Sleep Deprivation Exacerbates Ischemic Stroke Outcomes via Akkermansia Depletion and Metabolic Dysregulation

Aims Sleep disturbances are a potential risk factor for stroke. Our clinical cohort shows that insomnia is associated with a higher 90-day stroke recurrence rate, prompting an investigation into the underlying mechanisms, particularly the role of the gut microbiota. Methods We utilized a rat MCAO model of sleep deprivation (SD) combined with antibiotic (ABX)-induced gut dysbiosis. Neurological deficits were assessed through behavioral tests, and cerebral infarct volume was measured using TTC staining. Structural changes in brain and intestinal tissues were observed by H&E staining, while the expression of blood–brain barrier (BBB)-related proteins was detected by immunofluorescence and Western blot. Gut microbial composition was analyzed by 16S rRNA sequencing, and metabolomic analysis was performed using an untargeted LC–MS approach. Results In rats with an intact microbiota, SD had a limited effect on MCAO-induced ischemic injury. Strikingly, in ABX-induced dysbiosis, SD-exposed rats subjected to MCAO displayed more severe motor deficits, larger infarct volumes, heightened inflammation, and decreased expression of key intestinal and BBB proteins. Microbiota analysis identified Akkermansia as a potential key mediator, whose abundance was significantly decreased in the ABX + SD + MCAO group and negatively correlated with infarct size. Subsequent metabolomics profiling revealed a distinct dysregulation of Akkermansia -associated metabolites (including PG(14:0/15:0), 3-Methylbutylamine, N-Acetylcytidine, and N-Methylisoleucine). Conclusion In conclusion, our study proposes a mechanism whereby SD worsens stroke outcomes by depleting Akkermansia and disrupting metabolic homeostasis.