The comprehensive oral microbiome landscape unveils its interplay with poor oral health in esophageal squamous cell carcinoma risk

Growing evidence links poor oral health to an increased esophageal squamous cell carcinoma (ESCC) risk, with the oral microbiome recognized as a key contributor. However, human-based evidence remains limited. Here, we analyze salivary shotgun metagenomic data from 390 ESCC case-control pairs and 16S rRNA sequencing data from 206 incident esophageal cancer (EC) case-control pairs. We identify 50 bacterial species altered in ESCC (e.g., enriched Porphyromonas catoniae and depleted Campylobacter rectus) and disruptions in 54 biochemical pathways (e.g., inosine 5'-phosphate degradation). These features potentially mediate the association between poor oral health and ESCC. Notably, this association is stronger among individuals with lower Streptococcus mitis levels, implicating pathways related to thiamine salvage and energy metabolism. Consistent findings in the validation dataset further support the interplay between the oral microbiome and oral health in EC risk. Our results highlight the promise of precision-targeted microbial interventions to improve oral health for ESCC prevention and management.