基于“肠道微生态移植--致病因素拆分”滇白珠抗类风湿关节炎活性部位作用机制研究

本项目是前两个国家自然基金的深入和延续。滇白珠是西南少数民族治疗类风湿关节炎（RA）的常用药，申请者前期通过系列研究确定了滇白珠抗RA活性部位ARF，在明确其抗RA活性、药效成分组成及量效关系的同时，发现其与肠道菌群存在相互作用。近年来肠道菌群与RA的密切关系使其成为相关药物机制研究的热点，然而仅基于普通RA动物模型的研究模式存在局限性，无法确证哪些机制变化是药物通过调节肠道菌群产生的。本项目通过菌群移植，剥离非菌群致病因素及药物对宿主的直接作用，只将RA失调或经ARF调节恢复的肠道微生态传递给无菌动物，建立“菌群单病因”研究模型。并基于该研究模型，利用微生态测序、分子生物学、代谢组学等技术，从菌群失调的直接损伤作用、协同损伤作用及对易感性的影响方面，探究ARF抗RA的菌群调节相关作用机制，丰富其科学内涵，填补研究空白，同时为其他民族药的肠道菌群调节相关疾病治疗机制的研究提供新思路。

This project is the continuation and further study of the last two NSFC. Dianbaizhu is a common herb for the treatment of rheumatoid arthritis (RA) among ethnic minorities in southwest China. The applicant identified the anti-RA fraction (ARF) of Dianbaizhu through a series of previous studies. While elucidating the anti-RA activity, active components and PK/PD of ARF, it was found to have an interaction with gut microbiota. Recently, the close relationship between gut microbiota and RA has made gut microbiota become a hotspot for mechanism research of anti-RA drug. However, most of the research based on normal RA animal models have limitations, which is impossible to confirm which mechanism could be attributed to the microbiota regulative effect of drugs. This project intends to stripping the direct effect of drugs on host and pathogenic factors except gut microbiota change through gut microbiota transplantation. The gut microbial communities were transferred to the germ-free mouse, so as to establish a “microbiota single etiology” research model. Based on the research model, microecological sequencing, molecular biological and metabonomics technology was used to explore mechanism related to the gut dysbiosis reversed effect of ARF against RA from the prespective of the direct damage, collaborative damage and RA susceptibility caused by dysbacteriosis. The present study will enrich the scientific connotation of Dian baizhu, and will also provide a new idea for gut dysbiosis reversed effect related mechanism research of other ethnic drugs.