糖尿病家族化、年轻化倾向日益严重，如何阻断不良生活方式造成的糖代谢异常“遗传”给子代是阻止这一倾向的关键。我们前期研究发现糖代谢异常母鼠的子代发生糖代谢和胰岛功能异常，与胰岛素敏感性密切相关的PI3K/Akt/mTOR信号转导通路的重要分子表达下调，且子代“继承”了母代失调的肠道菌群，而肠道菌群可参与主要受Wnt通路调控的小肠干细胞的分化进而影响小肠黏膜屏障功能。据此我们提出假设：关键菌株及代谢产物通过母婴垂直传递调节子代小肠干细胞分化及小肠黏膜屏障功能，进而影响子代胰岛功能。本课题拟通过全微生物组关联分析鉴定子代胰岛功能异常发生机制中的关键菌株及代谢产物，并以悉生小鼠模型予以验证；探讨关键菌株代谢产物经Wnt通路调控小肠干细胞分化损伤小肠屏障，经Akt等通路降低胰岛素敏感性、导致胰岛功能异常的机理。从而为以肠道菌群为靶点的糖尿病精准干预和预防关口前移至妊娠期提供新的策略和理论依据。

The prevalence of diabetes in younger people has increased over the recent years. However, the underlying causes for this epidemic condition remain elusive. We propose that maternal transmission of gut microbiota plays a major role in the onset of diabetes in the young, if proven, will lead to a viable approach for the prevention. Our previous work suggested that maternal high-fat diet led to abnormal glucose metabolism and islet dysfunction of offspring, which is partly mediated by dysbiosis of gut microbiota from their dams. We show that dysregulation of maternal microbiota also down-regulates the expression of key genes involved in insulin signaling in the offspring, including the PI3K/Akt/mTOR signal pathway which regulates insulin sensitivity. Our preliminary studies showed that gut microbiota also regulated intestinal stem cell differentiation and barrier function, which has been proved to be mediated mainly by Wnt signal pathway. The proposed studies will test the hypothesis that the maternal gut microbiota plays a key role in regulating glucose homeostasis in offspring through gut-islet axis. Using a previously established animal model of abnormal glucose metabolism, we will investigate the effects of intrauterine environment, delivery mode, and lactation way on transmission of gut microbiota. Then, we will apply a strain-level, microbiome-wide association approach to characterize the specific bacterial strains and their metabolites which impact on islet function of offspring. Next,we will transplant these specific bacterial strains into germ-free C57BL/6J mice to verify their effects. Moreover, experiments will be carried out to reveal whether these specific strains of bacteria and their metabolites displacement will regulate intestinal stem cell differentiation and barrier function through modulation of the Wnt signal pathway. Finally, we will identify novel molecular mechanisms by which the specific bacteria strains regulate insulin sensitivity. Collectively, the proposed studies are expected to provide key insights on maternal gut microbiota for the prevention and treatment of diabetes mellitus in the offspring, with the ultimate goal of providing a more effective diabetes prevention program for the next generation through manipulation of gut microbiota during pregnancy.