Human gut microbiota, with its massive catalytical capacity and functional potential, may act as an ?endocrine organ? and significantly contribute to metabolic health. Indeed, basic microbiological research and culture- based human studies have elucidated multiple pathways through which human gut microbiota may modulate the risk of developing metabolic diseases, such as type 2 diabetes (T2D). Existing human studies also demonstrated promising evidence supporting a link between microbiome and prevalent diabetes, although few longitudinal studies have been conducted to establish a prospective relationship between microbiome and the risk of developing T2D. This proposal represents major research efforts to significantly accelerate the advances in the research of microbiome and T2D risk by examining prospective relationships between gut microbial composition, functional potential, and fecal metabolome that operate in candidate pathways and T2D risk. We will also use network analysis and other advanced methods to interrogate the overall metagenomic, metatranscriptomic, and metabolomic profiles in fecal samples for the identification of novel microbial features (i.e., microbes, their functional potential, gene transcription levels, and microbiota metabolites) and pathways that might be involved in the development of T2D. As a secondary aim, we will evaluate the interplay between diet and microbiome on fecal metabolome and T2D risk. Furthermore, these complementary, inter-connected study aims will be realized by an experienced investigator team consisting of researchers with expertise in microbiome, metabolomics, biomarker research, diabetes epidemiology, biostatistics, and bioinformatics. To facilitate better generalizability and internal validity of research findings, we will examine these novel associations in two US cohorts with complementary ethnic and socioeconomic profiles: Nurses? Health Study II and Hispanic Community Health Study / Study of Latinos. Rich resources of these two cohorts, including fecal samples, repeated assessments of diet, lifestyle, medical history, and use of medications, longitudinal follow- up on diabetes status, and infrastructure for sample preparation/storage and computing, will empower the investigators to accomplish the proposed aims cost-effectively. To strengthen between-institution collaboration and ensure a successful implementation of the proposed research, Drs. Qi Sun (at Harvard T.H. Chan School of Public Health) and Qibin Qi (at Albert Einstein College of Medicine) will share the responsibility of overseeing the overall conduct of research through the Multiple PI mechanism. In summary, this project will elucidate prospective associations of gut microbiome and fecal metabolome with T2D risk and facilitate discoveries of novel microbial features relevant to T2D risk. As such, the proposed research has a great potential to identify novel microbiota-related risk or beneficial factors for developing more targeted and individualized strategies for the prevention and management of diabetes.
/Relevance New technology that allows the classification of thousands of gut microbial features has made it possible to identify the many physiological and metabolic processes through which microbiota may influence the health of their hosts. Evidence from animal experiments and feeding studies has suggested that microbiota may modulate the risk of diabetes, although few prospective studies have been conducted to establish the relationship between gut microbiome and diabetes incidence. This study aims to examine microbiota composition, functional potential, and fecal metabolome in relation to the risk of developing diabetes in two well-established cohorts of U.S. men and women with complementary ethnic and socioeconomic backgrounds. Study findings will help identify novel microbial features as targets for developing individualized prevention and intervention strategies to alleviate the increasing societal and healthcare burden of diabetes.