普拉梭菌通过IL-22诱导肝脏巨噬细胞M2型极化抑制肝硬化进展的作用及机制研究

肠道菌群失调引起的肝脏慢性炎症与肝硬化发病密切相关，其中哪些细菌发挥关键作用及其机制尚不明确。巨噬细胞作为肝脏免疫微环境的重要组分，对肝硬化发展至关重要。我们研究发现：肝硬化患者肠道内普拉梭菌数量异常减少；该菌可减轻肝硬化小鼠的肝损伤，同时肝脏中IL-22高表达，M2型巨噬细胞比例增加。据此假设：普拉梭菌相关代谢产物可促进肝脏中IL-22的产生，进而诱导肝巨噬细胞向M2型极化，抑制肝硬化进展。本课题拟分析患者体内普拉梭菌的数量与肝硬化临床指标的相关性，明确该菌是否与肝硬化严重程度有关。利用普拉梭菌干预肝硬化小鼠，明确该菌在抑制肝硬化进展中的作用以及对肝肠代谢组学特征的影响。通过IL-22抗体阻断以及IL-22敲除小鼠，结合转录组测序探讨该菌调控肝脏巨噬细胞向M2型极化的分子机制。本项目从普拉梭菌调控肝脏免疫微环境的角度，揭示菌群失调在肝硬化发病中的新机制，为肝硬化治疗提供新靶点和实验依据。

Chronic liver inflammation caused by gut microbiota dysbiosis is closely related to the pathogenesis of cirrhosis, but which bacteria play a key role and their mechanisms are still unclear. As an important component of the hepatic immune microenvironment, macrophages are crucial to the development of liver cirrhosis. Our study found that: the number of Faecalibacterium prausnitzii (F.p) in the gut of patients with cirrhosis was abnormally reduced; The bacterium could alleviate liver injury in cirrhosis mice, meanwhile, IL-22 was highly expressed in the liver, and the proportion of M2-type macrophages was increased. Based on this, we hypothesize that the metabolites related to F.p can induce the polarization of hepatic macrophages to M2-type by promoting the expression of IL-22 in the liver, thus inhibiting the progression of cirrhosis. This study intends to analyze the correlation between the number of F.p in patients and the clinical indicators related to cirrhosis, so as to determine whether the bacterium is related to the severity of cirrhosis. We intend to use F.p to interfere with liver cirrhosis mice to clarify the role of this bacterium in inhibiting the progression of liver cirrhosis and its influence on the characteristics of hepatic and intestinal metabolomics. We will use antibodies to block IL-22 and IL-22 knockout mice, combined with transcriptome sequencing, to reveal the molecular mechanism of the F.p regulating hepatic macrophages polarization to M2-type. This project reveals the new mechanism of gut microbiota dysbiosis in the pathogenesis of liver cirrhosis from the perspective of F.p regulating the hepatic immune microenvironment, and provides new targets and experimental basis for the treatment of liver cirrhosis.