HBV肝硬化临床进展中肠道微生物组的动态规律及共代谢机制研究

Gut microbiome plays an important role in liver cirrhosis. However, the mechanism of it in development of liver cirrhosis remains to be unclear. It is already found out in our preliminary study that gut microbiome takes a part in the development of liver cirrhosis. Moreover, there are significant functional interactions between gut microbiome and the host, whereas the abundance of genes associated with nutritional metabolism is significantly reduced in HBV-associated liver cirrhosis. Therefore, it is assumed that gut microbiome may play a role in the development of liver cirrhosis by regulating the host metabolism. Based on the metagenomic data and urine samples from some healthy volunteers and HBV-associated liver cirrhosis that are produced in our previous study, this project plans to collect stool and urine samples from 25 compensated and 15 decompensated liver cirrhosis patients. We try to elaborate the dynamics of gut microbiome and its functional interactions with hosts during the development of liver cirrhoisis, to clarify the pathogenesis of liver cirrhosis from the view of microecology, and to provide the theoretical basis to the early of warning of liver cirrhosis and development of intestinal probiotics by integrated analysis of fecal metagenomics and urine metabolomics data.

肠道微生态与肝硬化关系密切，但其参与肝硬化发生发展的生物学机制不明确。我们在前期研究中发现，肠道菌群与肝硬化的临床进展相关。肠道菌群与宿主之间存在显著的功能性相互作用，而HBV后肝硬化患者肠道中与营养代谢相关的基因的丰度显著降低，提示肠道菌群可能通过调控宿主代谢参与肝硬化的疾病进展。本项目在先前研究中已经获得部分健康对照和HBV肝硬化患者的粪便宏基因组测序数据和尿液样本的基础上，拟新收集25例代偿期和15例失代偿期肝硬化患者的粪便和尿液样本，通过整合分析粪便宏基因组测序数据和尿液代谢组数据，阐述肝硬化临床进展过程中肠道微生物组的动态规律及其与宿主的功能性相互作用，阐明肝硬化临床进展的肠道微生态机制，寻找肝硬化的早期诊断标记物，为肝硬化早期预警和微生物制剂的开发提供理论基础。

肠道微生态与肝硬化关系密切，但其参与肝硬化发生发展的生物学机制不明确。我们在前期研究中发现，肠道菌群与肝硬化的临床进展相关。肠道菌群与宿主之间存在显著的功能性相互作用，而HBV后肝硬化患者肠道中与营养代谢相关的基因的丰度显著降低，提示肠道菌群可能通过调控宿主代谢参与肝硬化的疾病进展。本项目选择了先前研究中已经获得的年龄相匹配的47例健康对照、49例代偿期和46例失代偿期肝硬化患者的肠道菌群宏基因组测序数据，并利用液质联用技术获得对应健康对照/患者的尿液代谢物组信息，通过宏基因组-代谢组数据整合分析探讨了肠道菌群和尿液代代谢物组在肝硬化临床进展中的动态规律、肠道菌群与肝硬化进展的相关性，以及肝硬化临床进展过程中肠道微生物的共代谢机制。研究发现，肠道菌群参与肝硬化临床进展。参与植物细胞壁多糖和抗性淀粉代谢的菌（如Alistipes sp. HG5, Clostridium thermocellum）显著减少，导致能量供应减少、菌群之间的自饲和互饲网络紊乱，以及某些机会致病菌如Veillonella菌属增加。产丁酸菌的显著减少和与肠道粘膜降解有关的菌（如Ruminococcus gnavus）的增加为肝硬化患者的肠道屏障功能损伤以及系统性炎症提供了可能的解释。该研究为以肠道菌群为靶点的肝硬化患者早期检测和干预提供了可能。