IECs相关肠道免疫屏障损伤在急性胰腺炎致肠道细菌移位中的机制：Tlr5通路的作用

Intestinal bacterial translocation occurs in severity acute pancreatitis (SAP) patients play an important role in leading to sepsis and MOF, which bend to the mechanism of intestinal machinery and immune barrier function disorder, and the intestinal mucosal immune injury plays a particularly important role. Several studies found that intestinal epithelial cells (IECs) may not only build machinery barrier but also be involved in regulation of local immune and intestinal bacteria distribution through Toll-like receptor 5 (Tlr5) activation. On the basis of a model of SAP combined with intestinal bacterial translocation, we try to clarify the mechanism of intestinal immune barrier function disorder and bacterial translocation been directly or indirectly (with the help of lamina propria dendritic cells, LPDCs) regulated by Tlr5 signal system of IECs with techniques of conditional knockout (Tlr5f/f), co-stimulation to induce lymphocyte differentiation and bacterial tracing with biological fluorescent, etc. This work will not only provide an explanation for how SAP leading to intestinal bacterial translocation, more likely for the future of providing the theoretical basis for a new type of immunotherapy targets at IECs.

致病菌发生肠外移位是急性胰腺炎继发脓毒血症(SEPSIS)、多脏器功能衰竭(MOF)的重要因素。其机理为肠道机械及免疫屏障功能障碍。研究发现小肠上皮细胞（intestinal epithelial cells, IECs）在构筑了机械屏障的同时亦能通过其Toll样受体-5（Tlr5）激活参与肠道局部免疫及细菌分布的调节。故课题组拟在急性胰腺炎合并肠道细菌移位的小鼠模型平台上，采用条件性基因敲除（Tlr5 f/f）技术、体外共刺激诱导淋巴细胞分化以及生物荧光标记细菌示踪等技术进一步明确IECs及其Tlr5信号系统直接或在肠粘膜下树突状细胞（lamina propria dendritic cells, LPDCs）辅助下间接调控肠道免疫状态及细菌移位的机制。其不但为急性胰腺炎继发细菌移位提供科学解释，更有可能为开发以IECs为靶标的新型免疫治疗提供理论依据。

致病菌发生肠外移位是急性胰腺炎继发脓毒血症（SEPSIS）、多脏器功能衰竭（MOF）的重要因素，其机理为肠道机械及免疫屏障功能障碍。小肠上皮细胞（IECs）在构筑了机械屏障的同时亦能通过其Toll样受体-5（Tlr5）激活参与肠道局部免疫及细菌分布的调节。本研究在重症急性胰腺炎（SAP）合并肠道细菌移位的小鼠模型平台上，采用Tlr5全身敲除与IECs/LPDCs条件性敲除转基因小鼠模型，生物发光柠檬酸杆菌肠菌移位示踪、肠道免疫细胞改良提取方法、质谱流式（CyTOF）等技术，证实SAP导致多器官损伤与肠道生物屏障、机械屏障和免疫屏障破坏，引起肠菌移位，发现了Tlr5敲除虽然不影响胰腺本身的炎症损伤，但是可以缓解肠屏障破坏、肠菌移位，改善SAP小鼠预后，且该过程IECs与肠道固有层树突状细胞（LPDCs）可能在鞭毛蛋白-Tlr5信号途径密切联系，进一步明确了IECs及其Tlr5信号系统直接或经LPDCs调控肠道免疫状态及细菌移位的机制。本研究也提供了基于IECs/LPDCs与鞭毛蛋白-Tlr5信号途径的两类肠屏障维护措施，精细化的短肽型肠内营养、视黄酸可以有效改善SAP导致的肠屏障功能紊乱、减少肠菌移位。同时本研究不但为急性胰腺炎继发细菌移位提供了科学解释，更为开发以IECs及其Tlr5信号为靶标的新型免疫治疗提供理论依据。