Phage intervention improves colitis and response to corticosteroids by attenuating virulence of Crohn’s disease-associated bacteria

Abstract Adherent-invasive Escherichia coli (AIEC) exhibit proinflammatory properties and have been implicated in the pathogenesis of Crohn’s disease (CD), a form of inflammatory bowel disease (IBD). Antibiotic use in CD lacks specificity and may worsen microbiome disruption, prompting interest in bacteriophages (phages) for targeted microbiome editing. Here, we identified HER259, a phage active against the clinical AIEC strain NRG857c. Using gnotobiotic models of AIEC-driven colitis, we show that HER259 attenuates AIEC virulence, including suppression of the FimH adhesin through inversion of the fimS promoter to its ‘off’ orientation. Withdrawal of HER259 treatment leads to reversion of the fimS promoter and reactivated colitis in mice. HER259 phage also enhances the therapeutic effect of sub-therapeutic budesonide, independent of microbial drug metabolism. These findings support targeted phage therapy as an adjunct treatment approach in IBD, demonstrating modulation of bacterial virulence and improved response to conventional treatments which may reduce drug-related side effects. One Sentence Summary Bacteriophage HER259 improves colitis severity mediated by Crohn’s disease Escherichia coli NRG857c, and increases efficacy of budesonide.