The oral‒gut axis in periodontal disease: a systematic review of the associated human evidence of its mechanisms and implications for patient care.

Background: Periodontal diseases may influence systemic health through the oral-gut axis, with three mechanistic pathways proposed. Periodontitis-associated gut dysbiosis has been repeatedly observed and may plausibly extend to effects on drug metabolism, yet the literature on periodontitis-associated dysbiosis and that on its potential effects on medicine pharmacokinetics have not previsouly been bridged. Objective: To synthesise the available human evidence for each of the three pathways with a distinct focus on the interventional evidence, and to position the evidence to its clinical context alongside downstream outcomes and the implications for patients and clinicians. Our secondary aim was to connect the dysbiosis and pharmacokinetic literatures in a hypothesis-generating section. Design: This systematic review was registered on PROSPERO. PubMed and Scopus were searched and eligibility restricted to human studies. Results: A total of 76 studies were included following full-text assessment by two independent reviewers. Across the three pathways, the human evidence was placed in clinical context with its downstream outcomes. Direct evidence that periodontitis modeifies drug response in humans was not identified, however, we were able to provide a hypothesis-generating section that identifies four drug classes for which a periodontitis-mediated modification of drug response would be most clinically relevant. Conclusions: The oral-gut axis is a biologically plausible but, currently, under-evidenced route from periodontal disease to systemic and pharmacological outcomes. Future reserach should prioritise prospective comparative pharmacokinetic studies in periodontitis-affected popualtions and field-wide standardisation of methodology across oral-gut microbiome research.