Metagenome-based virome analysis identifies the oral viral signatures for periodontitis

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.