肠道共生菌AGN-Y01调控GLP-1的分子机制和生理意义的研究

肠道菌群对机体糖脂代谢有重要影响，但其分子机制仍不清楚。项目前期借助免疫缺陷引起的菌群失调模型，发现肠道共生菌AGN-Y01的丰度与小鼠糖脂代谢激素GLP-1水平及体重都显著相关； AGN-Y01定植可降低GLP-1基因表达，并伴随NFκB靶基因的上调。由于激活NFκB的TNFα可抑制GLP-1产生且AGN-Y01在代谢疾病病人肠道中富集，我们推测AGN-Y01可能通过NFκB抑制GLP-1进而促进代谢疾病的发生。本项目将首先明确NFκB抑制GLP-1的作用位点和转录调控机制，并利用遗传和类器官模型阐明AGN-Y01激活NFκB的先天免疫信号通路，最后通过菌群操纵研究AGN-Y01调控GLP-1对机体正常代谢及遗传和高脂饮食诱导的代谢疾病的影响，阐明其生理和病理意义。项目成果将不仅从分子水平上揭示肠道菌群调节机体糖脂代谢的新机制，也为操纵肠道菌群治疗肥胖及相关代谢疾病提供理论支撑。

Microbiota plays an important role in host metabolism and the development of obesity-related metabolic diseases. But the underlying mechanism is still largely unknown. Using immune deficiency-induced dysbiosis models, we found that a single intestinal symbiont AGN-Y01 significantly correlated with blood GLP-1 concentrations and body weights in mice. AGN-Y01 transplantation was sufficient to reduce GLP-1 expression while increase NFκB target gene expression. Because AGN-Y01 is enriched in the microbiota of patients with metabolic diseases and NFκB-activating TNFα has been shown to suppress GLP-1 production, we hypothesize that AGN-Y01 suppresses GLP-1 through NFκB, which promotes the development of metabolic diseases. To this end, we will first investigate mechanisms by which NFκB suppresses GLP-1 expression by transcriptional analysis. We will then employ mouse genetic models and intestine organoids to uncover the immune signaling pathway through which AGN-Y01 activates NFκB. We will further examine how AGN-Y01 influences host metabolism through GLP-1 under normal and metabolic disease conditions using genetic and high fat diet-induced obesity mouse models. This study will not only reveal novel molecular mechanisms underlying microbial regulation of host metabolism but may also provide new therapeutic targets for the treatment of metabolism diseases.