Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats
Abstract Background 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 prese...
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Biology of Sex Differences |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13293-020-00352-1 |
| _version_ | 1818427764154302464 |
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| author | Yumna El-Hakim Kathiresh Kumar Mani Amir Eldouh Sivani Pandey Maria T. Grimaldo Alan Dabney Rachel Pilla Farida Sohrabji |
| author_facet | Yumna El-Hakim Kathiresh Kumar Mani Amir Eldouh Sivani Pandey Maria T. Grimaldo Alan Dabney Rachel Pilla Farida Sohrabji |
| author_sort | Yumna El-Hakim |
| collection | DOAJ |
| description | Abstract Background 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. Method 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). Results 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. Conclusions 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. |
| first_indexed | 2024-12-14T14:50:54Z |
| format | Article |
| id | doaj.art-ee70658ce9004e0684e7e388be432306 |
| institution | Directory Open Access Journal |
| issn | 2042-6410 |
| language | English |
| last_indexed | 2024-12-14T14:50:54Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj.art-ee70658ce9004e0684e7e388be4323062022-12-21T22:57:08ZengBMCBiology of Sex Differences2042-64102021-01-0112111610.1186/s13293-020-00352-1Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley ratsYumna El-Hakim0Kathiresh Kumar Mani1Amir Eldouh2Sivani Pandey3Maria T. Grimaldo4Alan Dabney5Rachel Pilla6Farida Sohrabji7Women’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthWomen’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthWomen’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthWomen’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthWomen’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthDepartment of Statistics, College of ScienceDepartment of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M UniversityWomen’s Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-HealthAbstract Background 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. Method 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). Results 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. Conclusions 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.https://doi.org/10.1186/s13293-020-00352-1IschemiaSex differenceInflammationGut permeabilityGut dysbiosisDextrans |
| spellingShingle | Yumna El-Hakim Kathiresh Kumar Mani Amir Eldouh Sivani Pandey Maria T. Grimaldo Alan Dabney Rachel Pilla Farida Sohrabji Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats Biology of Sex Differences Ischemia Sex difference Inflammation Gut permeability Gut dysbiosis Dextrans |
| title | Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats |
| title_full | Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats |
| title_fullStr | Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats |
| title_full_unstemmed | Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats |
| title_short | Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats |
| title_sort | sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult sprague dawley rats |
| topic | Ischemia Sex difference Inflammation Gut permeability Gut dysbiosis Dextrans |
| url | https://doi.org/10.1186/s13293-020-00352-1 |
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