肠道菌群-胆汁酸调控FXR与NF-kB的相互抑制促进IBS-D肠粘膜炎症的机制研究

腹泻型肠易激综合征（IBS-D）是消化科常见病，其发病机制不清，缺少有效治疗。肠道菌群失调与IBS-D关系密切，其可通过调节胆汁酸代谢抑制胆汁酸受体FXR的活性，进而促进胆汁酸合成及肠道传输。另有研究表明FXR与NF-κB的相互抑制在炎症反应调控中至关重要，然而FXR在IBS-D肠粘膜炎症中的作用不清。我们前期研究发现IBS-D患者肠道总胆汁酸含量及初级胆汁酸比例升高，FXR的活性受抑制，调节肠道菌群可通过抑制NF-κB的活性改善肠粘膜炎症及患者症状。故推测异常菌群通过改变肠道胆汁酸的构成下调FXR对NF-κB的抑制作用，NF-κB激活负反馈抑制FXR的活性，诱发并放大IBS-D肠粘膜炎症。课题拟用动物模型探讨肠道菌群失调对胆汁酸代谢及肠粘膜炎症的影响；拟用肠道organoid研究胆汁酸对FXR下游通路的调节作用。本研究将完善肠道菌群在IBS-D的作用及机制，为IBS-D治疗提供新思路。

Diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most commonly diagnosed functional gastrointestinal disorders. However，its pathogenesis remains largely unknown and it lacks effective treatment. Studies have shown that intestinal microbiota dysbiosis was closely related to IBS-D. Abnormal gut flora can induce intestinal bile acid disorders and inhibit the activity of bile acid receptor FXR, the inhibition of FXR could then promote the synthesis of bile acid and contribute to the intestinal transition. Other studies showed that the mutual inhibition of FXR and NF-kB played critical roles in inflammation modulation, however, their roles in IBS-D mucosal inflammation reamined unclear. Our previous research showed that IBS-D patients displayed a decreased total fecal bile acid content and a decreased ratio of primary bile acid ratio；that the activity of FXR in IBS-D patients was inhibited；and that the modulation of intestinal flora could improve the patients' intestinal mucosal inflammation and the symptoms by inhibiting the activation of NF-κB. Therefore, it is speculated that the abnormal intestinal flora contributes to the onset and progression of IBS-D by changing the composition of intestinal bile acid, the dysregulation of bile acid down-regulates the inhibitory effect of FXR on NF-κB and induces the inflammation of IBS-D intestinal mucosal, the activation of NF-κB could then inhibit the activation and the expression of FXR, the mucosal inflammation is amplified. In this study, we intends to use animal models to investigate the effects of intestinal flora imbalance on bile acid metabolism and intestinal mucosal inflammation; we aim to use intestinal organoids to investigate the role of bile acids on the FXR downstream pathways. This study will improve the understanding of the role and mechanism of intestinal flora imbalance on IBS-D, and could provide a new basis for its treatment.