生、发展的重要阶段，截断其发展已成为肝病防治的焦点。中药有效成分组合或复方在实现中药复方“去粗取 精”基础上，回归中医方剂“整体配伍”学科特色，是中医药创新发展的方向。研究证实，剂量配比优化的绿原酸-栀子苷组合治疗NASH疗效显著，具有降低门静脉内毒素(LPS)含量、抑制枯否细胞M1极化的作用特点，或参与调控“肠-肝轴”作用机制。课题组提出科学假说:绿原酸-栀子苷组合调控“LPS-枯否细胞M1极化”信号通路治疗NASH是基于“肠-肝轴”学说。为验证该假说，本研究采用高脂饮食诱导的大鼠NASH模型以及LPS诱导枯否细胞M1极化与肝细胞共培养的体外模型，基于“肠-肝轴”学说，剖析肠道菌群结构、肠壁通透性、内毒素含量以及枯否细胞极化状态变化，同时围绕“LPS-枯否细胞M1极化”信号通路，揭示绿原酸-栀子苷组合治疗NASH的作用机理。研究结果表明，高脂饮食导致肠道菌群紊乱、肠粘膜通透性损伤、内毒素血症，肝脏枯否细胞极化、炎症介质释放的NASH“肠-肝轴”发病机制，绿原酸-栀子苷组合则具有从“肠-肝轴” 角度论治NASH的作用特点以及调控“LPS-枯否细胞M1极化”信号通路治疗NASH的作用机制。