Targeting catecholate siderophore systems enables precision depletion of gut enterobacteria during colitis

Adherent-invasive Escherichia coli (AIEC) is frequently isolated from the dysbiotic gut microbiome in inflammatory bowel disease and is implicated in disease progression, highlighting its potential as a therapeutic target. Here we show that iron acquisition is essential for AIEC colonization of the inflamed gut. Mechanistically, four catecholate siderophore receptors act redundantly to support AIEC growth under iron-limited conditions and during colitis. Immunization of colitis-prone Il10-/- mice against catecholate siderophores reduced intestinal AIEC colonization, particularly its association with the mucosa, while largely preserving overall gut microbiome composition. Longitudinal metagenomic profiling identified immunization-associated shifts in Akkermansiaceae and Lactobacillaceae, and experiments in gnotobiotic Il10-/- mice demonstrated that Limosilactobacillus reuteri, a member of the Lactobacillaceae, limited AIEC colonization, whereas Akkermansiaceae exacerbated disease. Our findings establish catecholate siderophore-mediated iron acquisition as a therapeutic target in AIEC and provide proof-of-principle that virulence-targeted immunization can selectively antagonize a disease-associated bacterium while preserving the gut microbiota