肠道菌群代谢物TMAO对2型糖尿病的影响及机制研究

The prevalence of type 2 diabetes is substantially increasing in recent years, which represents a major public health concern. The intestinal microbiota plays an important role in the development of type 2 diabetes, however, it is still unclear how intestinal microbiota participates in the pathogenesis of diabetes due to the complexity of the microbial community. Recent researches have found that intestinal microbiota-generated metabolite trimethylaine-N-oxide (TMAO) is an independent predictor of cardiovascular disease (CVD). Because diabetes is the major risk factor of developing CVD, and also share some common risk factors with CVD, it is hypothesized that TMAO might be important for the initiation and progression of diabetes based on the current progress in diabetes and our previous results. In this study, the human study will be used to investigate the influence of intestinal microbiota-generated metabolite TMAO, choline and carnitine on glucose metabolism. Then the mechanism of by which TMAO regulates glucose balance and diabetes through FoxO1 expression induced by Akt or JNK or both signaling pathways will be further explored by using animal models. This study will provide useful information for finding early biomarkers and potential therapeutic target for diabetes based on intestinal microbiota.

近年来2型糖尿病发病率的持续增长，已经成为威胁人类健康的重要公共卫生问题。肠道菌群对糖尿病的发展起到了重要的作用，但由于微生物群落的复杂性，肠道菌群如何参与到糖尿病发病机制中尚不十分清晰。研究发现，肠道菌群代谢物氧化三甲胺（Trimethylaine-N-oxide, TMAO）是心血管疾病的独立预测因子，由于糖尿病是导致心血管疾病的重要因素之一，同时糖尿病和心血管疾病也具有类似的危险因素，结合当前研究的最新进展与本课题组前期研究结果，我们认为TMAO极有可能在糖尿病的发生和发展中发挥重要作用。因此本研究拟通过人群研究和动物模型，系统观察肠道菌群代谢物TMAO及胆碱、肉碱对血糖代谢的影响，进一步阐明TMAO通过Akt还是JNK通路或者两者一起影响FoxO1表达，从而调控血糖平衡和糖尿病的作用机制，探寻糖尿病的早期生物标志物，为以肠道菌群为靶点的糖尿病预防和治疗提供证据。

肠道菌群代谢物氧化三甲胺（Trimethylaine-N-oxide, TMAO）是心血管疾病的独立预测因子，而糖尿病是导致心血管疾病的重要因素之一，TMAO对糖尿病和血糖代谢的影响和机制仍不是十分清楚。本研究基于病例对照研究，对1160名糖尿病、糖尿病前期和正常健康人群检测TMAO及其前体物（胆碱、甜菜碱、肉碱），结果发现TMAO是糖尿病的独立危险因素之一。接着本研究通过动物模型观察补充TMAO对小鼠血糖代谢的影响，结果发现TMAO可导致小鼠葡萄糖耐量下降，胰岛素敏感性降低，以及糖异生水平上升，而这些变化先于血糖发生变化之前，同时影响FoxO1的表达，提示TMAO可作为血糖代谢异常的预测指标。最后通过人群随机对照干预试验进行验证，发现TMAO的改变是HbA1C改善的有效预测指标，n-3多不饱和脂肪酸可能通过影响TMAO发挥对血糖的改善作用，研究结果进一步在动物实验中得到验证。本系列研究丰富了TMAO代谢谱作为糖尿病及糖尿病心血管病早期生物标志物的认识，为以肠道菌群及代谢物为靶点的糖尿病预防和治疗提供了理论证据。