# Epigenetics of the human gut microbiome

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $368,125

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10176496
- **Project number:** 5R01ES031576-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Eric John Alm
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,125
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176496

## Citation

> US National Institutes of Health, RePORTER application 10176496, Epigenetics of the human gut microbiome (5R01ES031576-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10176496. Licensed CC0.

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