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

Infection with the Gram-negative, microaerophilic bacterium induces 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 which infection 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 that infection greatly reduces NEIL2 expression. The infection-induced downregulation of NEIL2 was specific, as had no such effect. Using gastric organoids isolated from the murine stomach in coculture experiments with live bacteria mimicking the infected stomach lining, we found that infection is associated with the production of various inflammatory cytokines. This response was more pronounced in knockout (KO) mouse cells than in WT cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Notably, the -infected KO murine stomach exhibited more DNA damage than the WT. Furthermore, -infected KO mice had greater inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of DNA glycosylases in gastric specimens linked the reduced level to GC progression. Our results suggest that NEIL2 downregulation is a plausible mechanism by which infection impairs DNA damage repair, amplifies the inflammatory response, and initiates GC.