Insights into the effects of gut microbiota and circulating metabolites on oral cancer: Mendelian randomization analysis and clinical validation

Background Prior studies have indicated that alterations in the gut microbiota could potentially influence the occurrence of oral cancer. However, the causal relationship between gut microbiota and oral cancer, as well as whether circulating metabolites serve as mediators, remains unclear. Methods We employed bidirectional two-sample Mendelian randomization (MR) to explore the causal relationships between gut microbiota, circulating metabolites, and oral cancer. The inverse-variance weighting MR (IVW-MR) and generalized summary data-based MR (GSMR) were used as the primary methods, with various other MR methods used for supplementary analyses. Additionally, we explored the potential mediating effect of circulating metabolites in this relationship. The data on 471 gut microbial taxa, 233 circulating metabolites, and oral cancer used in this study were derived from their respective genome-wide association studies (GWAS). Additional clinical samples were used to validate the Mendelian randomization findings. Results The IVW-MR and GSMR analyses identified 15 gut microbial taxa positively associated with oral cancer (OR > 1, P < 0.05) and 20 gut microbial taxa negatively associated with oral cancer (OR < 1, P < 0.05), with no evidence of horizontal pleiotropy ( P > 0.05), heterogeneity ( P > 0.05), or reverse causality. Additionally, five positive (OR > 1, P < 0.05) and fifteen negative (OR < 1, P < 0.05) causal relationships were found between circulating metabolites and oral cancer, also showing no evidence of horizontal pleiotropy ( P > 0.05), heterogeneity ( P > 0.05), or reverse causality. Our study also revealed that the positive effect of Akkermansia muciniphila on oral cancer is mediated by citrate, while the negative effect of Veillonella on oral cancer is mediated through omega-3 fatty acids. These findings were supported by our clinical multi-omics profiling. Conclusions Oral cancer was found to be causally linked to the gut microbiota, with circulating metabolites acting as mediating factors in this association.