Campylobacter jejuni genotoxin promotes intestinal inflammation via the DNA damage-cGAS-STING signaling axis

The foodborne agent Campylobacter jejuni is a pervasive zoonotic pathogen and a major cause of gastrointestinal disease associated with inflammatory disorders in humans. While its genotoxin, cytolethal distending toxin (CDT), induces DNA damage, the toxicological signaling events linking this genotoxin to intestinal pathogenesis remain incompletely defined. In this study, we utilize a high-fidelity experimental pipeline combining in vitro systems, human induced pluripotent stem cell (iPSC)-derived intestinal organoids, and in vivo murine models to characterize this hazard. We demonstrate that CDT-induced double-strand DNA breaks (DSB) lead to cytoplasmic DNA accumulation and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. This sensing axis promotes type I interferon (IFN-β) production and pro-inflammatory responses, which were markedly attenuated upon STING knockdown. Our findings establish a mechanistic link between C. jejuni genotoxin-induced nuclear DNA damage and cGAS-STING-mediated intestinal inflammation.