Cross-site oral and esophageal microbiome signatures define diagnostic patterns and reveal mechanistic drivers of ESCC

The oral cavity and esophagus are contiguous mucosal sites whose microbiomes may jointly influence esophageal squamous cell carcinoma (ESCC). To address whether microbial alterations are shared across oral and esophageal niches and possess diagnostic potential in ESCC, we performed five-region 16S rRNA sequencing on paired oral swabs and esophageal tissues from 45 patients with ESCC and matched controls. We identified consistent enrichment of Porphyromonas , Fusobacterium , and Treponema , with the depletion of Neisseria , Rothia , and Actinomyces across both sites. These cross-site signatures showed strong diagnostic performance, supporting proof-of-concept non-invasive ESCC prediction using oral swabs. Functional prediction suggested altered microbiome-associated functional profiles, including enrichment of glycan- and amino acid-related pathways and reduced fatty acid metabolism. In a 4-NQO mouse model, P. gingivalis accelerated ESCC development and promoted inflammatory and immune-suppressive responses. Together, these findings identify shared oral-esophageal microbial signatures with potential diagnostic value in ESCC and support further validation of oral microbiome-based detection strategies.