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

肠道微生物和微生物衍生代谢物在人类 2 型糖尿病发展中的作用

基本信息

批准号：
10281005
负责人：
Amit Majithia
金额：
$ 64.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-02 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10281005
关键词：
Address Adipocytes Bile Acids Biochemical Biological Biological Markers Blood Circulation Branched-Chain Amino Acids Clinical Complex Computational Biology Data Development Diabetes Mellitus Disease Enrollment Epidemiology Etiology Exposure to Fasting Gene Cluster Genetic Genome Glucuronides Health Hepatocyte Human Human Microbiome In Vitro Individual Inflammation Insulin Insulin Resistance Interleukin-6 Investigation Knowledge Laboratories Link Maps Mass Spectrum Analysis Mediation Metabolic Metagenomics Metformin Microbe Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pathology Pharmaceutical Preparations Phenotype Plasma Prospective Studies Research Personnel Role Sampling Shotguns United States National Institutes of Health Validation Variant Volatile Fatty Acids Work base cohort design diabetic dysbiosis enzyme pathway fasting glucose fecal microbiome fecal transplantation follow-up gut microbes gut microbiome gut microbiota in vivo machine learning method metabolomics metagenomic sequencing microbial microbial genome microbiome microbiome alteration microbiome research multidisciplinary novel prospective skills small molecule whole genome

项目摘要

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.

项目概要越来越多的证据表明肠道微生物组是由数万亿组成的可修改的“第二基因组” 栖息在人类肠道内的多种微生物——与人类 2 型糖尿病 (T2DM) 相关。使用小鼠粪便移植的研究提出了一个中心假设：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然而，迄今为止，我们对驱动 T2DM 的特定微生物种类的了解还不够。人类 T2DM 的发展仍然非常有限。事实上，许多直觉都是横断面的，并且被反向因果关系所混淆。在人类 T2DM 中观察到的微生物组变化已被发现是该疾病的结果或治疗，包括二甲双胍药物，而不是 T2DM 的原因。来自肠道微生物的循环代谢物有助于 T2DM 的发展在此早期研究者 NIH R01 申请中，我们提出了最大的方案。使用芬兰 6921 名受试者队列研究肠道微生物组在 T2DM 中的作用 2002 年收集的粪便和血浆样本以及随后超过 15 年的临床随访。这项拟议的研究汇集了在人类微生物组方面拥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和微生物衍生代谢物在 T2DM 发生过程中的作用人类。