肠道稳态变化与肝病重症化的因果关系及相互作用机制研究

In China, nearly 130 million people are carriers of hepatitis B or C virus and 30 million are chronically infected. Besides, over 100 million people are troubled by Non-viral liver diseases such as fatty liver diseases, drug-induced liver diseases and autoimmune liver diseases. 10% to 20% of these liver diseases will aggravate to lethal hepatic Cirrhosis or hepatic failure, but their mechanisms remain unclear.. The liver is the first extra intestinal organ that encounters venous blood from the small and large intestines via the portal vein. Due to this unique blood supply system, the liver is vulnerable to exposure of intestine imbalance. Simultaneously, the liver can regulate digestive and immunological functions of intestines. It is reported that severe hepatic diseases are developed together with intestine imbalance. The causality and interaction between them are still puzzling, because too many factors, especially the complicated microbita in intestines, are involved in this process.. We have worked in the field of liver diseases and intestine imbalance for about twenty years. A series of significant discoveries are reported by our team. Some papers have been published in Nature Nano Technology, Hepatology ,PNAS and etc..In this program, we will firstly investigate the immunological and metabolic correlation between liver diseases and intestine imbalance using samples from patients. Then, we will try to disclose the causality and some important mechanism between these two diseases using germ free rat as main matirials. Our results will do great help to the preservation and treatment of serve liver diseases.

我国有肝炎病毒携带者及脂肪性、药物性等肝病患者逾2亿，由于肝病重症化机制不明、缺乏防治手段， 10%-20%可进展为肝硬化等高病死率重症肝病，严重危害人民健康和社会发展。肝肠在解剖位置和功能上密切相关，肠道稳态变化与肝病重症化同时存在、循环影响，如何区分它们间的因果关系，找出相互作用途径并阐明机制，是研究关键和世界难题。历经近二十年研究，课题组在重症肝病与肠道稳态失衡领域取得系列重大成果，论文发表在Nature Nanotechnology，Hepatology，PNAS等期刊，多次主办国际会议。本课题将深入揭示重症肝病患者肠道稳态失衡与肝病发生发展的关联；利用无菌大鼠和正常大鼠，研究去除和回补肠道菌群条件下：重症肝病对肠道稳态的影响，及肠道稳态变化对肝脏的作用与机制，从而阐明肝病重症化与肠道稳态变化的因果关系与机制，为肝病重症化防治提供新思路方法，具有重要理论研究和应用价值。

本项目圆满完成了既定任务，建立了世界上首个肝病肠道菌群基因集，揭示了肝硬化与肠道菌群的秘密，成果在Nature上发表；揭示肝衰竭的肠道宏基因组变化，为肝病重症化救治提供了微生态理论基础；阐明了肝硬化患者肠道免疫、代谢、微生态结构和功能的稳态变化及其与肝病发生发展的关联；揭示肠道菌群改变与非肥胖的非酒精性脂肪肝患者的肝功能相关性；揭示了早期肝癌患者的肠道微生态变化；揭示了肝衰竭过程中细菌易位与CD4+T细胞变化的因果关系；筛选到具有自主知识产权的益生菌动物实验显著防治肝衰竭和肝硬化；发现粪菌移植技术能够改善某些病毒性肝炎患者病情。成果在Nature， Environ Microbiol，J Proteomics等发表论文30篇（均标注项目编号）；获得发明专利5项；获国家科学技术进步奖特等奖1项，国家院终末期肝病综合诊治创新团队奖（一等奖）1项，国家科学技术进步奖一等奖1项；编写《医学微生态学》教材和国际首部《Infectious Microecology 》(Springer出版)；培养博士研究生9名，硕士研究生8名；项目负责人当选第五届国际人体微生组协会（IHMC）主席，举办2015年卢森堡国际人类微生态大会，举办5次全国性微生态学术大会，在国内外学术大会报告10余次，在国际肝病微生态的研究和应用中发挥了重要作用。