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.