The role of gut microbes and microbial derived metabolites in the development of type 2 diabetes in humans

项目摘要 越来越多的证据将肠道微生物组-由数万亿个 人类2型糖尿病（T2 DM）患者的肠道中存在多种微生物。 利用小鼠粪便移植的研究提出了一个核心假设，即肠道的变化 微生物组和源自这些微生物的生化副产物可能是关键调节剂 T2 DM的发展。然而，到目前为止，对驱动微生物的特定微生物物种的了解还不够。 人类T2 DM的发展仍然非常有限。T2 DM患者肠道微生物组的人体研究 在很大程度上是横向的，并被反向因果关系所混淆。事实上，许多肠道 已发现在人类T2 DM中观察到的微生物组变化是该疾病的后果 或治疗，包括二甲双胍，而不是T2 DM的原因。此外该 来自肠道微生物的循环代谢产物，有助于T2 DM的发展 还有待发现。在这个早期研究者NIH R 01申请中，我们提出了最大的 使用芬兰队列6921例患者进行的肠道微生物组在T2 DM中作用的前瞻性研究 2002年收集粪便和血浆样本，随后进行了15年以上的临床随访。 这项拟议的研究汇集了一个在人类微生物组方面具有深厚专业知识的多元化团队， 基于质谱的代谢组学，计算生物学，统计流行病学， 糖尿病病理生物学，以具体解决关键的生物学和临床问题， 肠道微生物和微生物衍生代谢产物在糖尿病发病中的作用 人类

PROJECT SUMMARY Mounting evidence links the gut microbiome – the modifiable “second genome” consisting of trillions of diverse microbes that inhabit the human gut – with type 2 diabetes mellitus (T2DM) in humans. Studies using fecal transplant in mice have raised the central hypothesis that changes of the gut microbiome and the biochemical by-products originated from these microbes may be key modulators of development of T2DM. To date, however, knowledge of the specific microbial species that drive the development of T2DM in humans remain very limited. Human studies of the gut microbiome in T2DM have largely been cross-sectional and confounded by reverse causality. Indeed, many of the gut microbiome changes observed in human T2DM have been found to be a consequence of the disease or treatments, including the medication metformin, rather than a cause of T2DM. In addition, the circulating metabolites derived from the gut microbes that contribute to the development of T2DM remain to be discovered. In this Early Stage Investigator NIH R01 application, we propose the largest prospective study of the role of gut microbiome in T2DM using a Finnish cohort of 6921 individuals with fecal and plasma samples collected in 2002 and over 15 years of subsequent clinical follow up. This proposed study brings together a diverse team with deep expertise in the human microbiome, mass-spectrometry based metabolomics, computational biology, statistical epidemiology, and diabetes pathobiology, to specifically address the key biological and clinical questions regarding the role of gut microbes and microbial derived metabolites in the development of incident T2DM in humans.