Su1483 YERSINIABACTIN-DRIVEN MACROPHAGE REPROGRAMMING REVEALS PATHWAYS LINKING AIEC TO CHRONIC INFLAMMATION AND INTESTINAL FIBROSIS

Gastroenterology · 2026-05-01

Targeted and quantitatively modeled biologic delivery via dual-functional probiotic yeast in inflammatory bowel disease

Journal of Controlled Release · 2026-04-05

Su1483 YERSINIABACTIN-DRIVEN MACROPHAGE REPROGRAMMING REVEALS PATHWAYS LINKING AIEC TO CHRONIC INFLAMMATION AND INTESTINAL FIBROSIS

Gastrointestinal Endoscopy · 2026-05-01

INTESTINAL E.COLI-PRODUCED YERSINIABACTIN INDUCES ZINC-DEPENDENT HIF-1A ACTIVATION TO PROMOTE PRO-FIBROTIC MACROPHAGES IN CROHN’S DISEASE

Gastroenterology · 2025-02-01

INTESTINAL E.COLI-PRODUCED YERSINIABACTIN INDUCES ZINC-DEPENDENT HIF-1A ACTIVATION TO PROMOTE PRO-FIBROTIC MACROPHAGES IN CROHN’S DISEASE

Inflammatory Bowel Diseases · 2025-02-01

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) promote 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 macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces pro-fibrotic 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 novel zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, enhancing the physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a pro-fibrotic trigger targeting macrophages in the inflamed intestine.

Adherent-invasive <i>Escherichia coli</i> in Crohn’s disease: the 25th anniversary

Gut · 2025-06-05 · 10 citations

In 1998, Arlette Darfeuille-Michaud, Christel Neut and Jean-Frederic Colombel discovered a novel pathovar of Escherichia coli , adherent and invasive Escherichia coli (AIEC), in the ileum of patients with Crohn’s disease (CD), that was genetically distinct from diarrheagenic E. coli , could adhere to and invade intestinal epithelial cells and survive in macrophages. The consistent association between AIEC and CD (approximately 30% across the world), their ability to exploit CD-associated genetic traits, and virulence in preclinical colitis models but not healthy hosts spurred global research to elucidate their pathogenicity. Research focused on integrating AIEC with the microbiome, metabolome, metagenome, host response and the impact of diet and antimicrobials has linked the luminal microenvironment and AIEC metabolism to health and disease. This deeper understanding has led to therapeutic trials and precision medicine targeting AIEC-colonised patients. In November 2023, prominent members of the AIEC research community met to present and discuss the many facets of basic, translational and clinical AIEC fields at ‘AIEC: past, present and future’ in NYC. This review is a summary of this international meeting highlighting the history of AIEC, knowledge accumulated over the past 25 years about its pathogenic properties and proposes a standardised approach for screening patients for AIEC.

Engineered Probiotic Saccharomyces boulardii Reduces Colitis-Associated Colorectal Cancer Burden in Mice

Digestive Diseases and Sciences · 2025-03-29 · 11 citations

A CONSORTIA OF CLINICAL E. COLI STRAINS WITH DISTINCT IN-VITRO ADHERENT/INVASIVE PROPERTIES ESTABLISH THEIR OWN CO-COLONIZATION NICHE AND SHAPE THE INTESTINAL MICROBIOTA IN INFLAMMATION-SUSCEPTIBLE MICE

Gastroenterology · 2024-01-25

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

Cell Host & Microbe · 2024-12-18 · 17 citations

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.

ZINC RESTRICTION BY INTESTINAL E. COLI - PRODUCED YERSINIABACTIN ACTIVATES HIF-1α IN MACROPHAGES TO PROMOTE CD-ASSOCIATED FIBROSIS

Gastroenterology · 2024-01-25