Adjuvant Treatment with an Oleuropein-Enriched Olive Leaf Extract Improves Periodontal Outcomes in Older Adults with Periodontitis: Metabolomic Insights from a Randomized Controlled Trial

Background Periodontitis is a prevalent chronic inflammatory disease in older adults, often linked to systemic conditions and metabolic alterations. Standardized plant extracts may provide consistent adjunctive therapeutic benefits. Purpose and Study Design This double-blind, randomized, placebo-controlled clinical trial (OLIVAGING; ClinicalTrials.gov: NCT05482373) evaluated whether a standardized olive leaf extract enriched to 40% oleuropein, given in addition to non-surgical periodontal therapy, improves clinical outcomes and modulates systemic metabolism. Sixty participants aged ≥50 years were randomized to receive either supplement or placebo for 120 days. Primary and secondary outcomes were probing pocket depth (PPD) and clinical attachment level (CAL). Plasma metabolomics was performed using untargeted UHPLC-QTOF-MS. Results Forty-three participants completed the study (23 treatment, 20 placebo). Compared with placebo, the treatment group achieved greater reductions in ΔPPD and gains in ΔCAL across multiple tooth categories and surfaces. Metabolomic profiling revealed distinct Δ patterns, with 17 metabolites differing between groups. Several, including tentatively identified valine, cinnamic acid, 10-hydroxy-2-decenoic acid, and cortisol, correlated with periodontal improvements, suggesting modulation of biological pathways related to inflammation, oxidative stress, and tissue homeostasis consistent with the know pharmacological effects of oleuropein. Conclusions Adjunctive use of an oleuropein-enriched leaf extract improved clinical periodontal outcomes and modulated systemic metabolic signatures in older adults. The standardized extract ensured therapeutic consistency, while metabolomics provided mechanistic insights into host inflammatory and metabolic responses. Findings support further evaluation of plant-derived bioactives as safe, multi-target adjunctive strategies for periodontitis management.