Fecal Microbiota Transplantation from Exercise-Preconditioned Mice Attenuates Post-stroke Cognitive Impairment by Preserving Gut and Blood-Brain Barrier Integrity.

Exercise preconditioning reduces post-stroke cognitive impairment (PSCI), but the contribution of the gut microbiota (GM) to barrier protection remains unclear. We examined whether exercise-preconditioned GM contributes to PSCI improvement and preservation of gut and blood-brain barrier (BBB) integrity. Mice were preconditioned with 4 weeks of voluntary wheel running prior to stroke induction. We assessed cognitive function, GM composition, fecal short-chain fatty acid (SCFA) levels, inflammation, and gut-blood-brain barrier (BBB) integrity. Then, we used fecal microbiota transplantation (FMT) to evaluate how GM contributes to the benefits of voluntary exercise. Our results showed that exercise remodeled the GM composition and elevated SCFAs levels. Also, exercise suppressed systemic, colonic, and neuroinflammation, enhanced the barrier-related protein (Occludin, Claudin-5, and ZO-1) levels, maintained barrier integrity, and alleviated cognitive dysfunction after ischemic stroke. FMT from exercised mice partially reproduced the cognitive and anti-inflammatory benefits. SCFA levels were associated with reduced inflammatory markers and increased expression of barrier-related proteins. The findings suggest that exercise preconditioning is associated with coordinated preservation of gut and BBB integrity and improved cognition after stroke. Moreover, FMT from exercised mice conferred partial protection against PSCI.