Multi‐Omics Signatures of Periodontitis and Periodontal Therapy on the Oral and Gut Microbiome

ABSTRACT Aim To characterize the impact of periodontitis and of Steps I–II of periodontal therapy on microbiome composition, function, and metabolic output across the oral and gut environments. Methods A multi‐omics analysis was performed on saliva and stool samples collected from 50 systemically healthy individuals with and without Stage III–IV periodontitis. For participants with periodontitis, samples were analyzed both at baseline and 3 months after Steps I–II of periodontal therapy. High‐throughput whole metagenome sequencing was used to profile microbial taxa and functional genes, NMR‐based metabolomics profiled host–microbial metabolites. Single‐omic differential abundance analysis between healthy samples and periodontitis samples was performed with MaAsLin2, while analysis between pre‐ and post‐treatment was conducted with timeOmics. Variable selection and subsequent supervised multivariate analysis to determine group‐separating markers utilized multi‐level sparse Partial Least Squares Discriminant Analysis (sPLS‐DA) through mixOmics. KEGG pathway enrichment was analyzed using clusterProfiler, whereas multi‐omic data integration was performed with multi‐block Partial Least Squares regression analysis. Results Periodontitis was associated with significant compositional and functional changes in both saliva and stool, with increased abundance of pathobionts and loss of health‐associated taxa in both niches. A subset of species was shared across oral and gut habitats, with detectable differences across clinical groups. As functional potential, periodontitis enriched microbial pro‐inflammatory pathways (lipopolysaccharide biosynthesis, bacterial motility) and depleted beneficial short‐chain fatty acid (SCFA)‐ and vitamin‐producing functions. Metabolomic profiles revealed reduced SCFAs and amino acids in periodontitis, with elevated pro‐inflammatory metabolites (succinate, trimethylamine) in both saliva and stool. Following therapy, microbial communities and their metabolic output partially reverted toward health‐associated profiles, particularly in saliva. Stool samples showed subtler but consistent shifts, including a decrease in some typically oral species and decreased succinate and methylamine and restoration of amino acid and SCFA‐related metabolites. Conclusions Periodontitis is associated with coordinated microbial and metabolic signatures across the oral and gut environments. Non‐surgical periodontal therapy promotes partial ecological restoration in both niches, supporting the view of oral health as a modifiable target for influencing systemic microbial homeostasis. Trial Registration ClinicalTrials.gov identification number: NCT04826926