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Introduction: Stroke is more prevalent in older population, and among this demographic, older women are at a higher risk for stroke, with worse outcomes and poorer recovery. Recent advances have suggested that intestinal bacteria affect stroke outcome and cardiovascular events. Emerging evidence suggests that interactions between gut microbiota and estrogens are critical in maintaining homeostasis in healthy premenopausal individuals. However, the mechanistic link between estrogen deficiency and gut microbiome among acute brain disorders has not been well established.Methods: Fecal samples from adult (cyclic, 5 months old) and middle-aged (acyclic, 12 months old) Sprague-Dawley female rats at pre (0d) and post (5d) middle cerebral artery occlusion (MCAO) were analyzed by Illumina-sequencing of the 16S rRNA gene. Animals were tested for infarct volume and sensory motor performance pre and/or post stroke. Rats were sacrificed at the early (2d) or late (5d) acute phase after MCAO to collect serum and tissue samples for histological and biochemical analyses.Results: Diversity of the gut microbiome was significantly decreased in estrogen-deficient middle-aged females at 0d (pre stroke) compared to estrogen-sufficient adult animals. Middle-aged rats at 5d post stroke had the most profound alterations in their microbiome, as significant separations were observed on PCoA plots of Unifrac distances. Middle-aged rats presented a larger infarct size as well as a significantly worse sensory motor function at 2d and 5d post MCAO as compared to adult female rats. Middle-aged rats had significantly increased gut leakiness at 5d post stroke compared to adult group. Moreover, the gut microbiome community was significantly altered by reproductive age, as evidenced by the increased members of Bacterroidates (S24-7 and Parabacteroides); and decreased members of the genus Akkermansia; and decrease members of the genus Bacillus in middle-aged female rats, suggesting a role for these bacteria in estrogen deficiency and stroke severity.Conclusions: These data provide the first evidence that reproductive age induces microbiome dysbiosis and gut leakiness in middle-aged female rats and underscores the link between microbiota and stroke outcome and severity.