Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability
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AbstractBackground: Sex differences in experimental stroke are well documented, such that adult males show worse outcomes compared to adult females, including greater infarct volume, increased stroke-induced mortality and more severe sensory-motor impairment. Based on recent evidence that gut dysbiosis may be an early response to stroke, the present study tested the hypothesis that in the acute phase, stroke will result in greater permeability of the gut blood barrier and gut dysbiosis in males as compared to females. Method: Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were conducted pre and 2d after MCAo. Fecal samples were analyzed for 16s sequencing and short chain fatty acids (SCFAs). Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Results: We confirmed stroke-induced sex differences, including greater mortality and sensory motor deficit in males as compared to age-matched female rats. Remarkably, fecal 16s sequencing showed greater bacterial diversity in females at baseline (prior to stroke) while 2 days after stroke, these measures were similar between the sexes. In contrast, fecal levels of short chain fatty acids (SCFAs) which are usually beneficial, were higher in males. MCAo-induced gut permeability was much worse in males as compared to females, as indicated by histological analysis, biochemical markers in serum, and serum measurement of fluorescent-labeled dextrans following oral gavage. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Predictive modeling indicated that markers of gut permeability were associated with stroke-induced sensory-motor impairment. Conclusions: Poor stroke outcomes in adult males is mirrored by increased gut permeability in this group. Additionally, these data suggest that constitutive sex differences in the diversity and richness of gut microbial communities may predispose better functional outcomes after stroke in females, and support the idea that preventative modification of the gut microbiome may reduce the risk for stroke in vulnerable populations such as the elderly or those with co-morbid conditions.
