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Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease
Ahn, J.-H., da Silva Pedrosa, M., Lopez, L. R., Tibbs, T. N., Jeyachandran, J. N., Vignieri, E. E., Rothemich, A., Cumming, I., Irmscher, A. D., Haswell, C. J., Zamboni, W. C., Yu, Y.-R. A., Ellermann, M., Denson, L. A., & Arthur, J. C. (2025). Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host and Microbe, 33(1), 71-88.e9. https://doi.org/10.1016/j.chom.2024.11.012
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.