Helicobacter pyloriinfection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells

Infection with the Gram-negative, microaerophilic bacteriumHelicobacter pyloriinduces an inflammatory response and oxidative DNA damage in gastric epithelial cells that can lead to gastric cancer (GC). However, the underlying pathogenic mechanism is largely unclear. Here, we report that the suppression of Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase that specifically removes oxidized bases, is one mechanism through whichH. pyloriinfection may fuel the accumulation of DNA damage leading to GC. Using cultured cell lines, gastric biopsy specimens, primary cells, and human enteroid-derived monolayers from healthy human stomach, we show thatH. pyloriinfection greatly reduces NEIL2 expression. TheH. pyloriinfection-induced downregulation of NEIL2 was specific, asCampylobacter jejunihad no such effect. Using gastric organoids isolated from the murine stomach in coculture experiments with live bacteria mimicking the infected stomach lining, we found thatH. pyloriinfection is associated with the production of various inflammatory cytokines. This response was more pronounced inNeil2knockout (KO) mouse cells than in WT cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Notably, theH. pylori-infectedNeil2-KO murine stomach exhibited more DNA damage than the WT. Furthermore,H. pylori-infectedNeil2-KO mice had greater inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of DNA glycosylases in gastric specimens linked the reducedNeil2level to GC progression. Our results suggest that NEIL2 downregulation is a plausible mechanism by whichH. pyloriinfection impairs DNA damage repair, amplifies the inflammatory response, and initiates GC.