肠功能障碍是促进重症急性胰腺炎（SAP）病情发展和感染性并发症发生的重要原因。短链脂肪酸（SCFAs）在维持肠黏膜屏障中具有重要作用，但在SAP发生发展及肠功能障碍中的作用及机制不明。有研究显示自噬可通过负性调节NLRP3激活抑制过度炎症反应。我们前期研究显示AP患者肠道产SCFAs细菌和SCFAs含量均明显减少，且重症患者尤为显著；并且SAP小鼠肠道自噬水平下降、NLRP3炎症小体活化与肠黏膜屏障损伤显著相关。因此，推测肠道SCFAs下降可能抑制肠道自噬进而引起NLRP3炎症小体激活导致SAP肠黏膜屏障损伤。本课题拟通过SAP小鼠模型和肠类器官模型系统研究SCFAs对SAP肠黏膜屏障功能及预后的影响，应用自噬基因敲除小鼠模型确定自噬在SCFAs维持SAP肠黏膜屏障功能中的作用及其对NLRP3的调控，以期明确SCFAs在SAP肠功能障碍中的作用及机制，为SAP肠功能障碍治疗探索新途径。

Intestinal mucosal barrier dysfunction is an important factor involved in the development of severe acute pancreatitis (SAP), the incidence of multiple organ failure and pancreatic necrosis. The intestinal short chain fatty acids (SCFAs) plays an important role in maintaining gut barrier. However, the effect of SCFAs on the gut injury of SAP and the mechanisms are unclear. The autophagy has been indicated to maintain the homeostasis of gut through regulating NLRP3 negatively, which inhibit the excessive inflammation. Our previous study showed that the SCFAs-producing bacteria and the amount of SCFAs were significantly decreased in AP compared to healthy controls, especially the patients with SAP. Meanwhile, the downregulation of autophagy and activation of NLRP3 inflammasome in the intestine was significantly correlated with the impairment of mucosal barrier in SAP mice. Thus, we speculate that the disturbance of SCFAs may inhibit the gut autophagy which activate the NLRP3 inflammasome and finally lead to the injury of intestinal mucosa in SAP. This project will systematically explore the influence of SCFAs on the intestinal barrier and prognosis of SAP in vitro and in vivo through mice model and gut enteroids. Moreover, we will illustrate the role of autophagy in SCFA-mediated gut barrier maintenance and its regulation on NLRP3. The implementation of this project will provide evidence for the effect and mechanisms of SCFAs on the gut dysfunction of SAP and explore the new treatment strategy for SAP patients with gut barrier dysfunction.