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Epigenetics of the human gut microbiome

人类肠道微生物组的表观遗传学

基本信息

批准号：
9790036
负责人：
Eric John Alm
金额：
$ 36.81万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790036
关键词：
7-deazaguanine Address Adenine Affect Bacteria Bacterial DNA Bacterial Genome Bacteriophages Behavior Cell Cycle Chemicals Chemistry Chromatography Clinical Collaborations Colon Carcinoma Consumption Coupled DNA DNA Methylation DNA Modification Process DNA Restriction-Modification Enzymes Development Disease Epigenetic Process Equilibrium Etiology Gene Expression Genes Genetic Engineering Genome Genomic Instability Genomics Goals Health Heritability Human Human Microbiome Immune system In Vitro Individual Inflammation Inflammation Mediators Inflammatory Bowel Diseases Inflammatory disease of the intestine Inherited Libraries Link Maps Mass Spectrum Analysis Metagenomics Methyltransferase Microbe Modification Mus Mycobacterium abscessus Oxidation-Reduction Oxidative Stress Oxygen Patients Phenotype Play Population Predisposition Program Research Project Grants Proteins Pseudomonas aeruginosa infection Research Resistance Role Sampling Sulfur System Testing Vertebral column Virulence Wound Infection analytical tool bacterial fitness base computerized tools epigenome gene function genomic tools gut bacteria gut microbes gut microbiome gut microbiota human disease human microbiota informatics tool innovation innovative technologies microbial microbiome microbiome research neutrophil new technology next generation sequencing novel oxidation pathogen pathogenic bacteria phosphorothioate tool virtual

项目摘要

Project Summary The proposed studies address the role of bacterial epigenetics in the human gut microbiome and their mechanistic links to health and disease. Virtually all microbes possess DNA modifications – the epigenome -- inherited marks that regulate gene expression and function as immune systems, most commonly in restriction- modification (RM). While well-characterized DNA methylation-based RM systems have been known since the 1970s, there are now >30 DNA modifications defined in bacteria and bacteriophage, including our recent discovery of phosphorothioate (PT) and 7-deazaguanine modifications. DNA modifications also regulate gene expression, such as the DNA adenine methyltransferase, DAM, and cell cycle-regulated methylase, CcrM, which control heritable gene expression affecting virulence and bacteriophage resistance, as well as non- heritable gene expression. While these examples of bacterial epigenetics have links to human disease, we know little about how DNA modifications determine or affect microbial populations in the gut, how they affect the behavior or survival of individual microbial species, or if there is a relationship between specific microbiome epigenetics and human health and disease. Here we use innovative analytics, informatics, and genomics tools to explore these questions, with an initial focus on a bacterial DNA modification found in ~15% of human gut microbes: PT modifications, in which a redox-active S replaces a non-bonding oxygen in the DNA backbone. The proposed studies are driven by the widespread distribution of PTs in bacterial pathogens and commensals, the susceptibility of PTs to oxidation by chemical mediators of inflammation, and the known effects of inflammation on gut microbiota, all of which suggest that inflammation could alter the balance of PT-containing gut microbes. However, we know virtually nothing about microbiome epigenetics, much less which gut bacteria possess redox-sensitive PTs and other epigenetic marks. We now propose to define the landscape of PT-containing bacteria in the healthy human gut, elucidate the role of PTs in microbiome changes during gut inflammation, and discover new epigenetic marks in the gut microbiome. We start by quantifying PTs and identifying PT-containing bacteria in fecal DNA samples from healthy donors to the Broad Microbiome Library and in ~7000 strains cultured from these samples (dnd genes found in 15%). We then test the idea that redox-sensitive PTs affect bacterial fitness in the inflamed gut, quantifying PT levels and PT-containing bacteria in 20-30 fecal samples from inflammatory bowel disease (IBD) patients. Finally, we will identify new DNA modifications in gut microbes, using novel technologies to discover DNA marks in banked fecal samples from BML donors and strains, and then link them to unique microbiome phenotypes and associations with human disease. The significance of this project lies in the potential role for PT-containing microbes in human health and disease, the potential clinical impact of PT- containing bacteria on IBD, and the development of new tools to discover new microbiome epigenetic systems.

项目总结