低CHO/高n-3 PUFA膳食通过重塑肠道菌群防治2型糖尿病的作用与机制研究

Type 2 diabetes mellitus (T2DM) is a challenging problem for public health worldwide. Accumulating data shows that the dysfunction of gut microbiota plays an important role in the development and progression of T2DM. In our previous study, we found that the intervention of low carbohydrate (CHO)/high n-3 polyunsaturated fatty acid (PUFA) diet could significantly improve the glucose levels and insulin sentivity of DB/DB mice, yet the mechanisms remained unclear. It has been demonstrated that the long term intervention of high CHO or high fat diet can induce the dysfuction of gut microbiota, while this dysfuction could be substantially alleviated by the dietary structure adjustment or the elevation of endogeneous n-3 PUFA levels. Therefore, we hereby propose the hypothesis that low CHO/high PUFA diet can significantly improve the glycemic control of T2DM patients via the remodelling of gut microbiota. Based on the population intervention and animal study, this project is designed to comprehensively evaluate the effects of dietary intervention on T2DM targeted on gut microbiota regulation, by using the techniques of PCR-DGGE, high throughput sequencing and systematic biology analysis. Our study is of great significance in further clarifying the effects and mechanism of gut mircobiota on T2DM, and also provide scientific evidence for the prevention and treatment of T2DM through the dietary management.

2型糖尿病（T2DM）是全球范围内的重大公共卫生问题。研究表明肠道菌群失调是引起T2DM发生发展的重要因素。我们在前期研究中发现低碳水化合物（CHO）/高n-3 PUFA膳食能显著改善DB/DB鼠的血糖水平和胰岛素敏感性，但具体机制尚不明确。本项目结合以往研究发现长期高CHO或高脂膳食摄入可引发肠道菌群紊乱，而膳食结构调整及增加体内n-3 PUFA水平可显著改善上述膳食所致的菌群失调，提出"低CHO/高n-3 PUFA膳食干预能显著改善T2DM患者的血糖调控，该作用的发挥与肠道菌群重塑密切相关"的研究假说，通过运用PCR-DGGE图谱分析、454高通量测序以及系统生物学分析等技术，从人群研究和动物实验两个层面，全面评价以肠道菌群调控为靶点的膳食营养干预在T2DM防治中的作用。本项目对进一步揭示肠道菌群调节与糖尿病发生发展的关系及作用机制，指导居民从膳食途径防治糖尿病具有重要意义。

随着营养学科的发展，通过膳食调整的方式进行T2DM的防治已受到越来越多的专家、卫生部门的领导以及社会大众的关注。结合既往研究结果，我们推测低碳水化合物结合高n-3 PUFA（低n-6/n-3 PUFA比）的膳食结构，可能发挥有效改善T2DM患者血糖调控的能力。试验干预分为高碳水化合物/低n-3 PUFA（High carbohydrate/low n-3 PUFA diet，HCD-3）、高碳水化合物/高n-3 PUFA（High carbohydrate/high n-3 PUFA diet，HCD+3）、低碳水化合物/低n-3 PUFA（Low carbohydrate/low n-3 PUFA diet，LCD-3）和低碳水化合物/高n-3 PUFA（Low carbohydrate/high n-3 PUFA diet，LCD+3）干预组。干预时间为12周。.与HCD-3对照膳食组相比，LCD+3膳食干预后，糖化血红蛋白（Hemoglobin A1c，HbA1c）HbA1c下降幅度在第12周达到最大，且明显大于HCD+3和LCD-3组的HbA1c的下降幅度。在干预第4周，LCD+3组就能够显著的降低T2DM患者的空腹血糖水平，HCD+3和LCD-3组出现显著的空腹血糖下调效应的时间均晚于LCD+3组。在第12周时，LCD+3组的受试者的空腹血糖水平下降了-1.32 mmol/L，且明显大于HCD+3和LCD-3组的空腹血糖下降幅度。.Spearman相关性分析结果提示，LCD+3膳食干预引起的肠道菌群的改变与HbA1c和空腹血糖的变化存在显著的相关性，结合干预期间变化大于1%的肠道菌群差异分析结果发现，LCD+3和LCD-3组Prevotella与HbA1c和空腹血糖存在显著的正相关，LCD+3和HCD+3组Roseburia的变化与HbA1c和空腹血糖存在显著的负相关。.本研究发现n-3 PUFA和LCD均能对T2DM受试者的血糖调控发挥有益的健康效应。当把将两者相结合时，LCD+3膳食干预会产生更快且更强的调控效应。同时，本研究发现LCD+3膳食结构对血糖调控的有益健康效应可能与其靶向调控T2DM患者的肠道中的Prevotella和Roseburia菌群水平有关。