京大戟醋制调节肠道菌群干预宿主代谢重塑肠道粘膜屏障功能降低肾毒性机制研究

京大戟有毒，《中国药典》规定用醋制法炮制。研究显示京大戟除具有胃肠道毒性还具有肾毒性，但其肾毒性的物质基础及醋制减毒机理尚未阐明。课题组前期研究发现，京大戟醋制后毒性二萜类成分结构发生了转化，同时肾毒性显著降低。进一步研究显示，醋制能够改善京大戟导致的肠道菌群失调，减少肠源性尿毒素的合成。我们推测，京大戟醋制后，毒性二萜类成分结构发生转化，通过改善肠道微生态和宿主代谢紊乱，重塑肠道粘膜屏障功能，从而发挥降低肾毒性且存效的作用。本项目拟基于肠-肾轴的京大戟醋制减毒研究思路，采用相似结构归一化法分析京大戟醋制前后化学物质变化规律；以干预肠道菌群和宿主代谢网络为切入点，综合中药化学、病理学、系统生物学等技术交叉融合，阐明京大戟醋制通过改善肠道菌群和机体宿主代谢网络紊乱，减轻肠道粘膜屏障功能损伤降低肾毒性的物质基础和作用机制。本研究为京大戟临床安全用药提供支撑，也为中药炮制机理研究提供新思路。

Euphorbia pekinensis is poisonous and processed with vinegar according to Pharmacopoeia of the People's Republic of China. The research confirmed that it has significant kidney toxicity besides gastrointestinal toxicity, but its material basis of toxicity and detoxification mechanism in vinegar-processing is still unclear. Our study showed that the nephrotoxicity of Euphorbia pekinensis processed with vinegar was significantly reduced. The structure of the main diterpenoids of Euphorbia pekinensis was transformed after vinegar-processing, at the same time, it could cause gut microbiota disorders and reduce urotoxin synthesis. Therefore, we suggest that the structure of toxic diterpenoids from Euphorbia pekinensis could be transformed after vinegar-processing, and then interfere with host metabolism by regulating gut microbiota, and remold intestinal mucosal barrier function, so as to play a role in reducing nephrotoxicity and preserving effect. This project intends to study the detoxification of vinegar processed Euphorbia pekinensis based on the gut-kidney axis. Analysis of chemical constituents of Euphorbia pekinensis before and after vinegar-processing is taken by similarity structure normalization method, taking the intervention of gut microbiota and host metabolism network as the breakthrough point. Based on the integration of chemistry of Chinese material medica, pathology, system biology and other technologies, this project elucidates the material basis and mechanism of vinegar-processed Euphorbia pekinensis in reducing nephrotoxicity through regulating gut microbiota and host metabolic network disorder, and reducing the damage of intestinal mucosal barrier function. Providing support for clinical safe medication of Euphorbia pekinensis, and reference for the research of the processing mechanism of traditional Chinese medicine.