肠道细菌Akkermansia muciniphila 在饮食诱导巴马猪胰岛素抵抗中的作用及机制研究

The gut microbiome has been demonstrated to play an important role in the occurrence and development of insulin resistance and type 2 diabetes. Results from mouse models have shown that Akkermansia muciniphila is closely related to insulin resistance. Oral administration of Akkermansia muciniphila significantly enhanced impaired glucose tolerance and could improve the fat accumulation and high blood glucose induced by high fat diet. However, the underlying mechanisms are not clear. Statistical analysis and preliminary results have indicated that Akkermansia muciniphila inversely correlated with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders in obesity mice. But, there are great differences between rodents and humans in eating habits and energy metabolism, especially in fat browning. What is more, oral intake reduces the quantity and activity of bacteria. This study aims to uncover the function of Akkermansia muciniphila in insulin resistance, elucidate the underlying relationship between Akkermansia muciniphila and adipose tissue inflammation, and reveal its regulation mechanism of insulin sensitivity, by means of cecal implanted with colonoscopy, in a Bama mini-pig insulin resistance model induced by our lab. Our results will provide a new insight in the role of gut microbiome in diabetes prevention and treatment, and a number of reliable basic data for breeding and application of type 2 diabetes model in bama miniature pig.

肠道菌群已被证实在胰岛素抵抗和2型糖尿病发生、疾病进展和治疗中发挥着重要作用。小鼠模型发现，肠道粘蛋白降解菌Akkermansia muciniphila与胰岛素抵抗密切相关。该菌口服可以改善高脂饮食诱导的糖耐量受损和脂肪蓄积，但机理不明。研究显示Akkermansia muciniphila丰度与小鼠白色脂肪组织炎性因子mRNA水平呈负相关。然而啮齿类动物在饮食习惯、能量代谢，特别是白色脂肪褐变等方面与人类有巨大差异。因此，本项目选用本室选育的糖尿病易感小型猪建立更接近于人的胰岛素抵抗模型，采用结肠镜盲肠植入的手段，在体内和体外两个层面研究Akkermansia muciniphila在胰岛素抵抗中的作用，与脂肪组织炎症的关系及其调控胰岛素信号通路的具体机制，为阐明肠道菌群对预防和治疗糖尿病的作用提供实验依据，同时为巴马小型猪2型糖尿病模型的选育和应用提供基础资料支持。

嗜粘蛋白阿克曼菌Akkermansia muciniphila已被证实可以在小鼠模型中改善饮食诱导的糖耐量受损和脂肪蓄积。本项目主要探讨了该菌对糖尿病小型猪的作用。本研究成功制备了巴马小型猪糖尿病模型和糖尿病合并动脉粥样硬化模型，获得了糖尿病小型猪肠道微生物和代谢产物变化情况，结果显示糖尿病小型猪拟杆菌比例降低而厚壁杆菌比例升高， beta熊去氧胆酸、二十二碳五烯酸等代谢产物升高。本研究证实了Akkermansia muciniphila在糖尿病小型猪和糖尿病合并动脉粥样硬化小型猪粪便中表达丰度降低。采用Akkermansia muciniphila对糖尿病小型猪干预3个月后体重未检测到明显改变，血糖略降低，但由于个体差异加大，无统计学差异。炎症因子检测分析显示，糖尿病小型猪IL-8、IL-10、TNF-α较正常对照组显著升高，而采用Akkermansia muciniphila干预后，这些炎症因子的表达均降低，提示Akkermansia muciniphila可以调节这些炎症因子相关的信号通路。后续本课题将进一步扩大样本量，明确Akkermansia muciniphila对糖尿病小型猪的作用，并对其炎症相关信号通路进行进一步的验证分析。