非甾体类抗炎药(NSAIDs)相关性小肠损伤发病率高、临床后果严重，但目前机制不明确，且无有效的治疗措施。课题组前期工作发现，地塞米松(DEX)可通过激活GR加重布洛芬对小鼠的小肠损伤。综合基因和代谢分析的结果，我们推测GR可能与PPARα协同作用诱导肠道UGT的表达，改变NSAIDs和胆汁酸代谢，进而抑制肠道FXR-FGF15/19信号通路，最终导致NSAIDs相关性小肠损伤。为验证该假说，本项目拟采用GR低表达、PPARα敲除和FXR敲除鼠以及多种细胞模型，通过分子细胞生物学、代谢分析等手段，阐明GR、PPARα和FXR在DEX加重NSAIDs小肠损伤中的作用；拟采用组织选择性FXR敲除鼠，明确肠道和肝脏FXR信号通路在NSAIDs相关性小肠损伤中的作用，并探索FXR激动剂和FGF19重组蛋白对其治疗和保护作用，为NSAIDs相关性小肠损伤的防治以及新型NSAIDs的开发提供新靶点。

Small intestinal injury caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is very common and clinically significant. However, the pathogenesis of NSAIDs-induced small intestinal injury remains elusive, and there are no proven-effective preventative and/or therapeutic measures. Our preliminary study demonstrated that dexamethasone (DEX) aggravated ibuprofen-induced small intestinal injury in mice via the glucocorticoid receptor (GR) signaling pathway. Based on our gene expression and metabolism data, we hypothesize that GR might interact with peroxisome proliferator-activated receptor alpha (PPARa) to induce the expression and activity of intestinal UDP-glucuronosyltransferases（UGTs), and thus increase the glucuronidation of NSAIDs and bile acids (BAs) in the intestine. The increased BA glucuronidation facilitates the elimination of BAs from the body, resulting in decreased BA concentrations and the subsequent “deactivation” of intestinal FXR-FGF15/19(fibroblast growth factor 15 or 19) signaling pathway, which plays a crucial role in regulating the intestinal integrity. To test our hypothesis, we will exploit various cell and murine models (GR-knockdown, PPARa- and FXR- mice), as well as molecular biology, cellular biology, and metabolism analytical techniques to determine the role of GR, PPARα and FXR in NSAIDs-induced small intestinal injury. We will elucidate the role of liver and intestine FXR signaling pathways in NSAIDs-induced small intestinal injury by using tissue-specific FXR- mice. Additionally, we will test the therapeutic potential of two FXR activators and FGF19 recombinant protein for NSAIDs-induced small intestinal injury. The proposed studies will lead to new strategies and therapeutic targets for treating NSAIDs-induced small intestinal injury.