Exploring the genetic determinants of the oral microbiome’s role in gastrointestinal cancer risk: Mendelian randomization and genetic correlation analysis in an East Asian population

BACKGROUND: The human oral microbiome plays a significant role in systemic health, including potential links to digestive tract cancers. However, few studies have examined the causal relationship between the oral microbiota and digestive tract cancers using robust methodologies. This study aimed to investigate the causal associations between specific oral microbiota and the risk of gastric, esophageal, colorectal, liver, and pancreatic cancers using a Mendelian randomization (MR) approach. METHODS: We employed a two-sample MR analysis using genome-wide association study (GWAS) data from 2,948 individuals from the CNGBdb for the oral microbiome and over 150,000 individuals from BioBank Japan for digestive cancers. Single nucleotide polymorphisms (SNPs) associated with the oral microbiota were selected as instrumental variables, and the inverse-variance weighted (IVW) method was used for causal estimates. Sensitivity analyses, including MR‒Egger regression and leave-one-out tests, were performed to assess pleiotropy and robustness. Linkage disequilibrium score regression (LDSC) was applied to explore genetic correlations. RESULTS: Our MR analysis revealed several suggestive associations between the oral microbiota and digestive tract cancers. For esophageal cancer, both Fusobacterium periodonticum (OR = 1.36, 95% CI 0.16-1.59, P < 0.001) and Fusobacterium massiliense (OR = 1.31, 95% CI 0.10-1.56, P = 0.003) were positively associated with increased risk, whereas Streptococcus (OR = 0.75, 95% CI 0.64-0.89, P < 0.001) and TM7x (OR = 0.77, 95% CI 0.63-0.94, P = 0.011) exhibited protective effects. For gastric cancer, Veillonella rogosae was significantly associated with increased risk (OR = 1.14, 95% CI 01.7-1.22, P < 0.001), whereas Haemophilus_D (OR = 0.86, 95% CI 0.78-0.95, P = 0.003) had a protective effect. For colorectal cancer, MR analysis combined with LDSC analysis revealed that Campylobacter_A_concisus_D_mgs_2798 (OR = 0.92, 95% CI 0.85-0.99, P = 0.028), Campylobacter_A_concisus_F_mgs_1384 (OR = 0.91, 95% CI 0.85-0.99, P = 0.019), and Stomatobaculum (OR = 0.90, 95% CI 0.83-0.98, P = 0.017) exhibited protective effects. In hepatic cancer, according to the MR and LDSC results, Leptotrichia was correlated with hepatic cancer, with an OR of 1.18 (95% CI 1.01-1.38, P = 0.032). For pancreatic cancer, Mogibacterium was associated with an increased risk (OR = 1.55, 95% CI 1.16-2.06, P = 0.003), and Pauljensenia had a protective effect (OR = 0.53, 95% CI 0.40-0.70, P < 0.001). CONCLUSION: This study provides novel insights into the causal role of specific oral bacteria in the development of digestive tract cancers. These findings highlight potential microbial targets for cancer prevention and intervention strategies.