Gut microbiota and gut-derived metabolites in defining multiple sclerosis phenotypic continuum

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which environmental factors play an important role in shaping disease risk, activity, and progression. Over the past decade, human and experimental studies have consistently shown alterations in the gut microbiome across the phenotypic spectrum of MS and have linked these changes to immune dysregulation, barrier dysfunction, neuroinflammation, and demyelination. Additionally, emerging evidence indicates that microbial function, particularly metabolite production plays a more direct role in shaping immune responses and associated neuropathology. Evidence from both human studies and experimental autoimmune encephalomyelitis models supports a functional role for microbial metabolites in shaping neuroimmune responses. Bacterially derived metabolites such as short-chain fatty acids, bile acids, polyamines, phytoestrogen metabolites, and tryptophan-derived compounds can influence T-cell differentiation, glial activation, epithelial integrity, and neuroimmune communication. Recent longitudinal studies also show associations between metabolite profiles and disability worsening. Because disease-modifying therapies, diet, and microbiome-directed interventions can reshape microbial metabolism, microbial metabolites may represent promising therapeutic targets in the gut-immune-brain axis. In this Review, we integrate current evidence to propose a mechanistic framework in which microbial metabolites act as central regulators of mucosal and systemic immunity that influence different aspects of MS biology. We discuss how this perspective shifts gut microbiome research from descriptive associations to biological mechanisms that more directly link the gut to immune responses and downstream neuropathology. We then evaluate therapeutic strategies that target microbial metabolism and outline key priorities for longitudinal, multi-omics, and interventional studies that are needed to enable microbiome-informed precision therapies in MS.