肠道菌群-宿主代谢物轴参与肝硬化进展的机制和菌群调控研究

Liver cirrhosis is associated with a high mortality. The number of cirrhotic patients in our country is very high and the control task is arduous. At present, it is found that the stage and complications of patients with liver cirrhosis significantly affect their survival rate, indicating that delaying and reversing the disease progression is critical to the treatment of cirrhosis. However, the existing antiviral treatment methods have limited effect on delaying the disease process, so it is urgent to elucidate the mechanism of liver cirrhosis progression and lay a foundation for the development of the new treatment plan. In the previous study, it was found that intestinal microbiome was closely related to the development of liver cirrhosis. Dysfunction of intestinal microbial structure in patients with liver cirrhosis can regulate the communications among intestinal microbiome and between intestinal microbiome and host through some small molecule metabolites, indicating that intestinal microbial-host metabolic axis plays an important role in the progression of liver cirrhosis. This study intends to use systematic functional genomics technology to comprehensively analyze the relationship between the structure and functions of intestinal microbiome and corresponding small molecule metabolites in the progression of liver cirrhosis, elucidate the roles of intestinal microbial-host metabolic axis in the progression of liver cirrhosis, and discuss the potential of flora intervention in delaying cirrhosis process. The results would provide effective theoretical and experimental support for remodeling the normal metabolic and communication networks between intestinal flora and delaying and reversing the clinical progression of cirrhosis.

肝硬化患者死亡率极高。我国肝硬化患者人数众多，防治任务艰巨。目前研究发现，肝硬化患者的疾病进程和并发症显著影响其生存率，延缓和逆转疾病进程对肝硬化治疗至关重要。然而，现有抗病毒等药物治疗方式在延缓疾病进程等方面的效果有限，亟需阐明肝硬化进展机制，为新治疗方案的开发奠定基础。申请人前期研究发现，肠道菌群与肝硬化进展相关。肝硬化患者肠道中菌群结构紊乱引发的功能紊乱可以通过相关的小分子代谢物调控肠道菌群之间以及肠道菌群与宿主之间的通讯，指示肠道菌群-宿主代谢物轴在肝硬化进展过程中起重要作用。本课题拟利用系统功能组学技术全面解析肝硬化进展过程中肠道菌群结构-功能-小分子代谢物之间的对应关系，阐明肠道菌群-宿主代谢物轴参与肝硬化进展的分子机制，探讨菌群调控在延缓肝硬化进程方面的潜力，以期为重塑肠道菌群之间的正常代谢和通讯网络来延缓和逆转肝硬化临床进展提供有效的理论和实验支持。

肝硬化患者死亡率极高。我国肝硬化患者人数众多，防治任务艰巨。目前研究发现，肝硬化患者的疾病进程和并发症显著影响其生存率，延缓和逆转疾病进程对肝硬化治疗至关重要。然而，现有抗病毒等药物治疗方式在延缓疾病进程等方面的效果有限，亟需阐明肝硬化进展机制，为新治疗方案的开发奠定基础。申请人前期研究发现，肠道菌群与肝硬化进展相关。肝硬化患者肠道中菌群结构紊乱引发的功能紊乱可以通过相关的小分子代谢物调控肠道菌群之间以及肠道菌群与宿主之间的通讯，指示肠道菌群-宿主代谢物轴在肝硬化进展过程中起重要作用。本研究在前期研究结果的基础上构建了非酒精性脂肪性肝病（NAFLD）的小鼠肝脏纤维化模型，利用肠道菌群宏基因组测序和代谢组学整合研究解析了肝脏纤维化相关肠道菌群小分子代谢物、肠道菌群功能和物种组成，发现3-苯丙酸是肠道菌群介导NAFLD纤维化的重要介质。此外，我们探讨了葛根芩连汤对肝脏炎症和纤维化的干预效果和相关机制，发现葛根芩连汤能从组织学水平改善NAFLD小鼠的疾病状态。进一步研究发现，葛根芩连汤经由肠道菌群-3-苯丙酸-TGR5轴调控NAFLD纤维化，为NAFLD患者的临床治疗提供了新思路。在本项目的经费支持下，申请人还探讨了单纯脂肪变NAFLD患者的血清蛋白组学改变，发现肝脏单纯脂肪变状态下患者的天然免疫响应即被激活，为开发NAFLD患者的早期干预和治疗方案提供了新思路。我们利用单细胞转录组学测序技术探讨了HBV患者不同炎症状态下肝脏穿刺样本中的细胞组成，发现HBV相关的肝脏炎症进展过程中存在两群不同的MAIT细胞亚群且参与了肝脏的炎症进展，提示MAIT细胞可能成为HBV相关肝脏炎症的潜在治疗靶点。我们还构建了单细胞转录组测序数据的时序分析算法scTITANS，为利用单细胞时序数据从宿主的角度挖掘疾病进展相关的关键基因和关键细胞提供了有效方法。