# Commensal bacteria resilience mechanisms in the inflamed intestine

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $344,114

## Abstract

PROJECT SUMMARY
 The human gut microbiota provides essential functions in human health. However, the microbiota is
constantly subjected to challenges such as intestinal inflammation, which drives the microbiota into a perturbed
state that can cause or exacerbate diseases. Therefore, microbial resilience, which maintains the structural and
functional stability of the gut microbiome in the face of perturbations, is crucial to host health. Despite a central
role in host health, the mechanisms underlying microbiota resilience remain poorly defined. During intestinal
inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients
such as iron, constituting stress that both commensal and pathogenic bacteria must cope with to survive. Enteric
pathogens overcome nutritional immunity using a series of exquisite mechanisms, including encoding receptors
for host iron-binding proteins and producing iron-chelating molecules termed siderophores. In contrast to these
well-studied strategies, how gut commensals survive iron starvation in the inflamed gut remains largely unknown.
We propose that maintaining iron homeostasis is an essential strategy for commensals to remain resilient during
gut inflammation. In preliminary studies, we demonstrated that the model gut commensal Bacteroides
thetaiotaomicron (B. theta) acquires iron by pirating siderophores from an enteric pathogen that induces intestinal
iron limitation. Our new preliminary data suggest that B. theta captures siderophores using an extracellular
lipoprotein. We further show that enteric pathogens such as Salmonella can exploit this capture mechanism to
“re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake,
our unpublished data demonstrate that B. theta employs small, non-coding RNAs to orchestrate iron
conservation to maintain intracellular iron homeostasis and combat nutritional immunity in the inflamed intestine.
As such, our central hypothesis is that B. theta couples siderophore acquisition with small RNA-mediated
intracellular iron conservation to maintain resilience in the inflamed gut. We will test our hypothesis by pursuing
the following specific aims: 1) Elucidate how siderophore acquisition mediates B. theta resilience and modifies
host nutritional immunity in the inflamed gut; and 2) Determine how B. theta maintains intracellular iron
homeostasis in the inflamed gut. The completion of this work will reveal the mechanisms by which gut
commensals adapt to iron limitation and how such adaptation shapes the structural and functional stability of the
microbiota during gut inflammation. This research is innovative because it adds commensal iron metabolism
as a previously unrecognized dimension to the intricate interactions between pathogen and nutritional immunity.
This proposed work is impactful because establishing a model for iron regulation in B. theta will provide
insights into how interp...

## Key facts

- **NIH application ID:** 10823366
- **Project number:** 5R01DK134692-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Wenhan Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $344,114
- **Award type:** 5
- **Project period:** 2023-04-07 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823366

## Citation

> US National Institutes of Health, RePORTER application 10823366, Commensal bacteria resilience mechanisms in the inflamed intestine (5R01DK134692-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10823366. Licensed CC0.

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