Periodontitis and Circadian Rhythm Disruption: Unveiling the Neuro-Immuno-Metabolic Axis

Abstract

Background: Periodontitis is a chronic inflammatory disease driven by dysregulated host immune responses. Emerging evidence suggests that circadian rhythm disruption acts as a significant biological stressor that impairs tissue repair and immune function. This review aims to propose a novel "neuro-immuno-metabolic axis" to explain the bidirectional relationship between periodontal inflammation and systemic chronobiological health. Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Google Scholar to identify peer-reviewed research, systematic reviews, and meta-analyses published up to the time of review. The search strategy focused on the intersection of periodontitis, clock genes such as Brain and Muscle ARNT-Like Protein-1 (BMAL1), Period (PER), and inflammatory markers including Interleukin-6, Tumor Necrosis Factor-Alpha, and the Receptor Activator of Nuclear Factor Kappa-B Ligand / Osteoprotegerin axis. Results: Periodontal inflammation acts as a systemic stressor, where cytokines like Interleukin-6 and Tumor Necrosis Factor-alpha dampen circadian amplitude and repress core clock genes like Brain and Muscle ARNT-Like Protein-1. Conversely, circadian rhythm disruption exacerbates periodontitis by skewing macrophages toward a pro-inflammatory M1 phenotype and dysregulating the Receptor Activator of Nuclear Factor Kappa-B Ligand / Osteoprotegerin ratio, leading to accelerated alveolar bone loss. Conclusion: Periodontitis and circadian rhythm disruption are linked through a self-perpetuating biological cycle. Recognizing this bidirectional axis allows for the development of chronotherapeutic strategies, such as timed melatonin supplementation or synchronized periodontal therapy, to improve clinical outcomes.