Investigating the impact of gut microbiota on gastric cancer through the involvement of immune cells: a comprehensive Mendelian randomization study and mediation analysis

Abstract

Purpose Recent observational studies have highlighted the role of altered gut microbiota (GM) involving the activation of the host immune system in the development of gastric cancer (GC), but the exact causal relationship and mechanisms at play are still not fully understood. Materials and Methods We used two-sample Mendelian randomization (MR) and Two-step mediation MR analysis with genetic data from published GWAS to examine the causal effect of 207 taxa and 205 bacterial pathways on GC. We focused on 731 immune cell traits as potential mediators. The primary methodological approach employed was inverse variance-weighted (IVW) estimation, augmented by a range of alternative estimators, notably the Bayesian weighted MR method. Results Our study indicated that four taxa and five bacterial pathways demonstrated a negative correlation with GC, while one taxon and two bacterial pathways showed a positive association. There was no evidence of reverse causality found in the reverse MR analysis. Additional validation was performed through sensitivity analyses. Mediation MR analyses revealed that the GM influences GC through various phenotypes of 16 immune cells acting as mediators. For example, s_Alistipes_sp_AP11 inhibited GC through NKT %T cell (total effect: -0.3234, mediation effect: 0.0212). The mediating effect further elucidates the complex relationship between GMs, immune cell traits, and their combined effects on GC. Conclusions Our research demonstrates a genetic connection between specific GMs and GC, emphasizing the possible role of immune cells as mediators, and the findings offer valuable perspectives on potential therapeutic strategies aimed at manipulating GM to address GC.