Is systemic inflammation a missing link between oral microbiome and oral squamous cell carcinoma? Results from...

To investigate whether systemic inflammation mediates the relationship between oral microbiome alterations and oral squamous cell carcinoma (OSCC) through multi-omics integration analyses.

Metagenomic sequencing of unstimulated saliva samples from 65 OSCC patients and 65 matched controls was performed. Plasma levels of 34 inflammatory cytokines were profiled using Luminex assay. Six machine learning models identified potential diagnostic microbial markers. Mediation analysis assessed whether inflammation serves as a mechanistic link between oral microbiota and OSCC.

OSCC patients exhibited reduced species richness and significant beta diversity alterations. Among 155 differential species identified, 25 were enriched in OSCC, including Capnocytophaga sputigena, Gemella haemolysans, Staphylococcus aureus, and several Streptococcus species, with higher abundance in poor oral hygiene conditions. The Boruta-CatBoost model achieved exceptional diagnostic performance (bootstrap AUC = 0.991; 5-fold cross-validation AUC = 0.947). Functional profiling revealed 22 metabolic pathways over-represented in OSCC, notably lipopolysaccharide biosynthesis. Nine circulating cytokines (IL-22, IL-6, IL-2, CCL5, GM-CSF, IL-1β, TNF-α, IL-18, IFN-α) were significantly elevated in OSCC patients. Mediation analysis revealed that IL-22 partially mediated the effect of Staphylococcus aureus on OSCC risk, while CCL5 mediated associations of Gemella haemolysans and Streptococcus species with OSCC (mediation proportions: 29.9-50.1%).

Our multi-omics integration suggests that systemic inflammation, particularly through IL-22 and CCL5 upregulation, serves as a mechanistic link between specific oral bacteria and OSCC risk, which could provide new strategies for OSCC prevention and early intervention.