肠道C.scindens菌通过肠-肝免疫轴(TLR2-肠源性CXCL1-肝内中性粒细胞胞外诱捕网)促进胆结石形成的机制研究

胆囊结石是消化系统疾病中社会经济成本最高的疾病之一，然而其成因仍是当前研究的难点。目前研究多集中于胆汁酸的肠-肝循环及肝细胞方向。本课题则聚焦于由肠菌、结肠上皮细胞、肝内免疫细胞及其间免疫介质构成的肠-肝免疫轴。我们前期筛选出肠道梭状芽胞杆菌（C.scindens），并发现该菌作用于结肠上皮细胞可通过模式识别受体TLR2，经NF-κB通路，促进趋化因子CXCL1释放入门静脉并入肝，在对肝组织的测序及免疫浸润分析发现肝组织内中性粒细胞浸润与C.scindens丰度相关。同时，发现肝内中性粒细胞胞外诱捕网（NETs）生成增多，NETs可作为胆固醇结晶的支架，加速结石形成。据此我们提出假说：肠道C.scindens通过肠-肝免疫轴（TLR2-肠源性CXCL1-肝内NETs）促进胆囊结石形成。本课题拟从分子、细胞及动物水平等多层次明确其具体机制，以期为胆囊结石防治提供新的思路并促进临床转化。

Gallbladder stone disease is one of the diseases with the highest social and economic cost among digestive system diseases. However, its cause is still a difficult problem in previous studies. At present, researches mainly focus on the hepatocyte and enteric-hepatic circulation of bile acid. This study focuses on the enteric-hepatic immune axis, which is composed of intestinal bacteria, colonic epithelial cells, intrahepatic immune cells and their immune mediators..We have already screened out intestinal clostridium scindens（C.scindens）, and found that the bacteria act on the colon epithelial cells by pattern recognition receptors(TLR2), via the NF-κB pathway. Then the bacteria promotes chemokines(CXCL1) release to portal vein, finally to liver.Transcriptome sequencing and immunity infiltration analysis showed that neutrophils infiltration in liver tissue of gallstone mice was positively correlated with the abundance of C.scindens. At the same time, the generation of neutrophils extracellular traps (NETs) in the liver of model mice were increased. NETs can act as a scaffold for cholesterol crystallizing and may accelerate stone formation..In view of the above, we hypothesize that intestinal C.scindens promotes gallstone formation through the enteric-hepatic immune axis (TLR2-enterogenous CXCL1-intrahepatic NETs). This study aims to clarify the specific mechanism from the molecular, cellular and animal levels, hoping to lay a theoretical foundation and provide new ideas for the prevention and treatment of gallbladder stone disease and promote clinical transformation.