Targeting siderophores to reduce adherent-invasive E. coli colonization: a potential therapy for Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) is characterized by chronic intestinal inflammation that frequently results in alterations of the intestinal microbial composition and is a growing epidemic affecting millions of people worldwide. The current treatments for IBD mainly target the patients’ immune system, but there is still no therapy that specifically targets the typical bloom of Proteobacteria, a major phylum of Gram-negative bacteria that includes various pathogenic species such as adherent-invasive E. coli (AIEC), a pathovar commonly associated with IBD. Bacteria require iron to survive in the host’s iron-restricted environment, and certain pathogenic bacteria secrete small molecules known as siderophores to aid in iron acquisition. Strategies to impede iron uptake by pathogens, like siderophore immunization, may allow for a more targeted strategy to reduce the Proteobacteria bloom during colitis. In this study, we investigated whether a vaccine that induces antibodies against the siderophore enterobactin (Ent) and the structurally similar salmochelin is protective against AIEC colonization in mice. We conjugated enterobactin to the immunogenic carrier Cholera Toxin B (CTB) and assessed the impact of CTB-Ent immunization on (I) the bloom of Proteobacteria and (II) providing protection against AIEC colonization during colitis. Immunized mice developed significant siderophore-specific antibody titers, and when the mice were infected with AIEC, they exhibited reduced AIEC colonization of the gastrointestinal tract. These results suggest that CTB-Ent immunization provided protection during infection with a siderophore-utilizing pathogen. Therefore, immunization against siderophores provides a more targeted approach in treating bacterial outgrowth of pathogens, which might be an attractive strategy to prevent AIEC outgrowth in patients with Inflammatory Bowel Disease in the future