Helicobacter pylori Infection, Metabolomic Signature and Extra‐gastric Cancer Risk: A Mediation and Mendelian Randomization Analysis

ABSTRACT Emerging evidence suggests that Helicobacter pylori ( H. pylori ) infection may contribute to extra‐gastric malignancies, but the mechanisms are unclear. Using untargeted metabolomics data from two prospective Chinese cohorts, we constructed an H. pylori associated metabolomic signature in 1800 baseline participants and evaluated cancer risks using conditional logistic regression in 1:1 matched case‐control studies for lung cancer ( n = 352 pairs), colorectal cancer (CRC; n = 190 pairs), esophageal cancer ( n = 146 pairs), and hepatocellular carcinoma ( n = 163 pairs), with confounder adjustment and sex stratification. Mediation analysis was performed to evaluate the mediating effects of the metabolomic signature and specific plasma metabolites on the observed associations. Mendelian randomization (MR) analysis was conducted to evaluate causal relationships. H. pylori infection was significantly associated with an increased risk of CRC (OR = 1.80, 95% CI: 1.13–2.85), especially driven by males (OR = 3.01, 95% CI: 1.44–6.31), but not with other cancers. Additionally, the H. pylori infection‐related metabolomic signature consisting of 26 metabolites (OR per standard deviation [SD] increment = 1.52, 95% CI: 1.03–2.25) and plasma metabolite methionine sulfone (OR per SD increment = 1.73, 95% CI: 1.16–2.58) were positively associated with CRC risk in males. Mediation analysis indicated partial mediation by the metabolomic signature (12.08%, 95% CI: 0.26–46.88%) and methionine sulfone (16.79%, 95% CI: 0.11–74.76%). MR analysis further supported a potentially causal association between methionine sulfone and CRC (OR = 1.08, 95% CI: 1.02–1.15). Collectively, these results implicate sex‐specific metabolomic alterations, particularly involving methionine sulfone, in mediating the relationship between H. pylori infection and CRC risk in males. These insights advance understanding of CRC pathogenesis and may inform targeted prevention strategies.