Maternal Microbiome-Derived Propionic Acid: A Key Regulator of Offspring Myelinogenesis Through Histone Lactylation-Mediated cGMP-PKG Activation

The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signaling, yet its influence on central nervous system (CNS) myelinogenesis, a pivotal process for neural circuit maturation, remains poorly understood. Here, using antibiotic-induced maternal dysbiosis models, we identify propionic acid (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 maturation. Mechanistically, PA induced histone H4K12 lactylation (H4K12la), thereby activating transcription of cGMP-PKG signaling components (e.g., Gna12) and upregulating Sox family transcription factors essential for oligodendrocyte differentiation. These findings establish a propionate-H4K12la-cGMP-PKG axis that links maternal microbial metabolism to offspring myelination, revealing SCFA-driven epigenetic regulation as a promising therapeutic avenue for CNS disorders.