The Gut Microbiome in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS whose risk and course are shaped by both genetic and environmental factors, among which the intestinal microbiota has emerged as a key, potentially modifiable contributor. People with MS frequently display altered gut microbiota, characterized by depletion of fiber-fermenting, short-chain fatty acid (SCFA)-producing commensals, and expansion of taxa associated with mucus degradation and proinflammatory metabolism. These compositional shifts are paralleled by broad changes in blood and CSF metabolites, including reduced SCFAs, tryptophan-derived aryl hydrocarbon receptor ligands, and secondary bile acids. In addition, several reports highlight the accumulation of aromatic amino acid-derived phenolic and indolic compounds and specific lipid mediators linked to neuroinflammation and neurodegeneration. In this up-to-date review, we synthesize evidence from experimental models and human studies showing how microbial metabolites can influence MS pathogenesis through converging mechanisms: modulation of gut and blood-brain barrier integrity; shaping of T-cell and B-cell responses; direct effects on microglia, astrocytes, and oligodendrocyte lineage cells after crossing into the CNS; and modulation of neural circuits, particularly those involving the vagus nerve. Finally, we highlight current gaps, including the need for longitudinal, harmonized multiomic cohorts, and mechanistic studies integrating microbiome, metabolome, and host readouts across gut, blood, and CNS. Overall, available data support a model in which coordinated disruption of the gut microbiota-metabolite axis, rather than any single pathogen, contributes to MS, opening avenues for microbiota-based and metabolite-based biomarkers and therapies aimed at restoring immune and neuroglial homeostasis.