# Sulfide metabolism at the host microbiome interface

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $67,582

## Abstract

Project Summary
Hydrogen sulfide (H2S) is a redox-active signaling molecule that modulates electron transport and energy
metabolism, and by largely unknown mechanisms, mediates neuro- and cardioprotection, vasodilation, the
hypoxic response, protein translation, epigenetics, aging, and both patho- and physiological responses in colon.
As H2S is also a respiratory poison at high doses, cells actively oxidize it to produce persulfides, sulfite,
thiosulfate, (collectively referred to as reactive sulfur species), and sulfate. Oxidative modification of protein
cysteine thiols to persulfides is postulated to be a primary mechanism by which H2S signals. The potential
involvement of other reactive sulfur species in signaling is however, unknown. Studies in our laboratory have
demonstrated that H2S impacts cellular redox metabolism via its dual effects on mitochondrial energetics, i.e.
increasing electron flux at low, and inhibiting it at high concentrations. The highest exposure to exogenous H2S
occurs in colon (0.2–2.4 mM) and is derived from gut resident microbiota, which synthesize sulfide. Preliminary
data in our laboratory reveal that colonic epithelial cells quantitatively oxidize exogenous H2S to thiosulfate, and
that the localization and expression levels of sulfide oxidation enzymes in murine colonocytes are strongly
influenced by the presence or absence of sulfate reducing bacteria in the gut. I hypothesize that the dynamic
interplay between host and microbial sulfur metabolites influences host metabolism and impacts longevity. Using
Caenorhabditis elegans as a model organism, which has the full complement of orthologous genes involved in
H2S biogenesis and oxidation found in humans and is readily amenable to genetic and dietary manipulation and
to life-span analyses, I will test my hypothesis by addressing the following two aims. (i) I will characterize how
alterations in H2S levels and reactive sulfur species impact organismal redox and histone modifications that are
linked to longevity and stress response in C. elegans. H2S levels and its oxidative byproducts will be modulated
by exogenous H2S, RNA interference knockdowns of host sulfide oxidation enzymes, and by diet, using
Escherichia coli with deletions in specific genes involved in sulfur metabolism. I will assess how exogenous
versus dietary H2S modulation affects organismal redox using the genetically encoded reduction-oxidation
sensitive GRX1-roGFP2 sensor and track changes in histone methylation and acetylation status with reported
links to redox, H2S availability, diet, and aging. (ii) I will investigate how differences in exogenous H2S exposure
from air versus gut microbes affects the expression and localization of host sulfide oxidation enzymes, the
abundance and type of reactive sulfur species, and their effect on lifespan. I will complement these studies with
metabolomic and transcriptomic analyses to identify pathways that are impacted by H2S exposure. The
successful completion...

## Key facts

- **NIH application ID:** 10328892
- **Project number:** 5F32GM140694-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David A Hanna
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328892

## Citation

> US National Institutes of Health, RePORTER application 10328892, Sulfide metabolism at the host microbiome interface (5F32GM140694-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328892. Licensed CC0.

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