人体肠道菌对炎性肠病中NF-kB介导的信号通路调控机制的研究

炎症性肠病是肠道粘膜屏障、免疫系统和肠道菌群之间一系列复杂的相互作用导致，然而，其致病机理并不清楚，既往研究表明，肠道菌通过分泌的小分子代谢物而参与肠上皮细胞的免疫调控，进而导致肠道免疫系统紊乱及疾病的发生。课题组前期已经完成了144株人体肠道菌的分离、鉴定及体外培养体系，建立了肠类器官体外培养体系，初步构建完成CRISPR/Cas9 mouse gRNA筛选文库，在人肠上皮Henle-407细胞中构建了NF-κB免疫信号通路报告筛选系统。在此基础上，本研究拟通过代谢组学和CRISPR/Cas9高通量筛选体系筛选出能激活天然免疫信号通路的肠道菌代谢小分子及作用靶点，在细胞和分子水平对肠道菌代谢物的作用机制进行深入研究，结合小鼠IBD模型，揭示特定肠道菌代谢产物致炎性肠病的致病机理，为精准治疗肠道菌相关的免疫性疾病提供可靠的理论依据和新的治疗靶点。

Inflammatory bowel disease is caused by a series of complex interactions between intestinal mucosal barrier, immune system and intestinal flora. However, its pathogenic mechanism is unclear. Previous studies have shown that intestinal microbiota participate in the immune regulation of intestinal epithelial cells through secreted small molecule metabolites, which leads to intestinal immune system disorders and diseases. Our team has finished the following studies during the early stage: isolation, identification, in vitro culture of 144 human intestinal bacteria, in vitro culture system of intestinal organoids, initial construction of CRISPR / Cas9 mouse gRNA screening library and the screening system for inflammatory bowel disease-related immune NF-κB signaling pathways in the human intestinal epithelial Henle-407 cells. Based on this, through metabolomics and CRISPR / Cas9 high-throughput screening system, this study intends to screen small molecules and effective targets of intestinal bacteria that can activate the natural immune signaling pathway. In-depth research on the action mechanism of intestinal bacteria metabolites at the cellular and molecular level, combined with mouse IBD model, reveals the pathogenic mechanism of inflammatory bowel disease caused by specific intestinal bacteria metabolites. Which provide reliable theoretical basis and new therapeutic targets for the precise treatment of intestinal bacteria-related immune diseases.