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

Nov 12, 2025Molecular neurobiology

Gut Bacteria Products and Their Role in Immune Activation and Nerve Damage in Multiple Sclerosis

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Abstract

Short-chain fatty acids (SCFAs) are associated with immune regulation and neuroinflammation in multiple sclerosis (MS).

MS is characterized by chronic neuroinflammation and neurodegeneration, with symptoms including motor deficits and cognitive impairment.
Traditional risk factors such as Epstein-Barr virus and vitamin D deficiency only partially explain MS onset.
Depletion of SCFA-producing bacteria is observed in MS patients, suggesting a link between gut microbiota and disease progression.
SCFAs may influence gut immune responses and modulate T cell differentiation during different phases of MS.
In progressive MS, SCFAs support mitochondrial function and reduce oxidative stress, potentially impacting neuroglial dynamics.
The complex effects of SCFAs indicate a need for precision medicine approaches in targeting microbiota-based interventions.

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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.