Th17细胞的分化及调控在黏附侵袭性大肠杆菌LF82加重UC中的作用和机制研究

Th17 cells were found to be involved in the development of inflammatory bowel disease (IBD) and many other autoimmune inflammatory disease in recent years. Especially, the IL-17 secreted by Th17 cells might play a key role among them. However, IL-17 seems to be both pathogenic and protected in the pathogenesis of IBD. The specific mechanism of IL-17 in IBD is still not clarified. In addition, the intestinal microbiota is also a key factor involved in the pathogenesis of IBD. One of the Escherichia coli strains--adherent-invasive Escherichia coli (AIEC) which can adhere and invade to the intestinal epithelial cells is currently the most thought possible crohn's disease (CD) pathogenic bacteria. Research also found that the number of AIEC in patients with ulcerative colitis (UC) is similar with CD, or even more. In previous studies, our team found the representative AIEC strain E. coli LF82 could increase the secretion of cytokines in Th17 cell related immune signaling pathway in the animal models of CD. But the exactly role of AIEC in the pathogenesis of UC is not clear, the effect of AIEC on individuals lack of IL–17 is still not clarified. We still don’t know if there is any synergies between differentiation and regulation of Th17 cell and AIEC. This project is on the basis of our previous work, we plan to reveal the role and mechanism of differentiation and regulation of Th17 cell in UC exacerbated by AIEC strain E. coli LF82 via animal models and some related experiments in vivo and in vitro. To carry out the project will help us to figure out the pathogenesis of IBD, which has important scientific significance.

近年发现的Th17细胞参与炎症性肠病（IBD）等多种自身免疫性炎症性疾病的发生发展，其分泌的IL-17在其中起关键作用。然而IL-17对IBD似乎起致病和保护的双重作用，其中的机制仍未阐明。肠道微生态是参与IBD发病的关键因素，其中具有黏附侵袭特性的大肠杆菌AIEC是目前认为最可能的克罗恩病（CD）致病菌，研究还发现溃疡性结肠炎（UC）患者体内AIEC与CD数量相当，甚至更多。课题组前期发现AIEC代表性菌株E. coli LF82可能通过调控IL-17相关免疫通路影响CD的炎症反应，而其在UC的发病中究竟起什么作用，缺乏IL-17的个体感染AIEC会产生何种结果，AIEC是否可通过Th17细胞加重UC尚不清楚。本项目拟在前期工作的基础上，通过模式动物及相关体内外实验揭示Th17细胞的分化调控在AIEC加重的肠道炎症中的作用和机制，项目的开展将有助于明确IBD的发病机制，具有重要科学意义。

IL-17对IBD的作用及其机制仍未阐明。具有黏附侵袭特性的大肠杆菌AIEC在UC的发病中究竟起什么作用，缺乏IL-17的个体感染AIEC会产生何种结果，AIEC是否可通过Th17细胞加重UC尚不清楚。因此，本项目拟在前期工作的基础上，通过模式动物及相关体内外实验研究了Th17细胞的分化调控在AIEC加重的肠道炎症中的作用和可能机制。.主要研究结果和结论：AIEC菌株LF82可破坏体外肠屏障细胞模型完整性、通透性，并增加IL-17的分泌，同时增加肠上皮细胞屏障培养上清中的TNF-α和IL-17分泌。在动物模型中，AIEC的菌株E.coli LF82可在C57BL/6小鼠结肠肠道定植，并可诱发小鼠结肠炎症，诱导IL-17水平的升高。此外，AIEC菌株LF82可加重DSS小鼠结肠炎症，并侵入组织深层，改变细胞骨架，影响肠道功能，增加肠道中的IL-17。在定植于IL-17-/-小鼠结肠后，AIEC菌株LF82可诱发小鼠结肠炎症，程度比野生型小鼠更重。AIEC菌株LF82还可进一步加重DSS诱导的IL-17-/-小鼠结肠炎症，IL-17可能对AIEC菌株LF82的感染起保护作用，其中的机制可能有IL-22的参与。