Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis.

Colibactin, a bacterial genotoxin produced by strains harboring the genomic island, induces cytopathic effects, such as DNA breaks, cell cycle arrest, and apoptosis. Patients with inflammatory bowel diseases, such as ulcerative colitis, display changes in their microbiota with the expansion of . Whether and how colibactin affects the integrity of the colonic mucosa and whether contributes to the pathogenesis of colitis is not clear. Using a gnotobiotic mouse model, we show that under homeostatic conditions, do not directly interact with the epithelium or affect colonic integrity. However, upon short-term chemical disruption of mucosal integrity, gain direct access to the epithelium, causing epithelial injury and chronic colitis, while mice colonized with an isogenic mutant incapable of producing colibactin show a rapid recovery. colonized mice are unable to reestablish a functional barrier. In turn, remains in direct contact with the epithelium, perpetuating the process and triggering chronic mucosal inflammation that morphologically and transcriptionally resembles human ulcerative colitis. This state is characterized by impaired epithelial differentiation and high proliferative activity, which is associated with high levels of stromal R-spondin 3. Genetic overexpression of R-spondin 3 in colon myofibroblasts is sufficient to mimic barrier disruption and expansion of . Together, our data reveal that are pathobionts that promote severe injury and initiate a proinflammatory trajectory upon contact with the colonic epithelium, resulting in a chronic impairment of tissue integrity.