Targeting siderophores to reduce colonization of adherent invasive e. coli in crohn's disease

The pathovar adherent-invasive Escherichia coli (AIEC) is a mucosa-associated bacterium that is frequently found in patients with Crohn’s disease (CD), but targeted treatment options are currently lacking. During intestinal inflammation, host-mediated iron limitation is a key strategy to restrict the outgrowth of pathogens. Various bacterial pathogens evade this nutrient limitation by secreting small, iron-chelating molecules known as siderophores. The siderophore enterobactin (Ent) is an important virulence factor for Gram-negative pathogens such as AIEC by promoting their expansion and competition over commensal microbes during colitis. Here, we developed an immunization-based approach to target bacterial siderophores during colitis and to reduce AIEC colonization in mice. We demonstrate that immunization with Ent (conjugated to the mucosal adjuvant cholera toxin subunit B, CTB) potently elicits fecal antibodies against Ent. Immunized animals show reduced AIEC colonization along with milder weight loss, less colonic shortening, and decreased histological severity scores. This phenotype is largely B cell-dependent, as immunized mice lacking mature B lymphocytes do not show protection during AIEC infection. Ent-specific B cells are primarily found in small intestinal Peyer’s patches and can be isolated by a flow cytometry-based sorting approach. This project paves the way to develop monoclonal antibodies against siderophores, which could provide a more targeted and narrow-spectrum strategy to reduce AIEC colonization in patients with CD.