小檗碱口服给药具有显著的抗类风湿关节炎作用，但血浆和组织浓度远低于体外细胞试验的最低有效浓度，其体内效应机制尚不清楚。本项目基于前期研究，考察小檗碱在胶原关节炎大鼠多次口服给药后的药动学行为，并结合肠道外给药试验证实其抗关节炎作用的肠道依赖性；筛选研究小檗碱对肠道和滑膜等部位抑炎性胃肠肽表达的影响，明确皮质抑素或/和生长抑素是其抗关节炎效应的关键中介；考察小檗碱对关节炎大鼠肠道菌群多样性和丰度的调控及其对短链脂肪酸产生的促进作用，阐明短链脂肪酸诱导上述抑炎性胃肠肽表达的分子机制；采用受体拮抗剂和基因沉默等手段，验证小檗碱“通过调节肠道菌群、促进短链脂肪酸产生，诱导皮质抑素或/和生长抑素表达，恢复Th17/Treg平衡，从而改善关节炎”的科学假说。预期成果为小檗碱的开发利用提供理论依据，亦为具有类似药动学特点化合物的抗类风关机制的研究提供借鉴，并加深对肠道微生态与类风关发生发展相关性的认识。

Berberine, orally administered, has marked anti-rheumatoid arthritis effect. However, its plasma/tissue concentrations are far below the minimal effective concentrations of in vitro cell experiments, and the in vivo mechanisms of action remain to be clarified. In accordance with our preliminary studies, this project confirms the intestine-dependent characteristics of the anti-arthritic effect of berberine based on its pharmacokinetic behaviors after multiple oral dosings and results obtained from parenteral administration experiment. The effects of berberine on the expressions of anti-inflammatory gastrointestinal peptides at different sites, such as intestinal dust and synovium, are comparatively studied in an attempt to identify that cortistatin or/and somatostatin are the key players for the anti-arthritic action of berberine. Furthermore, we will investigate the effects of berberine on diversity and richness of the gut microbiota as well as production of short-chain fatty acids (SCFAs) in arthritis rats, and gain insight into the molecular mechanisms for SCFAs enhancing the expressions of cortistatin or/and somatostatin. Finally, specific antagonists and RNA interference technique are used to verify the hypothesis that berberine functions by “regulation of gut microbiota-promotion of SCFAs production-induction of cortistatin or/and somatostatin expression-restore of Th17/Treg balance-amelioration of arthritis”. The findings will provide evidence for the development and utilization of berberine, offer a paradigm for the mechanistic studies of anti-arthritic compounds with similar pharmacokinetic characteristics to berberine, and enhance our understandings of the relationship between intestinal bacterial flora and rheumatoid arthritis.