Sex and age dimorphism of the gut-brain axis in ischemic stroke: A systematic review of preliminary studies

Recent studies have shown that stroke risk and outcomes are influenced by the microbiota composition and its strict relationship with the immune system. Age and sex are the main non-modifiable factors that shape microbiome composition. In order to evaluate the effects of these two variables on the microbiome in stroke pathogenesis we performed a systematic review of literature, including 10 studies in the final selection. In the critical analysis of data we focused on three aspects: gut permeability, molecular mediators (both inflammatory molecules and gut metabolites) and functional deficits. Males display higher post-stroke intestinal permeability than females and a youthful microbiome correlates with higher levels of mucin gene expression thus enhancing intestinal barrier function. Gut mast cells-derived histamine shows an age-dependent increase after stroke but it remains unknown whether it also shows sexual dimorphism in the context of stroke. IL-17 is significantly increased in males as compared to females. SCFAs promote recovery in aged mice. We registered a lack of evidence on the impact of hormonal differences on the stroke microbiome. An overall negative effect of aged microbiota on functional tests after stroke is a robust finding among many studies. However, the effects of sex-mediated microbiome variability on functional deficits after stroke remain elusive. The modifiable nature of the microbiome makes it suitable for therapeutic intervention, however we show that a lack of consideration for sex as a biological variable is a major limitation of current stroke clinical and pre-clinical microbiome research studies.