Exercise protects against PM2.5 exacerbated cerebral ischemia/reperfusion injury via the gut–brain axis in mice

Fine particulate matter (PM 2.5 ) is a harmful environmental pollutant that affects ischemic stroke. Exercise has been shown to protect against post-stroke cognitive impairment (PSCI) partly through the gut-brain axis. However, the gut–brain axis mechanisms underlying PM 2.5 -induced PSCI, as well as the modulatory role of exercise, remain poorly understood. In this study, C57BL/6 J mice underwent different exercise regimens prior to PM 2.5 exposure (5.45 mg/kg body weight). Results indicated that PM 2.5 exposure caused disruption of the intestinal epithelial barrier and triggered inflammatory responses. This was accompanied by reduced levels of tight junction proteins (ZO-1, Occludin, and Claudin-5) and increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, the inflammatory response further impaired blood-brain barrier (BBB) integrity, exacerbating cerebral ischemia/reperfusion (I/R) injury and impairing cognitive function. 16S rDNA sequencing of gut microbiota revealed that PM 2.5 disrupted intestinal microbial balance, reducing beneficial genera such as Lactobacillus and Streptococcus , while increasing potentially harmful taxa, including Desulfobacterota, Verrucomicrobia , and Hydrogenophaga . Importantly, exercise markedly attenuated PM 2.5 -induced PSCI via the gut-brain axis, with the strongest protective effect observed after 6 weeks of exercise. These findings provide a mechanistic basis for understanding how exercise attenuates PM 2.5 -induced PSCI. • PM 2.5 aggravates cerebral ischemia/reperfusion injury through the gut-brain axis and affects cognitive function. • Exercise can reduce PM 2.5 -induce d stroke damage and improve cognitive function by regulating the balance of the gut-brain axis. • A 6-week exercise cycle has a more obvious protective effect.