Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease

Ju-Hyun Ahn; Marlus da Silva Pedrosa; Lacey R Lopez; Taylor N Tibbs; Joanna N Jeyachandran; Emily E Vignieri; Aaron Rothemich; Ian Cumming; Alexander D Irmscher; Corey J Haswell; William C Zamboni; Yen-Rei A Yu; Melissa Ellermann; Lee A Denson; Janelle C Arthur

doi:10.1016/j.chom.2024.11.012

Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease

Cell Host Microbe. 2024 Dec 14:S1931-3128(24)00443-8. doi: 10.1016/j.chom.2024.11.012. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
³ Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA.
⁴ UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
⁸ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: janelle_arthur@med.unc.edu.

PMID: 39701098
DOI: 10.1016/j.chom.2024.11.012

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.

Keywords: Crohn’s disease; HIF-1α; adherent-invasive Escherichia coli; fibrosis; inflammatory bowel disease; intestinal E. coli; macrophage; metallophore; yersiniabactin; zinc.