Infectious bacteria, but not the microbiota, induce a NOX-ATM-cytokine pathway that controls epithelial turnover.

While the gut microbiota is essential for maintaining intestinal homeostasis, infection with pathogenic microbes induces epithelial stress and accelerates tissue renewal. Cytokine production and intestinal stem cell (ISC) activity are coordinated by stress-responsive pathways that link damage to inflammation and repair. In this study, we demonstrate that pathogenic microbes, but not innocuous microbiota, trigger DNA damage response characterized by an atypical accumulation of γH2av in aged enterocytes. γH2av accumulation occurred without detectable DNA breaks and required both the Ataxia Telangiectasia Mutated (ATM) kinase and the NADPH oxidase enzyme NOX. We show that ATM signaling serves as a stress response in enterocytes promoting their elimination. In parallel, ATM signaling enhances cytokine production, coordinates cell loss with ISC-mediated tissue repair, and is essential for survival during infections. Collectively, our findings demonstrate that a NOX-ATM-cytokine regulatory axis functions as a central epithelial response to pathogens and is crucial for regulating intestinal homeostasis.