Maternal microbiome-derived propionate regulates offspring myelination via histone lactylation

The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signalling, yet its influence on CNS myelinogenesis, a pivotal process for neural circuit maturation, remains poorly understood. Here, using antibiotic-induced maternal dysbiosis models, we identify propionate (PA), a short-chain fatty acid (SCFA) derived from the maternal microbiome, as a key epigenetic modulator of oligodendrocyte precursor cell (OPC) differentiation. Maternal antibiotic-induced gut dysbiosis led to significant hypomyelination in offspring, an effect that could be rescued by postnatal PA supplementation. PA not only enhanced developmental myelination but also promoted remyelination following lysolecithin-induced demyelination by inducing OPC differentiation. Mechanistically, PA induced histone H4 lysine 12 lactylation (H4K12la), thereby activating transcription of cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signalling components (e.g. Gna12) and upregulating Sox family transcription factors essential for oligodendrocyte differentiation. Taken together, our findings delineate a PA-H4K12la-cGMP-PKG pathway that links maternal microbial metabolism to offspring myelination, offering a promising SCFA-mediated epigenetic strategy for the treatment of CNS demyelinating disorders.