Sex differences in experimental stroke outcomes are well documented, such that adult males have a greater infarct volume, increased stroke-induced mortality, and more severe sensory-motor impairment. Based on recent evidence that the gut is an early responder to stroke, the present study tested the hypothesis that sex differences in stroke severity will be accompanied by rapid and greater permeability of the gut-blood barrier and gut dysbiosis in males as compared to females. Male and female Sprague-Dawley rats (5–7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Sensory-motor tests were conducted pre- and 2 days after MCAo. Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Histological analysis of the gut was performed with H&E staining, periodic acid-Schiff for mucus, and immunohistochemistry for the tight junction protein, ZO-1. Fecal samples obtained pre- and post-stroke were analyzed for bacterial taxa and short-chain fatty acids (SCFAs). After stroke, males displayed greater mortality, worse sensory-motor deficit, and higher serum levels of proinflammatory cytokines IL-17A, MCP-1, and IL-5 as compared to females. MCAo-induced gut permeability was rapid and severe in males as indicated by dextran extravasation from the gut to the blood in the hyperacute (< 2 h) and early acute (2 days) phase of stroke. This was accompanied by dysmorphology of the gut villi and dysregulation of the tight junction protein ZO-1 in the acute phase. Fecal 16s sequencing showed no differences in bacterial diversity in the acute phase of stroke. Predictive modeling indicated that markers of gut permeability were associated with acute sensory-motor impairment and infarct volume. These data show that extensive leakiness of the gut barrier is associated with severe post-stroke disability and suggest that reinforcing this barrier may improve stroke outcomes.

中文翻译：

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卒中结果的性别差异与成年斯普拉格-道利大鼠肠道通透性的快速而严重的变化相对应


实验性卒中结果的性别差异已得到充分记录，例如成年男性的梗塞体积更大、卒中引起的死亡率增加以及感觉运动障碍更严重。根据最近的证据表明肠道是中风的早期反应者，本研究检验了这样的假设：与女性相比，中风严重程度的性别差异将伴随着肠道血液屏障的快速和更大的渗透性以及肠道菌群失调。雄性和雌性 Sprague-Dawley 大鼠（5-7 个月大）接受内皮素 (ET)-1 诱导的大脑中动脉闭塞 (MCAo)。在 MCAo 之前和之后 2 天进行感觉运动测试。使用肠道通透性生物标志物评估血清样本中的肠道通透性，并使用大小分级的葡聚糖进行功能测定。通过 H&E 染色、粘液高碘酸希夫染色和紧密连接蛋白 ZO-1 的免疫组织化学对肠道进行组织学分析。对中风前和中风后获得的粪便样本进行细菌分类和短链脂肪酸（SCFA）分析。中风后，与女性相比，男性死亡率更高，感觉运动缺陷更严重，促炎细胞因子 IL-17A、MCP-1 和 IL-5 的血清水平更高。在中风的超急性期 (< 2 h) 和早期急性期 (2 天) 中，右旋糖酐从肠道外渗到血液中，表明 MCAo 诱导的肠道通透性在男性中快速且严重。这伴随着急性期肠道绒毛的形态异常和紧密连接蛋白 ZO-1 的失调。粪便 16s 测序显示中风急性期的细菌多样性没有差异。 预测模型表明，肠道通透性标志物与急性感觉运动损伤和梗塞体积相关。这些数据表明，肠道屏障的广泛渗漏与严重的中风后残疾有关，并表明加强这一屏障可能会改善中风的结果。