胰岛β细胞Fxr感应肠道菌群动态调控胰岛β细胞功能储备发育的作用机制研究

胰岛β细胞功能储备不足是2型糖尿病发病的核心病理生理机制。阐明β细胞功能储备建立机制是防治2型糖尿病的关键。哺乳期内β细胞发育和mass扩容是成年后β细胞功能储备建立的关键步骤，但其调控机制尚不清楚。肠道菌群及其次级代谢物可介导环境因素影响宿主代谢器官功能，而其发育成熟也在哺乳期内完成。课题组前期实验证明：肠道菌群发育成熟过程中胆汁酸代谢能力升高；而菌群相关胆汁酸组分可通过胰岛胆汁酸信号参与调控β细胞功能储备及糖尿病治疗预后。课题组研究发现：胰岛β细胞胆汁酸受体Fxr表达适时下降是出生后β细胞促进Pdx1、MafA表达，代谢重塑及成熟功能储备建立的必要条件。课题组将利用可诱导β细胞特异过表达小鼠，在不同时间点过表达Fxr，比较小鼠胰岛β细胞功能储备变化，利用靶向代谢组学，宏基因组学及单细胞测序等技术，研究哺乳期β细胞Fxr在感应肠道菌群发育，建立胰岛β细胞功能储备中的作用及动态调控机制。

The irreversible loss of β cell functional preserve is the core pathogenesis of Type 2 diabetes. It has been known that weaning is the key period in individual to establish sufficient β cell functional mass in the life time, after that the β cell mass is kept in slow turnover rate and maintaining in a steady volume until drastic environmental changes occur. Though the key pancreatic transcription factors to modulate the process of β cell functional maturation during have been identified, the mechanism whereby they sense the environmental cues and how they mediate the cues to regulate β cell mass homeostasis awaits to be clarified and currently heatedly studied. Our previous work has suggested that mTORC1, the main cellular nutrient sensor, is essential for β cell functional maturation to build up sufficient β cell functional repertoires as well as compensatory capacity. However, the first sensor of nutrient intake changes in human body is gut microbiome. We have confirmed that the differences of bile acids profiles reflected the different enterotypes, i.e. the different types of gut microbiome symbiosis in the human. During weaning, the switch of food types drives the gut microbiota of infant maturing, which synchronizes with the maturation of host metabolic organ, such as endocrine pancreas. In the aid of β cell specific knock-in Fxr (bile acid receptor) mouse model, we found the timely sequestered BA signalling in pancreatic islets could be key to normal β cell maturation during weaning. We herein propose this project to study on the potential link between the gut microbiome and endocrine pancreas maturation and the underlying molecular mechanism (bacterial bile acid metabolism) of cross talk between gut microbiome and endocrine pancreas during postnatal maturation. By employing the inducible organ specific knock in mouse model, single cell RNA seq and single cell ATAC seq on primary islets，histochemistry, islet biology, metagenomics and metabolomics, we will compared the β cells with overexpression Fxr at different time points during weaning and hence study the potential molecular mechanism regulated by and key time window it works to establish sufficient β cell functional repertoire. We will identify specific BA species and microbial taxa that might target β cell and be involved in its maturation. This project will allow us to identify microbiota derived druggable targets on enhancing pancreatic beta cell preserve that could prevent and treat T2D.