肠道菌群-代谢物-免疫轴调节糖脂代谢稳态作用

Abundant evidence demonstrate that gut microbiota has been more and more involved in the regulation of glucose and lipid homeostasis. However, the function of gut microbiota, at species level, on metabolism; and how gut microbiota communicate with host organs to regulate metabolism are still largely unknown. We previously performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to clinical phenotypes. Further, by functional examination in mouse models, we found that the candidate gut microbial species (e.g.Bacteroides and Clostridium)play direct roles in the regulation of adiposity or glucose metabolism, and more importantly they contributed to amino acid and bile acid metabolism respectively. It is also reported that bacteroides and clostridium such as B.thetaiotaomicron are important to Treg cell differentiation, which are more and more involved in inflammation and metabolism. Therefore, we propose that gut microbiota-metabolite-immune axis may play crucial roles in the regulation of glucose and lipid homeostasis. Investigating the interaction and mechanism of different modules in this axis will give us better understanding of the complicated glucose and lipid homeostasis. In this proposal, we will incorporate multi-omics study in human cohort and functional examination in different mouse models, to characterize gut microbiota-metabolite-immune axis in obesity and type 2 diabetes; to screen the key gut microbial species or metabolite regulating glucose and lipid homeostasis; and to uncover the interactive mechanisms underlying gut microbiota/metabolite and host organs, providing novel intervention targets regarding glucose and lipid metabolism.

多项研究表明，肠道菌群已成为糖脂代谢稳态平衡的新的调节因素，然而，在具体菌种水平，哪些肠道共生菌发生了改变？以及肠道共生菌通过何种途径与宿主代谢器官对话调控糖脂代谢？这些关键科学问题仍是该领域的空白，亟待解决。我们前期通过中国青少年肥胖队列肠道宏基因组与代谢组学研究首次筛选出一系列代谢相关肠道共生菌，通过功能研究证明，候选肠道共生菌（拟杆菌、梭菌菌种）可调节宿主糖脂代谢，并参与氨基酸、胆汁酸代谢途径；此外，该两类菌种在宿主免疫细胞分化中发挥重要作用，由此，我们提出肠道菌群-代谢物-免疫轴可能是参与糖脂代谢稳态调节的新的重要途径，理清该信号轴各节点的关联和作用机制对于从整体上认识糖脂调控复杂网络具有重要科学意义。本项目将借助人群队列和细菌功能平台，建立肥胖、2型糖尿病人群肠道菌群-代谢物-免疫轴特征，筛选调节糖脂代谢关键因子，明确肠道菌群-代谢物与代谢器官对话机制，提出新的糖脂代谢干预靶点。

本项目基于人群队列多组学数据库，借助细菌功能平台和动物模型，从多维度、多脏器解析肥胖、2型糖尿病肠道菌群-代谢物-免疫轴特征，并建立与糖脂代谢关联网络，其中包括肠道菌群调控脂肪组织免疫微环境、益生菌改善糖脂代谢效应、以及减重手术逆转肥胖机制等内容。免疫代谢方面，关注肠道菌群调控脂肪组织免疫微环境的跨器官作用机制，探究肠道菌群-代谢物-免疫轴在代谢紊乱中的改变，对调控Treg的特定菌组合进行功能特征和代谢谱分析，挖掘肠道特定菌群调控脂肪免疫细胞的物质基础和作用机制，在此基础上尝试通过特定菌或菌源代谢物补充治疗代谢紊乱的可行性。性别差异驱动的肠道菌群代谢调控方面，应用粪菌移植、抗生素清菌和无菌小鼠等模型，揭示雄激素通过调节肠道菌群和循环谷氨酰胺和 Gln/Glu 比率来恶化葡萄糖稳态，从而导致不同性别之间葡萄糖代谢差异的机制。肠道菌群和药物联用代谢干预方面，利用高通量宏基因组测序及生物信息学分析发现益生菌联合小檗碱治疗可显著改变肠道菌群组分包括肠道布氏瘤胃球菌。体外实验首次发现该菌的次级胆汁酸转化旺盛，创新性揭示益生菌可能通过联合小檗碱降低布氏瘤胃球菌及脱氧胆酸生成，从而阻断肠道胆汁酸信号，达到增强小檗碱改善糖代谢的效果。脑肠轴相关代谢调控方面，静息态磁共振成像（fMRI）扫描、肠道激素谱分析、粪便样本宏基因组测序，对减重手术病人“脑—肠轴”进行了全面评估，发现VSG 术后增加的梭菌的相对丰度与 aGLP-1 分泌、右侧壳核脑区活动、体重的改善相关，创新性发现术前"右侧壳核-右侧眶额叶皮层"之间的脑功能连接可预测术后体重的减轻获益。本项目旨在阐明肠道菌群/代谢产物调节肠道免疫和糖脂代谢作用以及与代谢靶器官互作机制，筛选调节糖脂代谢的关键肠道微生物/代谢产物和免疫细胞亚群，明确肠道菌群-代谢物与代谢器官对话机制，提出新的糖脂代谢干预靶点。