Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-Induced Gut Permeability
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abstract
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 gut dysbiosis and greater permeability of the gut blood barrier in males as compared to females. Male and female Sprague Dawley rats (5-7 months of age) were subject to endothelin-1-induced middle cerebral artery occlusion (MCAo). Fecal samples, blood draws and sensory motor tests were collected/conducted pre and 2d after MCAo. Fecal samples were subject to 16s sequencing. Serum samples were subject to gas chromatography for short chain fatty acid (SCFA) analysis. Gut permeability was assessed by histology, biochemical markers in serum and functional assays using oral dextran gavage. We confirmed stroke-induced sex differences, including increased mortality and more severe sensory motor deficit in males as compared to age-matched female rats. Fecal 16s sequencing showed greater bacterial diversity in females at baseline (pre stroke) while 2 days after stroke, these measures were similar between the sexes. Fecal levels of SCFAs, which are usually beneficial, were higher in males. In contrast, MCAo-induced gut permeability was much worse in males as compared to females. Male rats had a decreased villus length to crypt length ratio, higher levels of biochemical gut permeability markers in serum and higher levels of fluorescent-labeled dextrans following oral gavage in serum. Additionally, males had higher serum levels of proinflammatory cytokines IL-17A, MCP-1, IL-5 and EGF compared to females after stroke. Collectively, these results indicate that the worse stroke outcomes seen in males is associated with increased gut permeability in this group. These data suggest that therapeutics that target the gut epithelium in order to reinforce the gut-blood barrier post stroke may be an effective intervention especially in populations such as the elderly or those with co-morbid conditions who have already been shown to have more permeable barriers.
