槲皮素与肠道菌群相互作用防治2型糖尿病的功能与机制研究

Diabetes is one of the most important non-communicable diseases that threaten human health. It has become a research hotspot to improve the disorder of glucose metabolism by regulating the balance of gut microbiota. Our previous study found that quercetin intake in Chinese was negatively related with the prevalence of type 2 diabetes mellitus (T2DM), and quercetin could improve the microecological balance and repair the intestinal barrier in rats with gut microbiota disorder. Based on these we propose the scientific hypothesis that quercetin may improve glucose metabolism by interacting with gut microbiota. This project intends to combine in vitro and in vivo experiments, using High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS), metagenome and bioinformatics techniques to study db/db mice. The effects of quercetin on the species, abundance and metabolites of gut microbiota in db/db mice were studied. The absorption efficiency of quercetin metabolites and the biological function of quercetin metabolites affecting glucose metabolism were studied in vitro, and the biological pathway and possible molecular mechanism of quercetin improving glucose metabolism under the action of intestinal flora were revealed. This project is a useful exploration of the mechanism of quercetin improving glucose metabolism. It can not only provide theoretical basis for the further application of quercetin in the prevention and treatment of T2DM, but also provide new ideas and directions for the prevention and treatment of T2DM.

糖尿病是威胁人类健康最主要的非传染性疾病之一。通过调节肠道菌群平衡，改善机体糖代谢紊乱已成为研究热点。本课题组在前期研究发现，中国人槲皮素摄入量与2型糖尿病（T2DM）患病率成显著负相关关系，并且槲皮素可以改善肠道菌群紊乱大鼠体内的微生态平衡，修复肠屏障。基于此，我们提出槲皮素可能通过与肠道菌群的相互作用而改善糖代谢的科学假说。本项目拟结合体内外实验，以db/db小鼠为研究对象采用液质联用、宏基因组学和生物信息学等技术，深入研究槲皮素对db/db小鼠肠道菌群种类、丰度和菌群代谢产物的影响，以及因此改善糖代谢的机制；体外实验研究槲皮素代谢产物的吸收效率和影响糖代谢的生物学功能，揭示槲皮素在肠道菌群作用下改善糖代谢的生物学途径和可能的分子机制。本项目是对槲皮素改善糖代谢机制的有益探索，不仅可以为槲皮素进一步应用于T2DM的防治提供理论依据，还可以为T2DM的预防与治疗提供新的思路和方向。

本项目组提出，槲皮素可能通过与肠道菌群的相互作用而改善糖代谢的科学假说，旨在为应用营养干预手段防治T2DM的发生发展提供新的思路和手段。本项目以db/db小鼠为研究对象，通过16S rRNA技术检测槲皮素干预对小鼠肠道菌群丰度、种类的影响；通过非靶向代谢组分析技术，检测槲皮素干预对小鼠肠道菌群代谢产物的影响；并利用生物信息学技术构建菌群变化与血液生化指标的关联，结果表明槲皮素干预db/db后，小鼠体内变形菌与FBG、HOMA-IR、MCP-1和MDA的水平正相关。拟杆菌与D-LA呈正相关，与GSH-PX呈负相关。大肠埃希菌、志贺菌与FBG、胰岛素、HOMA-IR、MCP-1、MDA、LPS水平呈正相关。在潜在的细菌生物标志物方面，丹毒菌科与LPS呈负相关。在属水平上，Rikenellaceae_RC9_gut_group与GSH-PX和SOD呈正相关，与D-LA呈负相关。此外，Dubosiella与FBG和瘦素水平呈负相关。g_Faecalibaculum和s_Faecalibaculum_rodentium 与DAO呈正相关，与LPS呈负相关；细胞实验证实，槲皮素及其代谢产物可以在一定程度上改善胰岛抵抗细胞（HepG2和C2C12）模型糖代谢的机制，相关机制正在研究中。本项目的研究结果表明，槲皮素可以改善糖尿病模型动物的肠道菌群丰度和分布，可作为特异性防治T2DM的肠道益生元加以开发。