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

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Item Type:Article
Title:Short-term mucosal disruption enables colibactin-producing E. coli to cause long-term perturbation of colonic homeostasis
Creators Name:Harnack, C. and Berger, H. and Liu, L. and Mollenkopf, H.J. and Strowig, T. and Sigal, M.
Abstract:Colibactin, a bacterial genotoxin produced by E. coli strains harboring the pks 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 E. coli. Whether and how colibactin affects the integrity of the colonic mucosa and whether pks+ E. coli contributes to the pathogenesis of colitis is not clear. Using a gnotobiotic mouse model, we show that under homeostatic conditions, pks+ E. coli do not directly interact with the epithelium or affect colonic integrity. However, upon short-term chemical disruption of mucosal integrity, pks+ E. coli gain direct access to the epithelium, causing epithelial injury and chronic colitis, while mice colonized with an isogenic ΔclbR mutant incapable of producing colibactin show a rapid recovery. pks+ E. coli colonized mice are unable to reestablish a functional barrier. In turn, pks+ E. coli 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 E. coli. Together, our data reveal that pks+ E. coli 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.
Keywords:Inflammtory Bowel Diseases, Colitis, Microbiota, Mucosal Barrier, Colibactin, E. Coli, Stem Cells, Regeneration, Animals, Mice
Source:Gut Microbes
Publisher:Taylor & Francis
Page Range:2233689
Date:10 July 2023
Official Publication:https://doi.org/10.1080/19490976.2023.2233689
PubMed:View item in PubMed

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