The Sequential Threshold Model: A Unified Framework for Microbiome-Driven Periodontitis Progression

Periodontitis affects nearly one billion people, yet its episodic, site-specific, age-dependent progression is not explained by linear pathogen-burden models. We propose the Sequential Threshold Model (STM), a bistable framework in which progression at a previously diseased but currently stable site requires two sequential events. First, a systemic host gate opens: butyrate-driven histone deacetylase (HDAC) inhibition and NF-{kappa}B blockade reduce the senescence-associated secretory phenotype (SASP) surveillance program below the level needed to contain a dysbiotic biofilm. Second, a local microbial gate is crossed when a critical hemin threshold initiates gingipain-dependent positive feedback. Two longitudinal paired-site cohorts, subgingival metatranscriptomic and gingival crevicular fluid, support a six-month transcriptomic breakpoint, a predicted cytokine hierarchy, and primarily cell-state divergence. Formalized as an age-dependent ordinary differential equation, the STM explains five clinical phenomena as consequences of bistability and yields six testable predictions, with implications for epigenetic biomarkers and host-targeted therapy.