Gut microbiota-metabolite axis in gastric cancer: Genetic causality and Ruminococcus subgroup shifts.

Observational studies have long suggested an association between gut microbiota dysbiosis and gastric cancer, yet the causal relevance and underlying biological pathways remain poorly defined. Here, we applied a comprehensive Mendelian randomization (MR) framework to gut microbiota and gastric cancer GWAS summary statistics to identify 14 microbial taxa significantly associated with gastric cancer risk. Sensitivity analyses, including tests for horizontal pleiotropy, heterogeneity, and genetic co-localization, revealed no strong evidence of shared causal variants (H4 < 2%); however, convergent results across five complementary MR models support overall causal inference. Mediation analysis further identified a partial pathway from the taxon ebi-a-GCST90027718 to gastric cancer via the metabolite met-c-926 (sdLDL), accounting for 4.31% of the total effect. Preliminary 16S rRNA sequencing in a pilot cohort (n = 5 per group) revealed divergent shifts in Ruminococcus subgroups without disrupting overall community stability, though these observations require replication. Collectively, this study establishes a genetically anchored evidence chain linking host genetics, gut microbiota, and gastric cancer pathogenesis, providing insights for microbiota-targeted prevention strategies.