Chronic periodontitis induces neurobehavioral deficits via microbiota–glia–endocrine interactions [RNA-Seq]

Periodontitis is increasingly linked to diverse brain disorders, yet causal mechanisms remain elusive. Here we demonstrate that ligature-induced oral dysbiosis in mice is sufficient to perturb central function. Six weeks of periodontitis produced anxiety-like behavior and motor deficits, accompanied by microglial depletion, reduced neuronal activity and region-selective transcriptional down-regulation in the frontal cortex. Pharmacological microglial ablation phenocopied, and glucocorticoid-receptor blockade rescued, these abnormalities, implicating microglia and activation of the hypothalamic–pituitary–adrenal axis. 16S rRNA gene sequencing revealed significant shifts in oral and gut microbiota that were partially normalized by a broad-spectrum antibiotic cocktail. Antibiotics alone elevated corticosterone but did not affect microglia or behavior, indicating that dysbiosis and glucocorticoids act synergistically on the brain dysfunction. Antibiotic treatment restored microglial density and behaviors in ligature mice, despite plasma corticosterone levels remaining elevated and comparable to those in antibiotic-treated controls. Our findings suggest oral dysbiosis as a tractable driver of neuroimmune dysfunction and redefine periodontitis as a systemic disorder with direct consequences for brain health.