Impact the impact of gut microbiota on gastric cancer via immune cells: a comprehensive Mendelian randomization study and mediation analysis

Abstract

Abstract Purpose Recent observational studies have highlighted the role of altered gut microbiota (GM) in the activation of the host immune system and the resulting of gastric cancer (GC). However, the exact causal relationship and mechanisms of action are still not fully understood. Materials and methods Genetic data from published genome-wide association studies (GWASs) were employed to determine the causal effects of 207 taxa and 205 bacterial pathways on GC via two-sample Mendelian randomization (MR) and two-step mediation MR analysis. In this study, 731 immune cell traits served as potential mediators. An inverse variance-weighted (IVW) estimation, augmented by a range of alternative estimators, notably the Bayesian-weighted MR method, was employed as the primary methodological approach. Results Four taxa and five bacterial pathways were found to be negatively correlated with GC, whereas one taxon and two bacterial pathways were a positively correlated with GC. Reverse causality was not found in the reverse MR analysis. Additional validation was performed using a sensitivity analysis. Mediation MR analyses revealed that the GM influences GC through various phenotypes of 16 immune cells that act as mediators. For example, s_Alistipes_sp_AP11 was found to inhibit GC through NKT %T cell (total effect: -0.3234, mediation effect: 0.0212). This mediating effect further highlights the complex relationship among GMs, immune cell traits, and their combined effects on GC. Conclusions Our findings highlight the genetic connection between specific GMs and GC, emphasizing the potential role of immune cells as mediators, and offering valuable perspectives on potential therapeutic strategies that manipulating the GM to address GC.

Keywords

• Gut microbiota
• Gastric cancer
• Immune cells
• Mendelian randomization study
• Single nucleotide polymorphisms