基于肠道菌群研究食源性 AGEs 致胰岛素抵抗的作用及机制

In the recent 30 years, the incidence of type 2 diabetes in China has shown "out of control" growth, and environmental factors, especially fast "westernization" of dietary structure, is considered to be the main cause. Advanced glycation end products (AGEs) plays an important role in the pathogenesis of insulin resistance (IR). As diet is the main source of AGEs, dietary AGEs may be one of the main causes for IR, but the exact mechanism remains unclear. Imbalance of gut microbiota structure can lead to obesity and IR, and diet is the main regulating factor for gut microbiota. Moreover, our previous preliminary research shows that the increase intake of AGEs changed the structure of gut microbiota, and also increased IR. Therefore, this project will explore the mechanisms of dietary AGEs in the pathogenesis of insulin resistance based its effect on gut microbiota. Firstly, we will detect the effect of increased dietary AGEs on gut microbiota and IR, and analysis the relationship between gut microbiota and IR. Then, the experiments of fecal microbiota transplantation in germ-free mice will be designed to verify the effect of gut microbiota on IR. Finally, in a randomized controlled study, we will detect the effect of decreased dietary AGEs on gut microbiota and IR in subjects with pre-diabetes. This project will provide new experimental data for the mechanism of diet in the pathogenesis of type 2 diabetes by gut microbiota.

近30年来中国2型糖尿病发病率“失控”地增长，环境因素尤其是膳食结构快速“西方化”被认为是主因。晚期糖基化终末产物（AGEs）在胰岛素抵抗（IR）中起着重要作用。由于膳食是AGEs的主要来源，因而食源性AGEs可能是膳食营养不良导致IR的主要原因，但确切机制仍不清楚。肠道菌群结构失衡能够导致肥胖和IR的发生，膳食是调控肠道菌群的主要因素。而且，我们前期初步研究显示，增加AGEs摄入能改变肠道菌群结构并增加IR。因此，本项目拟基于肠道菌群研究食源性AGEs致IR的作用及机制。首先，检测食源性AGEs对小鼠IR和肠道菌群的作用，分析肠道菌群变化与IR的关系；然后，通过无菌小鼠的粪菌移植实验以验证肠道菌群变化对IR的作用；最后，通过随机对照研究减少食源性AGEs摄入对糖尿病前期人群肠道菌群和IR的作用。从而为膳食通过肠道菌群致2型糖尿病的作用机制提供新的实验数据。

近30年来中国2型糖尿病发病率“失控”地增长，环境因素尤其是膳食结构快速“西方化”被认为是主因。晚期糖基化终末产物（AGEs）在胰岛素抵抗（IR）中起着重要作用。由于膳食是AGEs的主要来源，因而食源性AGEs可能是膳食营养不良导致IR的主要原因，但确切机制仍不清楚。肠道菌群结构失衡能够导致肥胖和IR的发生，膳食是调控肠道菌群的主要因素。因此，本项目拟基于肠道菌群研究食源性AGEs致IR的作用及机制。本研究结果显示，高AGEs饮食降低了小鼠肠道菌群的α和β多样性，并且发现丁酸盐产生菌的丰度降低可能导致结肠上皮屏障的损伤，引发慢性全身性低度炎症，从而参与IR的发生。减少食源性AGEs的摄入可以明显改善糖尿病前期患者胰岛素抵抗和糖代谢。该研究为膳食通过肠道菌群致IR和2型糖尿病的作用机制提供新的实验数据。