基于肠肝轴的FKN/CX3CR1信号通路在非酒精性脂肪性肝炎中的作用及葛根芩连汤调控机制研究

Fatty liver is the second major disease in all liver diseases, NASH has received more attention as the rate-limiting step of the worse outcome of fatty liver. In recent years, the role of inflammatory microenvironment based on gut-liver axis in the pathogenesis of NASH has been attached importance. FKN/CX3CR1 is a special Chemokine signaling pathway which has become an important new target in regulating the balance of anti-inflammatory Cytokines and pro-inflammatory factors and modulating the intestinal barrier function and liver injury by endotoxin. Gegen Qinlian Decoction as an conventional ascending spleen Yang, clearing heat and removing dampness classic recipes, showing new use recently, has been found a prominent role in NASH treatment. It works in intestinal, but showing function in liver, coinciding with the idea of gut-liver axis. This study is intended to verify the pharmacological effects of Gegen Qinlian Decoction on NASH. And try to find the profound therapeutic mechanism through the regulation pathway by FKN/CX3CR1 signaling. By reproducing NASH model, with histological and molecular biological techniques on three levels of body, tissue, molecule, we try to find FKN/CX3CR1 signaling pathway related molecules changes and the regulation mechanism by Gegen Qinlian Decoction. Results of the study are expected to promote TCM prevention and treatment on NASH.

脂肪肝已经成为中国第二大肝病，NASH作为脂肪肝恶性化的限速步骤广泛受到关注。近年来，基于肠肝轴的肠屏障炎性微环境在NASH发病机制中的作用越来越受到重视。FKN/CX3CR1 作为特殊的趋化因子信号通路，调节抗炎因子和促炎因子的平衡，成为调节肠道屏障功能和干预内毒素对肝脏损伤的重要新靶点。葛根芩连汤作为升发脾阳、清热燥湿经典方剂，近年来老药新用，发现其对NASH发挥显著的干预作用，作用在肠，显效于肝，与肠肝轴的思想较为吻合。本课题拟进一步验证葛根芩连汤对NASH的药理效应，并从FKN /CX3CR1信号调节途径深入研究葛根芩连汤对NASH治疗机制，通过复制NASH模型，采用组织学、分子生物学等技术，从整体-组织-细胞三个层次探讨FKN/CX3CR1信号通路相关分子变化和葛根芩连汤的调控机制。预期研究结果对促进中医药防治NASH提供重要的基础及应用价值。

脂肪肝已经成为中国第二大肝病，NASH作为脂肪肝恶性化的限速步骤广泛受到关注。近年来，基于肠肝轴的肠屏障炎性微环境在NASH发病机制中的作用越来越受到重视，FKN/CX3CR1作为特殊的趋化因子信号通路，调节抗炎因子和促炎因子的平衡，成为调节肠道屏障功能和干预内毒素对肝脏损伤的重要新靶点。葛根芩连汤作为升发脾阳、清热燥湿经典方剂，近年来老药新用，发现其对NASH发挥显著的干预作用，作用在肠，显效于肝，与肠肝轴的思想较为吻合。本课题验证了葛根芩连汤对NASH的药理效应，并从FKN /CX3CR1信号调节途径深入研究葛根芩连汤对NASH治疗机制，通过复制NASH模型，采用组织学、分子生物学等技术，从整体-组织-细胞三个层次探讨FKN/CX3CR1信号通路相关分子变化和葛根芩连汤的调控机制。研究发现，葛根芩连汤能够调节NASH脂质代谢，改善肝脏脂质堆积，肝脏炎症浸润，降低血清TC、TG、LDL-C水平；葛根芩连汤提高了肠道紧密连接蛋白ZO-1、Occludin、Claudin-1和炎症相关因子CX3CR1的表达，对FKN /CX3CR1信号具有调节作用，表明葛根芩连汤在改善肠屏障的同时，具有调节肠道炎症微环境的作用。进一步的研究发现，葛根芩连汤能够调节肠道菌群，该方在一定程度上改善肠道菌群紊乱，增加肠道菌群的多样性及丰度，调节了NASH的肠道生物屏障。这可能是葛根芩连汤治疗NASH的潜在机制之一。因此，从目前的研究结果来看，葛根芩连汤对NASH具有防治作用，其机制可能在于调节脂质代谢的同时，通过肠-肝轴的途径，改善肠道微环境和保护肠屏障的作用，降低肠道通透性，进而降低了血清内毒素水平和低度炎症状态，起到改善NASH的药理作用。此研究结果为促进中医药防治NASH提供基础及临床参考价值。