胆汁酸调控炎症小体信号及其在炎症性肠病中的作用机理研究

Epidemiological investigations show that colitis patients are complicated with bile acid imbalance, indicating the pivotal roles of bile acids may play in chronic colitis as some important endogenous signaling molecules, and their disorders may be the initial pathogenic factors to the occurrence of chronic colitis. Our previous studies have confirmed that colitis can be alleviated via restoring bile acids from disregulation to homeostasis and found that bile acids may regulate inflammasome signal pathways. Based on these findings, the project aims to investigate mechanisms pertaining to colitis caused by disorders of bile acids based on idea that imbalance of the proportion of one kind of bile acids, deoxycholic acid (DCA) and the other kind of bile acids, cholic acid (CA) can induce colitis as they are some internal damage-associated molecular patterns (DAMPs) that can activate inflammasomes. The point of this project is to illustrate mechanisms concerning DCA activate NLRP6-IL18 inflammasome signal pathway on intestinal epithelial cells to maintain intestinal barrier integrity and CA activate NLRP3-IL-1βinflammasome signal pathway on monocytes or macrophages to facilitate the pathogenesis of colitis. First, we would find target cells and involved inflammasome signaling isoforms that mediate the effects of DCA and CA on gut immunity, then we would confirm the pathways and mechanisms of DCA-NLRP6-IL18 inflammasome signal on intestinal epithelial cells and CA-NLRP3-IL-1βinflammasome signal on macrophages and their effects on treating colitis by using strategies like bone marrow transplantation or gene knockout. We hope to reveal the positive regulating effects of endogenous molecules on regulating intestinal immune function and related diseases, as well as their underlying mechanisms.

流行病学研究显示肠炎患者伴随胆汁酸代谢紊乱，提示其可能是慢性肠炎发生的始动因素或重要环节。本课题已证实调控胆汁酸内稳态能减缓肠炎发生，并发现胆汁酸可以调控炎症小体信号。本项目基于前期研究基础提出“胆汁酸是激活炎症小体的内源性DAMPs，脱氧胆酸DCA/胆酸CA比例失调是诱发肠炎的重要机制”的学术思想，拟阐明胆汁酸紊乱促进肠炎发生的用机制，重点阐明DCA）激活肠上皮细胞中NLRP6-IL18信号促进维持肠粘膜屏障功能、CA激活单核/巨噬细胞中NLRP3-IL1β信号促进肠炎发生的分子机制。探讨DCA、CA调节肠道免疫功能作用的靶细胞类型及炎症小体亚型，并运用骨髓重组、基因敲除等方法确证DCA-IEC(NLRP6/IL18)及CA-M ø（NLRP3/IL1β）通路在肠炎中的作用与机制；期望基于本项目研究揭示内源性活性分子在肠道免疫功能调控与相关疾病中的作用及机制。

本项目基于前期研究基础提出“胆汁酸是激活炎症小体的内源性DAMPs，脱氧胆酸DCA/胆酸CA比例失调是诱发肠炎的重要机制”的科学假说，拟阐明胆汁酸紊乱促进肠炎发生的用机制。围绕以上研究目标及项目研究计划，我们基于肠炎动物模型、体外肠细胞、类器官等水平，阐明了DCA激活肠上皮细胞中NLRP6/IL18信号促进维持肠粘膜屏障功能的机制与隐窝干细胞增殖/维持杯状细胞功能相关；基于肠道菌群重构的策略，定量干预DCA/CA比例可以有效干预肠炎的发生发展，提示，靶向调节胆汁酸代谢稳态是潜在肠炎辅助治疗策略。进一步，我们分析了临床溃疡性结肠炎患者的菌群与胆汁酸代谢紊乱与病理活动的关联，研究揭示，胆汁酸肠道代谢比例失衡可作为代谢标记物诊断溃疡性结肠炎以及定量区分缓解期/活动期。基于本项目研究，我们提出胆汁酸代谢比例可作为溃疡性结肠炎的辅助诊断标记物和干预策略。