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Updated: Jun 4, 2025
Chronic Salmonella Infection Induced Intestinal Fibrosis
Published on: September 22, 2019
Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease
Ju-Hyun Ahn1, Marlus da Silva Pedrosa1, Lacey R Lopez1
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
Insights
Adherent-invasive E. coli (AIEC) yersiniabactin sequesters zinc, stabilizing HIF-1α in macrophages. This promotes intestinal fibrosis in inflammatory bowel disease (IBD) by disrupting immune responses and tissue remodeling.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Inflammatory bowel disease (IBD) fibrosis is a significant complication with poorly understood mechanisms.
- The gut microbiota, particularly adherent-invasive Escherichia coli (AIEC), is implicated in IBD pathogenesis.
- Previous work showed AIEC producing yersiniabactin (Ybt) promotes intestinal fibrosis in a mouse model.
Purpose of the Study:
- To investigate how Ybt-mediated metal sequestration by AIEC affects macrophage function in IBD-associated fibrosis.
- To elucidate the role of hypoxia-inducible factor 1-alpha (HIF-1α) in mediating the profibrotic effects of Ybt in macrophages.
Main Methods:
- Analysis of macrophage abundance and co-localization with AIEC in human IBD-fibrosis tissues and mouse fibrotic lesions.
- Assessment of Ybt's effect on macrophage gene expression, specifically profibrotic markers.
- Investigation of Ybt's impact on HIF-1α stabilization and nuclear translocation in macrophages.
- Measurement of intracellular zinc levels in macrophages exposed to Ybt-producing AIEC.
- Evaluation of the role of zinc-dependent HIF-1α hydroxylation in the observed effects.
Main Results:
- Macrophages are abundant in human IBD-fibrosis and mouse fibrotic lesions, co-localizing with AIEC.
- Ybt induces profibrotic gene expression in macrophages by stabilizing HIF-1α, a metal-dependent regulator.
- Ybt-producing AIEC deplete macrophage intracellular zinc, inhibiting zinc-dependent HIF-1α hydroxylation and stabilizing HIF-1α.
- HIF-1α-expressing macrophages are found at sites of active disease in human IBD and mouse models.
Conclusions:
- Microbiota-mediated metal sequestration by AIEC's Ybt is a novel trigger for intestinal fibrosis.
- Ybt disrupts macrophage immune signaling and tissue remodeling through zinc depletion and HIF-1α stabilization.
- Targeting microbiota-derived metal sequestration may offer a therapeutic strategy for IBD-associated fibrosis.
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