Effects of gut microbiota on the susceptibility of ischemic stroke in mice

Ischemic stroke is a highly prevalent disease with limited therapeutic options, and emerging evidence suggests that the gut microbiota influences stroke pathophysiology. However, whether the gut microbiota affects individual susceptibility to ischemic stroke remains unclear. Here, middle cerebral artery occlusion was performed to stratify mice into ischemic stroke-sensitive (SEN: reaching humane endpoints within day 1) and ischemic stroke-resistant (RES: surviving to day 7) groups based on post-stroke survival. SEN mice exhibited more severe brain injury than RES mice, accompanied by increased systemic inflammation and elevated intestinal permeability. Fecal microbiota from SEN or RES donors was transplanted into antibiotic-treated recipients. Mice receiving SEN microbiota developed significantly worse outcomes compared with those receiving RES microbiota. Multi-omic analyses of cecal contents, including 16S rRNA gene sequencing and liquid chromatography-mass spectrometry/mass spectrometry-based untargeted metabolomics, identified reduced butyrate-producing bacteria and altered glutathione metabolism as potential contributors to stroke susceptibility. Collectively, these findings demonstrate that gut microbiota and microbial metabolites modulate susceptibility to ischemic stroke. IMPORTANCE: The role of the gut microbiota in determining susceptibility to ischemic stroke has remained poorly defined. This study demonstrates that microbiota dysbiosis and metabolite alterations functionally increase vulnerability to stroke injury, highlighting the gut microbiome as a potential target for risk stratification and preventive interventions. Modulating the gut microbiota may therefore represent a novel strategy for reducing stroke susceptibility.