Normal gastric tissue Helicobacter pylori infection is associated with tissue cell composition, and cell type-specific epigenetic age acceleration, mitotic tick rate, and repetitive element methylation alterations.

Helicobacter pylori (H. pylori) infection is a well-established risk factor for gastric adenocarcinoma, one of the leading causes of cancer-related death worldwide. While H. pylori infection induces significant DNA methylation changes, the cell type-specific epigenetic mechanisms contributing to carcinogenesis are not understood. To investigate these mechanisms, we analysed publicly available DNA methylation data from normal gastric mucosa of gastric cancer cases and controls stratified by H. pylori infection status, as well as tumour tissue from stomach adenocarcinoma. Using cell-type deconvolution and statistical modelling, we assessed epigenetic age acceleration, mitotic tick rate, cell-type composition, repetitive element methylation, and differentially methylated cell types. We reveal that (1) H. pylori infection is associated with increased epigenetic age acceleration and mitotic tick rate after adjustment for cell-type, independent of cancer status; (2) H. pylori infection corresponds to reduced epithelial and fibroblast proportions and increased infiltration of immune cell types, independent of cancer status; and (3) H. pylori infection influences LINE-1 and ERV repetitive element methylation in a cell type-specific fashion, particularly in epithelial and monocyte lineages. Our findings suggest that H. pylori infection induces lasting, cell-specific epigenetic alterations that may promote a pro-inflammatory and carcinogenic gastric microenvironment through altered cell pathways, genomic instability, and sustained inflammation.