Metabolomics in Multiple Sclerosis: Advances, Challenges, and Clinical Perspectives-A Systematic Review

Abstract

Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder marked by inflammation, demyelination, and neuronal loss within the central nervous system. Despite advances in diagnostics, current tools remain insufficiently sensitive and specific. Metabolomics has emerged as a promising approach to explore MS pathophysiology and discover novel biomarkers. This PRISMA-guided systematic review included 29 original studies using validated metabolomic techniques in adult patients with MS. Biological samples analyzed included serum, cerebrospinal fluid, and feces. Consistent metabolic alterations were identified across several pathways. The kynurenine pathway demonstrated a shift toward neurotoxic metabolites, alongside reductions in microbial-derived indoles, indicating inflammation and gut dysbiosis. Energy metabolism was impaired, with changes in glycolysis, tricarboxylic acid (TCA) cycle, and mitochondrial function. Lipid metabolism showed widespread dysregulation involving phospholipids, sphingolipids, endocannabinoids, and polyunsaturated fatty acids, some modulated by treatments such as ocrelizumab and interferon-β. Nitrogen metabolism was also affected, including amino acids, peptides, and nucleotides. Non-classical and xenobiotic metabolites, such as myo-inositol, further reflected host-microbiome-environment interactions. Several studies demonstrated the potential of metabolomics-based machine learning to distinguish MS subtypes. These findings highlight the value of metabolomics for biomarker discovery and support its integration into personalized therapeutic strategies in MS.

Keywords: immunometabolism; metabolomics; multiple sclerosis.

Figure 1

PRISMA flowchart.

Figure 2

Consensus model of metabolic progression in multiple sclerosis. CIS most commonly shows increased glycolytic output (↑ glucose, ↑ lactate) and an early kynurenine pathway shift (↓ KYNA). RRMS additionally features ↓ essential amino acids, ↓ protective lipid mediators, and ↓ microbiota-derived indoles. SPMS is characterized by ↑ ketone bodies, ↑ arachidonic-acid derivatives (HETEs), ↑ spermidine and ADMA, and ↓ nucleotides. PPMS more often exhibits ↓ osmolytes together with microbial metabolites (↓ myo-inositol, ↑ p-cresol sulfate), ↓ specific ceramides, and ↑ steroid hormones/neurosteroids. Gray arrows indicate convergence toward shared processes—neuroinflammation, mitochondrial dysfunction, and neurodegeneration. Color coding: blue, energy metabolism; orange, lipid metabolism; green, nitrogen metabolism; beige, kynurenine pathway; slate, nucleotide metabolism; yellow, microbiota/xenobiotics. Patterns synthesize directionality reported across studies and do not imply causality; evidence for progressive forms remains comparatively limited.