肠道屏障功能和肠道菌群参与急性胰腺炎(AP)病程进展，具体机制不明。我们前期研究发现耗竭潘氏细胞或灌胃共生菌E.coli MG1655均加重AP。同时，肠道Toll样受体4（TLR4）和外周血M1型单核细胞表达增加。我们推测，潘氏细胞调控的E.coli MG1655可能经肠道TLR4-固有层巨噬细胞M1极化途径加重AP进展。本课题先分析AP患者E.coli MG1655、肠道巨噬细胞和外周血单核细胞变化关系；分别采用肠道上皮和骨髓单核细胞TLR4-/-鼠，肠道无菌鼠行体内实验，小肠类器官与骨髓/血液单核细胞/肠道巨噬细胞共培养行体外实验，予E.coli MG1655和耗竭潘氏细胞/补充其抗菌肽，明确潘氏细胞经E.coli MG1655-肠固有层巨噬细胞M1极化-AP重症化的作用和分子机制。本课题的完成将从宿主肠道上皮-细菌-先天性免疫角度阐明AP发病机制，为临床治疗提供理论依据和新思路。

Gut barrier and intestinal microbiota are involved in the progress of acute pancreatitis (AP), while the mechanism has not been fully elucidated. Our previous study showed that depletion of Paneth cell and gavage of commensal bacteria E. coli MG1655 aggravated AP in rats, respectively. Meanwhile, M1 monocyte counts in peripheral blood and TLR4 expression in gut were increased in AP. We hypothesize that E. coli MG1655 controlled by Paneth cell regulates AP severity via gut TLR4-macrophage M1 plarization in lamina propria. This project will firstly analyze the changes and relationship of E. coli MG1655, intestinal macrophages and peripheral monocytes in AP patients. We then use the intestinal epithelia and myelomonocyte TLR4-/- mice and gut microbiota-depleted mice respectively in vivo, co-culture system of intestinal organoid and bone marrow/peripheral monocytes /intestinal macrophages in vitro. We will gavage E. coli MG1655 and ablate Paneth cells/antimicrobial peptide supplement. We want to clarify the mechanism of Paneth cells-E. coli MG1655-macrophage M1 polariztion-AP aggravation. This project aims to elucidate the mechanism of gut-gut bacteria-innate immunity in pathogenesis of AP and apply for the new insight and theoretical basis for AP treatment.