原花青素通过肠道菌群-胆汁酸轴下调FXR信号通路改善妊娠糖尿病的机制研究

膳食营养因素是妊娠糖尿病（GDM）代谢转归最重要的可调控因素。胰岛素抵抗是GDM的重要病因，人群和动物研究报道原花青素（PA）可改善胰岛素抵抗。我们前期检测了2019-03年建立的625对GDM前瞻性队列标本发现：膳食PA摄入量与孕期血糖、血胆汁酸水平密切相关；随后发现PA可降低GDM小鼠血糖并调节血清总胆汁酸水平，并在体外研究中剂量依赖性下调FXR表达。原花青素对GDM胰岛素抵抗影响如何？是否与肠道菌群-胆汁酸代谢轴有关？相关研究极少，亦无研究探讨其作用机制。我们拟采用基因表达调控、靶向代谢组学等技术，在高GDM风险小鼠模型明确PA对GDM胰岛素抵抗的改善作用，阐明：PA是否通过改变肠道微环境（数量、种类、丰度），影响BSH活性，从而调节胆汁酸代谢改善GDM胰岛素抵抗？并从FXR通路探讨PA经肠道菌群-胆汁酸代谢轴改善GDM的具体分子机制。本研究将为补充膳食PA防治GDM提供重要线索。

Dietary nutrition is the most important controllable factor affecting the metabolic turnover of gestational diabetes mellitus (GDM) and its clinical outcomes of mothers and infants. Insulin resistance is an significant cause of GDM. It has been reported that procyanidin (PA) can improve insulin resistance in human and animal studies. We analyzed the 625 pairs of samples of the GDM prospective cohort established from March 2019 and found that dietary procyanidin (PA) intake was closely related to blood glucose, and erum bile acid levels during pregnancy. Then we found that PA could reduce blood glucose and regulate serum total bile acid levels in animal models, as well as down-regulate FXR expression in a dose-dependent manner in in vitro. What is the effect of PA on insulin resistance of GDM? Is it related to intestinal flora - bile acid metabolic axis? However, there are few studies to explore the effects and mechanisms of the intestinal flora on the procyanidins metabolism during the development of GDM, nor to explore the bile acid metabolism on the development of GDM. Therefore we intend to use gene expression regulation, targeted metabonomics and other technologies to clarify the improvement effect of PA on GDM in mice model of GDM, and whether PA can improve the insulin resistance of GDM by changing the intestinal microenvironment (quantity, species, abundance) to regulate bile acid metabolism? Furthermore, the specific molecular mechanism of PA improving GDM through intestinal flora--bile acid metabolic axis will be explored through FXR pathway. This study will provide critical clues for the prevention and treatment of GDM by supplementation of dietary procyanidins.