代偿性与失代偿性肝硬化肠道微生物组学变化研究

Liver Cirrhosis is a common clinical chronic progressive liver disease, causing as high as 45% lethallty rate. Cirrhosis of the liver disease progression can be divided into the compensation period and decompensation period, of which, the decompensation period is the advanced stage of liver cirrhosis. Although there were researches focus on intestinal microecological imbalance of patients with liver cirrhosis, the relationship between intestinal microecology and liver cirrhosis progression, and mechanism of how the intestinal microecological imbalance participated in decompensated cirrhosis were yet remain unknown.This project intends to take large-scale metagenomics sequencing method for comparative analysis of large samples of liver cirrhosis compensatory period patients, decompensation period and healthy people, combining bioinformatics and multivariate analysis techniques to find flora and functional genes associate with decompensated cirrhosis. Each key strain will inoculate to germ-free mice to validate the effect on liver metabolism and changes in fibrosis to discover the mechanism and pathway of intestinal microecological disorder participated in decompensated cirrhosis. The study will provide experimental basis for clinical treatment of cirrhosis and theoretical basis for probiotics development.

肝硬化是临床上常见的慢性进行性肝病，病死高达45%，随着肝硬化病情进展可分为代偿期和失代偿期，失代偿期为肝硬化的晚期。虽然对肝硬化患者的肠道微生态失衡研究较多，但关于肠道微生态与肝硬化进展的因果关系以及肠道微生态失衡如何参与肝硬化失代偿的机制目前尚不明确，需进一步深入研究。本项目拟采取大规模宏基因组测序的方法对大样本肝硬化代偿期、失代偿期患者以及健康人肠道菌群进行深入研究，结合生物信息学和多元分析技术，期望找到影响肝硬化失代偿相关标志菌群和功能基因，然后将关键菌群进行小鼠模型验证，分析每种关键菌株对无菌鼠肝脏生物代谢和纤维化改变的影响，进而阐释肠道微生态紊乱参与肝硬化失代偿的机制和通路。该研究将为临床肝硬化治疗及微生态制剂的研发提供理论依据和实验基础。

肝硬化是临床上常见的慢性进行性肝病，病死率高达45%。肝硬化分为代偿性肝硬化和失代偿性肝硬化，其中失代偿性为肝硬化的晚期。虽然对肝硬化患者的肠道微生态失衡研究较多，但关于肠道微生态与肝硬化进展的因果关系以及肠道微生态失衡如何参与肝硬化失代偿的机制目前尚不明确，需进一步深入研究。因此，本研究通过分析共计275例志愿者（包括92例代偿性肝硬化病人、69例失代偿肝硬化病人、114例健康人）的宏基因组测序数据，比较了健康组、代偿性肝硬化组与失代偿性肝硬化组之间肠道菌群的物种组成、丰度与基因功能的差异，找到了与肝硬化发生发展相关的关键菌群及功能基因。同时利用差异菌群构建了诊断模型，结果显示这些差异菌群标志物能够很好的区分肝硬化患者与健康人。此外，通过KEGG代谢通路分析，发现鉴定到的关键菌群参与了谷胱甘肽代谢通路、糖酵解/糖异生代谢通路以及酪氨酸代谢通路等，以上结果显示肠道菌群可能是通过这几个代谢通路的变化影响肝硬化的发生发展。本研究通过比较代偿性肝硬化、失代偿性肝硬化与健康人之间的肠道菌群差异，最终发现了与肝硬化发生发展相关联的关键菌群及代谢通路，进一步阐释了肠道微生态紊乱参与肝硬化失代偿的机制和通路，为肝硬化发展监测及诊断提供了新方法，为开发肝硬化新型微生态干预手段打下理论基础。