Maternal microbiome-derived propionate regulates offspring myelination via histone lactylation

Area of Science:

• Neuroscience
• Microbiology
• Epigenetics

Background:

• The maternal gut microbiome impacts offspring neurodevelopment via metabolite signaling.
• The role of maternal microbiome in central nervous system (CNS) myelinogenesis is unclear.

Purpose of the Study:

• To investigate the role of maternal gut microbiome metabolites in offspring CNS myelinogenesis.
• To identify specific microbial metabolites that modulate oligodendrocyte precursor cell (OPC) differentiation.

Main Methods:

• Antibiotic-induced maternal gut dysbiosis model in mice.
• Assessment of offspring myelination and OPC differentiation.
• Supplementation with propionate (PA) to rescue dysbiosis effects.
• Mechanistic studies involving histone lactylation and gene expression analysis.

Main Results:

• Maternal dysbiosis caused hypomyelination in offspring, which was reversed by PA supplementation.
• PA enhanced developmental myelination and promoted remyelination after demyelination.
• PA induced histone H4K12 lactylation (H4K12la), activating cGMP-PKG signaling and Sox transcription factors crucial for oligodendrocyte differentiation.

Conclusions:

• Propionate (PA) acts as an epigenetic regulator linking maternal gut microbial metabolism to offspring myelination.
• A novel PA-H4K12la-cGMP-PKG pathway is identified, crucial for oligodendrocyte differentiation.
• PA represents a potential SCFA-mediated epigenetic strategy for treating CNS demyelinating diseases.