Microbially-derived short-chain fatty acids impact astrocyte gene expression in a sex-specific manner

Recent investigations in neuroscience implicate the role of microbial-derived metabolites, such as short-chain fatty acids (SCFAs) in brain health and disease. The SCFAs acetate, propionate and butyrate have pleiotropic effects within the nervous system. They are crucial for the maturation of the brain's innate immune cells, the microglia, and modulate other glial cells through the aryl-hydrocarbon receptor. Investigations in preclinical and clinical models find that SCFAs exert neuroprotective and antidepressant affects, while also modulating the stress response and satiety. However, many investigations thus far have not assessed the impact of sex on SCFA activity. Our novel investigation tested the impact of physiologically relevant doses of SCFAs on male and female primary cortical astrocytes. We find that butyrate (0-25 ​μM) correlates with increased Bdnf and Pgc1-α expression, implicating histone-deacetylase inhibitor pathways. Intriguingly, this effect is only seen in females. We also find that acetate (0-1500 ​μM) correlates with increased Ahr and Gfap expression in males only, suggesting immune modulatory pathways. In males, propionate (0-35 ​μM) correlates with increased Il-22 expression, further suggesting immunomodulatory actions. These findings show a novel sex-dependent impact of acetate and butyrate, but not propionate on astrocyte gene expression.