Unveiling the Impact of Porphyromonas gingivalis ‐Associated Periodontitis on Stroke Outcome in Mice

Background Periodontitis is a chronic inflammatory condition with infectious origin that affects the tissues supporting the teeth. Increasing epidemiological evidence suggests that periodontitis is a risk factor for ischemic stroke with associated adverse outcomes. However, the underlying mechanism of this association remains incompletely elucidated. Methods We used a C57BL/6J mice model of ischemic stroke induced by transitory occlusion of the middle cerebral artery in the presence or absence of ligature‐induced periodontitis using Porphyromonas gingivalis ‐soaked ligatures. Stroke severity was evaluated through infarct volume, sensorimotor deficit, blood–brain barrier (BBB) integrity, and markers of systemic and brain inflammation. The direct effect of P gingivalis on BBB endothelial cells was further explored in vitro. Results Mice with P gingivalis ‐associated periodontitis showed a significant exacerbation of stroke severity: larger infarct volume, more severe sensorimotor deficit, greater BBB disruption, and increased brain neutrophil infiltration compared with sham. Systemic inflammation was also markedly elevated. Intravenous administration of P gingivalis alone, without gingival injury, before transitory occlusion of the middle cerebral artery was sufficient to amplify brain inflammation and stroke lesions. In vitro P gingivalis, through its gingipain proteases, directly impaired BBB integrity by increasing endothelial permeability and disrupting tight‐junction proteins. Conclusions Our findings demonstrate that P gingivalis ‐associated periodontitis worsens ischemic stroke outcome both indirectly by enhancing systemic and brain inflammation and directly via BBB disruption. These results highlight periodontitis as a modifiable risk factor and potential therapeutic target for improving stroke prognosis.