Modulation of Murine Hippocampal Synaptic Plasticity by Microbial Metabolites: Sex-Specific Effects of the...

The microbiota-gut-brain-axis is a bidirectional communication system between the trillions of microbes in the gastrointestinal tract and the brain. This axis influences brain processes like learning and memory, but the underlying mechanisms aren't fully understood. Microbial metabolites, particularly short-chain fatty acids (SCFAs) from dietary fibre fermentation, are considered key mediators. We investigated the effects of the three most abundant SCFAs, acetate, butyrate, and propionate, on ex vivo hippocampal slice electrophysiology to explore potential sex-specific mechanisms. We used physiologically relevant concentrations to ensure translational relevance. Our findings show that a 40-min exposure to 3 μM butyrate enhanced long-term potentiation (LTP) in both male and female mice. Butyrate's effects were mediated by the free fatty acid receptor 3 (FFAR3), as its inhibition with β-Hydroxybutyrate (BHB) abolished the enhanced potentiation in slices from female mice, but not males. BHB alone had no effect on LTP in either sex. To understand this dimorphism, we examined messenger ribonucleic acid (mRNA) expression of FFARs and SCFA transporters in cornu ammonis 1 (CA1) hippocampal tissue but found no explanatory differences. Acetate and propionate had no significant effect on LTP, basic synaptic efficacy, or short-term plasticity. In conclusion, our study provides novel insights into the sex-specific modulation of hippocampal synaptic plasticity by butyrate. Our data suggest that FFAR3 activation is crucial for these effects in females, highlighting the gut microbiota's potential to shape hippocampal function. Further studies are warranted to investigate the behavioural consequences of enhanced hippocampal butyrate and to fully parse the mechanisms behind the sex differences we observed.