Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke
Abstract Background Stroke induces gut dysbiosis and reduces microbial production of short-chain carboxylic acids (SCCAs), which negatively correlates with stroke outcomes. Previous studies have demonstrated that SCCA supplementation can improve functional recovery, with one recent study suggesting...
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2025-07-01
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| Series: | BMC Neuroscience |
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| Online Access: | https://doi.org/10.1186/s12868-025-00959-3 |
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| author | Ashley de Witte Juliana Montoya Sanchez Emerson Daniele Jingan Chen Yibang Fan Pranav Khatri Daniela Lozano Casasbuenas Angel Zhang Kathryn G. Todd Maryam Faiz Matthew Churchward |
| author_facet | Ashley de Witte Juliana Montoya Sanchez Emerson Daniele Jingan Chen Yibang Fan Pranav Khatri Daniela Lozano Casasbuenas Angel Zhang Kathryn G. Todd Maryam Faiz Matthew Churchward |
| author_sort | Ashley de Witte |
| collection | DOAJ |
| description | Abstract Background Stroke induces gut dysbiosis and reduces microbial production of short-chain carboxylic acids (SCCAs), which negatively correlates with stroke outcomes. Previous studies have demonstrated that SCCA supplementation can improve functional recovery, with one recent study suggesting this occurs via modulation of microglial responses. However, the effects of individual SCCAs on microglial responses remain unclear, particularly across sexes and following a more clinically relevant, post-stroke treatment protocol. To address this gap, we investigated the effect of post-stroke supplementation with butyrate on stroke outcomes and microglial responses in both male and female mice over time. Results Post-stroke butyrate treatment produced sex-specific microglial responses. In females, butyrate increased microglial ramification at chronic timepoints in vivo and enhanced IL6 release following IFNγ stimulation in vitro. These microglial changes were not observed in males. Despite the distinct microglial responses, butyrate treatment did not correlate with improved stroke outcomes in either sex, as measured by lesion volume and functional recovery. Conclusions Our findings reveal previously unknown sex differences in microglial responses to butyrate following stroke. Despite these microglial changes in females, butyrate treatment did not improve functional outcomes in either sex, suggesting that sex-specific optimization of dosing and delivery may be needed for therapeutic efficacy. |
| format | Article |
| id | doaj-art-58d988ba10244d069bf176a0e2f2fb12 |
| institution | Kabale University |
| issn | 1471-2202 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj-art-58d988ba10244d069bf176a0e2f2fb122025-08-20T03:42:26ZengBMCBMC Neuroscience1471-22022025-07-0126111310.1186/s12868-025-00959-3Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor strokeAshley de Witte0Juliana Montoya Sanchez1Emerson Daniele2Jingan Chen3Yibang Fan4Pranav Khatri5Daniela Lozano Casasbuenas6Angel Zhang7Kathryn G. Todd8Maryam Faiz9Matthew Churchward10Division of Anatomy, Department of Surgery, University of TorontoNeurochemical Research Unit, Department of Psychiatry, University of AlbertaInstitute of Medical Sciences, University of TorontoDivision of Anatomy, Department of Surgery, University of TorontoDivision of Anatomy, Department of Surgery, University of TorontoDivision of Anatomy, Department of Surgery, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University of TorontoDivision of Anatomy, Department of Surgery, University of TorontoNeurochemical Research Unit, Department of Psychiatry, University of AlbertaDivision of Anatomy, Department of Surgery, University of TorontoNeurochemical Research Unit, Department of Psychiatry, University of AlbertaAbstract Background Stroke induces gut dysbiosis and reduces microbial production of short-chain carboxylic acids (SCCAs), which negatively correlates with stroke outcomes. Previous studies have demonstrated that SCCA supplementation can improve functional recovery, with one recent study suggesting this occurs via modulation of microglial responses. However, the effects of individual SCCAs on microglial responses remain unclear, particularly across sexes and following a more clinically relevant, post-stroke treatment protocol. To address this gap, we investigated the effect of post-stroke supplementation with butyrate on stroke outcomes and microglial responses in both male and female mice over time. Results Post-stroke butyrate treatment produced sex-specific microglial responses. In females, butyrate increased microglial ramification at chronic timepoints in vivo and enhanced IL6 release following IFNγ stimulation in vitro. These microglial changes were not observed in males. Despite the distinct microglial responses, butyrate treatment did not correlate with improved stroke outcomes in either sex, as measured by lesion volume and functional recovery. Conclusions Our findings reveal previously unknown sex differences in microglial responses to butyrate following stroke. Despite these microglial changes in females, butyrate treatment did not improve functional outcomes in either sex, suggesting that sex-specific optimization of dosing and delivery may be needed for therapeutic efficacy.https://doi.org/10.1186/s12868-025-00959-3ButyrateShort-chain carboxylic acids (SCCAs)Sex differencesIschemic strokeMicrogliaGut-brain axis |
| spellingShingle | Ashley de Witte Juliana Montoya Sanchez Emerson Daniele Jingan Chen Yibang Fan Pranav Khatri Daniela Lozano Casasbuenas Angel Zhang Kathryn G. Todd Maryam Faiz Matthew Churchward Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke BMC Neuroscience Butyrate Short-chain carboxylic acids (SCCAs) Sex differences Ischemic stroke Microglia Gut-brain axis |
| title | Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke |
| title_full | Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke |
| title_fullStr | Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke |
| title_full_unstemmed | Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke |
| title_short | Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke |
| title_sort | post stroke butyrate treatment shows sex dependent microglial responses but does not improve outcomes in a mouse model of endothelin 1 sensory motor stroke |
| topic | Butyrate Short-chain carboxylic acids (SCCAs) Sex differences Ischemic stroke Microglia Gut-brain axis |
| url | https://doi.org/10.1186/s12868-025-00959-3 |
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