肝激酶B1（LKB1）是重要的蛋白激酶，在肠道上皮细胞生理功能调节中具有重要作用。前期我们发现肠道上皮细胞特异性LKB1敲除导致小鼠肠道上皮细胞白介素-18及相关抗菌肽产生显著减少，引起小鼠促肠炎性菌群紊乱及菌群代谢物组成改变，加重小鼠对DSS诱导的急性肠炎易感性。但LKB1及其下游信号通路如何调控IL-18表达并不清楚，LKB1在肠道黏膜免疫调控中的功能也不明确。IL-18组成性表达于肠道上皮细胞，并受到精密调控。本项目假设肠道上皮细胞LKB1调控IL-18表达是直接调控和间接调控的协同作用。我们将通过结肠体外培养、肠道类器官培养，IL-22、LPS、Flagellin、Poly dA:dT等体外刺激来探讨LKB1是否直接调控IL-18表达及其机制；同时探讨LKB1是否通过肠道菌群及其代谢物间接调控IL-18表达及机制。我们的研究将为LKB1在肠道黏膜免疫调控中的研究提供新的思路。

Liver kinase B1, a critical protein kinase, plays essential roles in modulating physiological functions of intestinal epithelium. Previously, by using intestinal-epithelial cell specific LKB1 knockout mice (LKB1△IEC), we found that specific deletion of LKB1 in intestinal epithelium results in markedly reduced production of IL-18 and IL-18-target antimicrobial peptide by intestinal epithelial cells on naive condition, which also leads to colitogenic dysbiosis as well as dysregulated gut microbiota-associated metabolites expression in LKB1-deficient mice. What's more, LKB1△IEC mice are more susceptive to DSS induced acute colitis. But, how LKB1 deficiency leads to impaired IL-18 production remains unknown, also, the functions of LKB1 in regulating intestinal mucosal immune barrier function are largely unknown. IL-18 is highly expressed in intestinal epithelial cells and tightly controlled. We hypothesize that LKB1 modulate IL-18 production in intestinal epithelium both intrinsically and extrinsically. We will test our hypothesis by ex vivo stimulation with IL-22, LPS, Flagellin, Poly dA:dT (intrinsic) as well as specific gut microbiota-associated metabolites (extrinsic). This study is to explore the exact mechanism by which LKB1 modulate IL-18 production and to define the roles of LKB1 in regulating intestinal mucosal immune barrier function, thus may provide new therapeutic strategies for UC in the future.