脱硫弧菌鞭毛蛋白活化肠上皮新型受体LRRC19促进炎症性肠病发生的机制研究

炎症性肠病(IBD)发病激增与高脂饮食(HFD)及肠道菌群失调有关。文献及我们均发现IBD患者及HFD小鼠中脱硫弧菌过度生长，该菌及其鞭毛蛋白均可促进肠道炎症，但机制未明；研究报道肠上皮细胞新型受体LRRC19可识别鞭毛蛋白并启动肠粘膜慢性炎症，我们也发现IBD患者及HFD小鼠中肠上皮LRRC19表达上调，并可激活肌球蛋白轻链激酶(MLCK)破坏肠道屏障；我们还发现Lrrc19基因缺陷可减轻HFD诱导的肠屏障破坏。故我们假设脱硫弧菌鞭毛蛋白可通过活化LRRC19-MLCK信号轴促进IBD发生。本研究首先在IBD患者和多种SPF及GF的IBD模型中探讨HFD促进IBD发生中脱硫弧菌的重要作用；进而运用Lrrc19基因缺陷模型和体外实验解析脱硫弧菌的致病机制以及鞭毛蛋白与LRRC19蛋白的互作；最后评价多种措施调节LRRC19-MLCK信号轴的疗效。本项目将为IBD发病及防治的研究提供新思路。

The high prevalence of inflammatory bowel disease (IBD) is closely related to high-fat diet (HFD) and gut microbiota dysbiosis. Previous studies and our data have demonstrated that the overgrowth of Desulfovibrio has been found in IBD patients and HFD-treated mice. Moreover, Desulfovibrio and its flagellin could promote intestinal inflammation, however, the mechanisms remain unclarified. As a novel gut epithelial immune receptor, leucine-rich repeat C19 (LRRC19) has been reported to be involved in the recognition of the flagellin, leading to chronic intestinal mucosa inflammation. We further found that LRRC19 was upregulated in IBD patients and HFD-treated mice, and could activate myosin light chain kinase (MLCK) and disrupt the intestinal barrier. Moreover, we also found that Lrrc19 gene deletion alleviated HFD-induced intestinal barrier disruption. Therefore, we suppose that the flagellin of Desulfovibrio could promote IBD through activating LRRC19-MLCK signaling axis. This hypothesis will be addressed by 3 specific aims. Aim 1 will explore the pivotal role of Desulfovibrio in IBD patients and multiple IBD animal models using specific pathogen free (SPF) and germ-free (GF) facilities. Aim 2 will further investigate the pathogenesis of Desulfovibrio and interaction of Flagellin/LRRC19 proteins using Lrrc19-/- mice model and in vitro study. Finally, aim 3 will evaluate the preventive effects of the multiple methods targeting LRRC19-MLCK signaling axis on IBD promoted by HFD. In all, this project will provide new insights into the pathogenesis and treatment of IBD.