辣椒素通过调节肠道菌群-胆汁酸轴防治2型糖尿病的作用与机制研究

2型糖尿病（T2DM）是危害人类健康的重大疾病。新近研究表明，肠道菌群紊乱导致的胆汁酸代谢下游通路失调在T2DM发生发展中起重要作用。辣椒素（CAP）具有抗炎、调节血脂、增强胰岛素敏感性的作用，但对T2DM的防治效应及机制尚不明确。结合我们前期发现CAP能改善妊娠糖尿病患者的血糖水平并调节健康人群的肠道菌群组成及胆汁酸代谢，本项目提出“CAP可通过重塑肠道菌群-胆汁酸轴影响其下游血糖调控通路，进而抑制T2DM发生发展”的科学假说。通过人群研究和动物实验，运用高通量测序、宏基因组分析、无菌动物模型、Cas9转染、预测模型构建等技术，率先研究辣椒素干预诱导的肠道菌群和胆汁酸代谢的特征性变化，同时围绕肠道菌群-胆汁酸代谢-TGR5、FXR信号通路开展辣椒素的血糖调控效应机制研究。该课题旨在揭示辣椒素通过重塑肠道菌群-胆汁酸轴发挥血糖改善效应这一新机制，并为从膳食营养途径防治T2DM提供新策略。

Type 2 diabetes mellitus (T2DM) is a challenging problem for public health worldwide. Recent studies suggest that the disorder of downstream bile acid metabolic pathways induced by gut microbiota dysfunction play important roles in the development and progression of T2DM. Capsaicin (CAP) has beneficial effects on anti-inflammation, lipid metabolism regulation and insulin sensitivity improvement. However, the effect and mechanism of CAP on T2DM is still unclear. Based on our previous findings that CAP can improve the glycemic control in gestational diabetic patients and regulate the gut microbiota and bile acid metabolism in healthy population, we hereby propose the hypothesis that dietary CAP can significantly improve the glycemic control of T2DM patients via the remodeling of gut microbiota-bile acid axis and subsequent regulation on its downstream pathways. Based on the population intervention and animal study, this project is designed to comprehensively evaluate the effects of dietary CAP on T2DM targeted on the regulation of gut microbiota-bile acid axon-TGR5 and FXR pathways, by using the techniques of high throughput sequencing, metagenomic detection, germ-free animal model, Cas9 transfection and predictive model establishment. Our study is of great significance in further clarifying the effects and mechanism of gut microbiota-bile acid axis remodeling on T2DM control, and also provides scientific evidence for the prevention and treatment of T2DM through the dietary management.