Abstract
BACKGROUND: Periodontitis (PD) is a chronic infectious disease driven by bacterial biofilms, yet the oral virome's role in pathogenesis remains poorly understood. OBJECTIVE: This cross-cohort meta-analysis aims to define PD-associated viral signatures, characterize predicted virus-host interactions, and evaluate the diagnostic potential of viral biomarkers. METHODS: We integrated 89 saliva (44 PD, 45 healthy) and 86 subgingival plaque (48 PD, 38 healthy) metagenomes from six public cohorts for a unified virome analysis. RESULTS: We identified 156 viral operational taxonomic units (vOTUs) significantly associated with PD (105 in saliva, 66 in subgingival plaque and 15 shared). PD-enriched vOTUs were predicted to target periodontal pathogens including Porphyromonas gingivalis, whereas Streptococcus-targeting phages were decreased. PD-associated vOTUs harbored diverse bacterial defense and anti-defense systems, with those enriched in PD overrepresenting lysozyme and replication-associated genes. Diagnostic models based on key viral markers achieved robust performance, with AUCs of 0.95 (saliva) and 0.92 (subgingival plaque) for classifying PD. CONCLUSION: This study delineates a distinct oral virome profile in PD, highlights predicted virus-host interactions, and underscores the potential of viral biomarkers for PD diagnosis,providing a basis for future investigations into viral ecology and phage-based interventions.