脆弱拟杆菌上调LC3/ROS通路促进MUC2分泌调控溃疡性结肠炎黏膜稳态的机制研究

Interactions of gut commensal bacteria and intestinal epithelium plays an essential role in the homeostasis and recovery of mucosa and thus determines the development of Ulcerative Colitis(UC). LC3/ROS pathway is regarded as a vital signal pathway in intestinal MUC2 secretion induced by gut commensal bacteria. However, the exact bacteria that mediate this function remains unknown. In our previous research, we observed flora disturbance and the impairment of gut mucosa in DSS-induced colitis model, while the bacteroides fragilis we isolated could significantly alleviated colitis and promote the expression of LC3 and MUC2. Besides, it also regulated the intestinal mucosal flora in mice of colitis. Based on our research, we speculate bacteroides fragilis may exert its function through LC3/ROS pathway to increase the secretion of MUC2, thus regulate intestinal microbiota, maintain the homeostasis of mucus layer and finally alleviate gut inflammation in UC. In this project, we plan to construct the mouse model of UC, combined with C. rodentium model, clinical specimens, transgenic animals and organoid culture, to unveil the the regulation pattern and mechanism between commensal bacteria and gut mucosa, as well as gut mucosa and pathogenic bacteria. This may provide a new insight on the beneficial effect of commensal bacteria on UC intestinal mucosal barrier, and lay a groundwork for the clinical application of bacteroides fragilis in UC.

肠道共生菌与黏膜上皮的相互作用不仅影响溃疡性结肠炎（UC）的发生发展，而且在UC肠黏膜稳态的修复中发挥重要作用。LC3/ROS信号通路被认为是肠道共生菌介导杯状细胞MUC2分泌进而维持肠黏膜稳态的重要通路，但具体哪些细菌对其进行调控仍未明确。前期工作中,我们发现DSS实验性肠炎小鼠肠黏膜屏障受损，黏膜菌群紊乱，而我们自主分离得到的脆弱拟杆菌能明显改善这一现象，且增加小鼠肠道LC3蛋白和杯状细胞MUC2的表达。我们推测脆弱拟杆菌可能通过LC3/ROS通路促进UC肠道杯状细胞MUC2的分泌，进而调控肠黏膜菌群，维持肠黏膜稳态，最终缓解UC肠道炎症。本项目拟构建小鼠肠炎模型和柠檬酸杆菌感染模型，结合临床标本、转基因动物和类器官培养,深入探讨共生菌与肠黏膜上皮、肠黏膜上皮与致病菌之间相互作用的调控模式。本项目将为共生菌改善UC肠黏膜稳态提供新的理论依据,也为脆弱拟杆菌防治UC的临床应用奠定基础。

肠道共生菌与黏膜上皮的互相作用不仅影响溃疡性结肠炎的发生发展，而且在UC肠黏膜稳态的修复中发挥重要作用。LC3/ROS信号通路被认为是肠道共生菌介导杯状细胞MUC2分泌进而维持肠黏膜稳态的重要通路，但具体哪些细菌对其进行调控仍未明确。前期工作中,我们发现DSS实验性肠炎小鼠肠黏膜屏障受损，黏膜菌群紊乱，而我们自主分离得到的脆弱拟杆菌能明显改善这一现象，且增加小鼠肠道LC3蛋白和杯状细胞MUC的表达。我们推测脆弱拟杆菌可能通过LC3/ROS通路促进UC肠道杯状细胞MUC2的分泌，进而调控肠黏膜菌群，维持肠黏膜 稳态，最终缓解UC肠道炎症。本项目拟构建小鼠肠炎模型和柠檬酸杆菌感染模型，结合临床标本、转基因动物和类器官培养,深入探讨共生菌与肠黏膜上皮、肠黏膜上皮与致病菌之间相互作用的调控模式。本项目将为共生菌改善UC肠黏膜稳态提供新的理论依据,也为脆弱拟杆菌防 治UC的临床应用奠定基础。