非酒精性脂肪肝病(Non-alcoholic fatty liver disease，NAFLD)是具有高发病率的全球性肝脏疾病，其病理机制不明，缺乏有效的治疗手段。肠道菌群是诱发NAFLD的重要因素，次级胆汁酸（Secondary bile acids, SBAs）由肠道菌群生产，但NAFLD患者肠道菌群中产生SBA的菌种及其调控机制还不清楚。我们在前期研究中发现：NAFLD患者SBAs浓度升高且FXR信号被抑制。本项目将首先利用宏基因组学数据，明确NAFLD病人肠道菌群产生SBAs的菌种，评估胆汁酸guild的生态作用；进一步结合代谢组学和宿主转录组学，阐明NAFLD发病过程中“胆汁酸-微生物组-NAFLD”肠肝轴变化模式。本项目的完成将从多维角度阐明肠道菌群介导的胆汁酸代谢通过肠肝轴影响FXR信号通路促进NAFLD的新机制，为基于肠道菌群的NAFLD临床干预治疗提供新干扰策略。

Non-alcoholic fatty liver disease is a globally highly prevalent liver disease, whose pathogenesis remains unclear and effective treatment is not currently available. It has been reported that gut microbiota is one of vital factors contributing to the pathogenesis of NAFLD. Notably, gut microbiota is responsible for transforming primary bile acids into secondary bile acids (SBAs). However, it is not known which species synthesize SBAs, nor is known how the bile acid “guild” microbes collaborate on bile acid metabolism. Our preliminary study demonstrated elevated SBAs production and suppressed FXR-mediated signaling in NAFLD patients. Therefore, this project will take advantage of metagenomics data to identify the microbial species responsible for the elevated SBA production in NAFLD, and this knowledge will lead to the understanding of the mechanism for SBA producing “guild” species collaborate on SBA production. Then metabolomics and transcriptomics data will be integrated to determine how the patterns of “bile acids-microbiome-NAFLD” change via gut-liver axis from multi-scale view. Accomplishing the proposed study will clarify the potential role of the gut microbiota-mediated bile acid metabolism in the pathogenesis of NAFLD via gut-liver axis, and establish a novel NAFLD intervention strategy targeting the bile acid “guild” species in the gut microbiome.