“肠道菌群-生物钟轴”在生命早期发育环境与糖代谢异常中的作用

Robust evidence suggests that abnormal developmental environment in early life increases metabolic diseases in adult life. The mechanism of “metabolic memory” in early life has become one of the hot spots in the field of international diabetes research. Our preliminary research investigated the relationship between adverse intrauterine developmental environment and glucose metabolism and the underlying epigenetic mechanisms by combining clinical trial and trans-generational mice model. In recent years, increasing evidence has shown that changes in gut microbiota and circadian clock in adults may play an important role in the development of diabetes.Thus, to investigate the novel mechanism of “metabolic memory”, we will use trans-generational mice model to research the effects of maternal high-fat diet on metabolism throughout the whole life in the offspring. Furthermore, we will measure the changes of clock genes and clock-controlled genes in central and peripheral clock and measure the changes of gut microbiota and their metabolites. Integrated analysis of gut microbiota and clock genes is key to elucidate the role of ‘gut microbiota-circadian clock axis’ in high-fat diet during early life leading to abnormal glucose metabolism. This study is novel that it will integrate early nutrition, gut microbiota, metabolomics and circadian clock and will give a new interpretation to metabolic memory. It is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.

大量研究表明生命早期不良发育环境显著增加成年期代谢性疾病的风险，有关这种生命早期“代谢记忆”机制研究已成为国际糖尿病领域的热点之一。前期本课题组利用临床研究和动物模型初步探讨了宫内不良发育环境对成年期糖代谢的影响及其中可能参与的表观遗传学机制。近年越来越多的证据显示成人肠道菌群和生物钟改变在糖尿病发生发展中可能起重要作用，因此本课题拟在前期研究基础上进一步探索生命早期“代谢记忆”的新机制，拟通过建立跨代小鼠模型，观察生命早期高脂饮食对子代不同阶段糖代谢的影响，检测中枢及外周生物钟时钟基因及其下游调控基因的改变，同时检测肠道菌群及其代谢产物的变化，并将二者进行整合分析，深入探讨早期不良营养对子代糖代谢的影响及“肠道菌群-生物钟轴”在其中所起的作用。从多个层面，将早期营养、肠道菌群、代谢组学、生物钟相整合，以全新的视角开展生命早期“代谢记忆”的机制研究，为糖尿病早期防控提供理论基础和新的靶点。

生命早期不良发育环境显著增加成年期患代谢性疾病的风险，被称为“代谢记忆”。近年越来越多的证据显示肠道菌群和生物钟改变在“代谢记忆”中可能起重要作用，本课题通过建立母代孕前期和孕期高脂饮食（HF）跨代小鼠模型，明确生命早期高脂饮食对子代不同阶段代谢节律的影响，利用多组学，结合eJTK_Cycle和Circacompare检测外周生物钟、肠道菌群及其代谢产物的节律变化，从肠道菌群和生物节律的全新视角探索生命早期“代谢记忆”的新机制，挖掘其中的关键分子。结果显示，母代HF导致4周龄（幼年期）和16周龄子鼠（成年期）糖耐量受损和肝脏脂肪变性，并导致血清中血糖获得节律，总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）失去节律。转录组学结果显示，母代HF改变肝脏转录本的生物节律，其中523个基因获得节律，332个基因失去节律，富集分析发现改变节律的基因显著富集在糖酵解/糖异生等糖脂代谢相关的通路上。进一步探究肠道菌群在介导母代HF跨代调控子代代谢节律中发挥的作用，通过4周龄和16周龄子鼠肠道菌群16srRNA和宏基因组测序，发现Candidatus_Arthromitus持续失去节律并与血清TC和LDL-C显著相关。KEGG分析发现菌群获得节律的功能富集在生成乙酸的模块，4周龄小鼠靶向代谢组学验证乙酸在血清和肝脏获得节律，并与肝脏获得节律的基因G6pc（糖异生关键酶）显著相关，提示菌群代谢产物乙酸可能在介导母代HF扰乱子代循环和肝脏的糖代谢节律中发挥重要作用。该研究将为医疗生物钟学在识别与对抗早期糖脂代谢异常中的应用提供理论基础，为糖尿病早期防控提供新的思路和靶点。未来关于Candidatus_Arthromitus和乙酸等关键菌群和代谢物跨代调控代谢表型的因果关系研究将进一步展开。