# Iron homeostasis in sustaining commensal resilience in the inflamed gut

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,295

## Abstract

Abstract
 The homeostatic gut microbiota provides essential functions to multiple aspects of human health,
including modulating the interactions between host and enteric pathogens. Perturbations, such as intestinal
inflammation, can shift the beneficial microbiota to an imbalanced state frequently referred to as dysbiosis, which
instead exacerbates inflammatory disease outcomes in susceptible individuals. As such, microbial resilience is
crucial to maintaining the structural and functional stability of the gut microbiome in the face of perturbations.
Despite the central role in host health, mechanisms underlying microbiota resilience remain largely unexplored.
 During intestinal inflammation, the host immune system impedes invading pathogens through the
sequestration of iron, among other micronutrients, in a process termed nutritional immunity. While decades of
research have described how pathogens utilize small iron-chelating molecules termed siderophores to survive
and thrive in the iron-starved inflamed gut, commensal survival strategies during nutritional immunity remain
largely unknown. Our preliminary studies suggested that the prominent gut commensal Bacteroides
thetaiotaomicron (B. theta) can capture iron from siderophores produced by enteric pathogens. Additionally, B.
theta can prioritize its iron expenditure through the activation of a small RNA-mediated iron-sparing response,
thereby conserving the limited iron for essential cellular processes. I hypothesize that B. theta couples
xenosiderophore piracy and iron-sparing response through the action of small RNA to maintain
resilience in the iron-limited inflamed gut. I will test this hypothesis using genetic, biochemical, and
computational approaches in tandem with in vitro growth assays and murine models of infectious colitis.
Experiments proposed in Aim 1 will determine the contribution of xenosiderophore piracy to B. theta fitness,
using in vitro growth kinetics and mouse models of intestinal inflammation. Experiments in Aim 2 will define the
mechanism, regulatory targets, and fitness contribution of iron-responsive B. theta sRNA during iron-limitation
in vitro and in vivo. This proposed work is innovative because it presents a heretofore unexplored microbial
factor in microbiome structure during intestinal inflammation. This proposed work is impactful because
establishing a model for iron regulation in B. theta will provide insights into how interphylum iron metabolism and
intracellular iron homeostasis may broadly contribute to gut microbiota resilience in the inflamed gut.

## Key facts

- **NIH application ID:** 10900141
- **Project number:** 1F31AI178950-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ryan T Fansler
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,295
- **Award type:** 1
- **Project period:** 2024-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900141

## Citation

> US National Institutes of Health, RePORTER application 10900141, Iron homeostasis in sustaining commensal resilience in the inflamed gut (1F31AI178950-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900141. Licensed CC0.

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