The Gut–Myelin Axis: Microbial Metabolites in Oligodendrocyte Biology and Remyelination

The gut microbiota–brain axis has emerged as a key regulator of central nervous system (CNS) development and function. Beyond its established roles in immunity and behavior, growing evidence indicates that microbial-derived metabolites influence glial biology, including oligodendrocyte development and myelination. In this review, we synthesize current findings supporting a role for microbial metabolites—particularly short-chain fatty acids (SCFAs), tryptophan-derived indoles, and secondary bile acids—in regulating oligodendrocyte precursor cell (OPC) proliferation, differentiation, and myelin formation. We examine the molecular and cellular mechanisms involved, including epigenetic regulation through histone deacetylase inhibition, G-protein–coupled receptor signaling, nuclear receptor activation, and metabolic support pathways. Experimental and clinical studies indicate that butyrate modulates oligodendrocyte lineage progression via chromatin remodeling, indole derivatives signal through the aryl hydrocarbon receptor (AhR) to attenuate neuroinflammation and promote glial homeostasis, and secondary bile acids act through receptors such as TGR5 and the vitamin D receptor to support pro-remyelinating environments. Additionally, microbial acetate contributes to acetyl-CoA pools necessary for lipid biosynthesis and epigenetic regulation within oligodendrocytes. Notably, dysbiosis and reduced availability of microbial metabolites have been consistently reported in Multiple Sclerosis (MS), a demyelinating disorder characterized by impaired remyelination, suggesting that microbiome-targeted strategies—including dietary interventions and postbiotic supplementation—may complement existing therapies. Collectively, current evidence supports the concept that microbial metabolites function as systemic modulators of CNS myelination, linking dietary and microbial inputs to oligodendrocyte biology and highlighting promising avenues for translational research in demyelinating diseases.