Microbial modulation of CNS remyelination in multiple sclerosis: the missing link in gut-brain axis research

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) marked by demyelination and neurodegeneration. While much attention has focused on immune dysregulation and neuroinflammation, the failure of effective remyelination is a key driver of disease progression, especially in progressive MS. Recently, the gut microbiome has emerged as a potent modulator of systemic immunity and CNS function, influencing processes such as neuroinflammation and neurogenesis. This review examines current evidence on microbiota-derived metabolites, including short-chain fatty acids (SCFAs), indole derivatives, and bile acids, and their potential roles in pathways associated with oligodendrocyte precursor cell (OPC) biology and remyelination. Evidence from preclinical models, including germ-free systems, fecal microbiota transplantation (FMT), and probiotic interventions, suggests that microbial signals can modulate immune responses and CNS environments that may indirectly affect demyelination and repair processes. However, direct causal effects on OPC differentiation and functional remyelination remain incompletely established. We critically evaluate the strengths and limitations of existing studies, highlighting inconsistencies across experimental models and the context-dependent nature of microbiota-host interactions. Clinical evidence remains limited, with current studies primarily assessing inflammatory or metabolic outcomes rather than direct measures of remyelination. Key translational challenges include uncertainties regarding metabolite bioavailability in the CNS, cell-specific mechanisms of action, and reproducibility of microbiome-targeted interventions.