# Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke

## TL;DR

Post-stroke butyrate treatment affects microglial responses differently in male and female mice but does not improve stroke outcomes.

## Contribution

The study reveals sex-specific microglial responses to post-stroke butyrate treatment and shows no improvement in functional outcomes.

## Key findings

- Butyrate treatment increased microglial ramification and IL6 release in females but not in males.
- Despite sex-specific microglial changes, butyrate did not improve stroke outcomes in either sex.
- The results suggest the need for sex-specific optimization of SCCA-based therapies.

## Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12868-025-00959-3.