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

项目总结 越来越多的证据表明肠道微生物群--由万亿组成的可修改的“第二基因组” 存在于人类肠道的各种微生物--人类患有2型糖尿病(T2 DM)。 在老鼠身上进行粪便移植的研究提出了一个中心假设，即肠道的变化 微生物组和由这些微生物产生的生化副产物可能是关键的调节器 对2型糖尿病的发展有一定影响。然而，到目前为止，关于推动细菌生长的特定微生物物种的知识 T2 DM在人类中的发展仍然非常有限。2型糖尿病患者肠道菌群的人体研究 在很大程度上是横截面的，并被反向因果关系搞混了。事实上，许多人的胆量 在人类T2 DM中观察到的微生物组变化被发现是这种疾病的结果 或者治疗，包括药物二甲双胍，而不是T2 DM的原因。此外， 肠道微生物的循环代谢产物有助于T2 DM的发展 仍有待发现。在这一早期阶段的Investigator NIH R01应用中，我们提出了最大的 肠道微生物群在2型糖尿病中作用的前瞻性研究--使用一组6921人的芬兰队列 2002年收集了粪便和血浆样本，随后进行了15年的临床随访。 这项拟议的研究汇集了一个在人类微生物群方面拥有深厚专业知识的不同团队， 基于质谱学的代谢组学、计算生物学、统计流行病学和 糖尿病病理生物学，专门解决有关糖尿病的关键生物学和临床问题 肠道微生物及其代谢产物在2型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.