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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Vivek Kumar Sharma

摘要

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.