Microbiota-Derived SCFAs in Multiple Sclerosis: From Immune Priming to Neurodegeneration.

Multiple sclerosis (MS) is a chronic, immune-mediated neuroinflammatory and neurodegenerative disorder characterized by demyelination, axonal injury, and widespread disruption of central nervous system (CNS) integrity. Clinically heterogeneous and often presenting in young adults-especially women-MS manifests with motor deficits, cognitive impairment, depression, fatigue, sexual and sensory dysfunctions, and autonomic disturbances. Despite advances in immunotherapies, including disease-modifying agents and monoclonal antibodies, current treatments inadequately address progressive neurodegeneration or restore neuronal integrity. Traditional risk factors such as Epstein-Barr virus infection, vitamin D deficiency, smoking, and childhood obesity only partially explain disease onset, reflecting the multifactorial and elusive nature of MS pathogenesis. Recent research has turned attention toward the gut-brain axis, particularly the role of intestinal dysbiosis and microbial metabolites in modulating systemic and CNS inflammation. Among these, short-chain fatty acids (SCFAs)-produced through microbial fermentation of dietary fibres-have emerged as pivotal regulators of immune homeostasis, neuroinflammation, and glial function. Furthermore, MS patients consistently exhibit a depletion of SCFA-producing bacteria, implicating these metabolites development and progression of MS. In the prodromal phase, SCFAs influence gut immune priming and tolerance; in relapsing-remitting MS, they modulate T cell differentiation, cytokine profiles, and remyelination processes; and in progressive MS, they support mitochondrial function, reduce oxidative stress, and influence neuroglial dynamics. While SCFAs show promise as diagnostic biomarkers and adjunctive therapeutic targets, their context-dependent, bidirectional effects necessitate a precision-medicine approach. This review synthesizes current insights into the stage-specific roles of SCFAs across the MS disease continuum. The present work not only elucidates the mechanistic underpinnings of SCFA action in MS but also outlines future directions for microbiota-centred interventions tailored to disease stage and individual microbiome profiles.