Metabolic Remodeling in Multiple Sclerosis: How Lipid Dysregulation Shapes Brain Lesions
Multiple sclerosis (MS) is a complex inflammatory disorder of the central nervous system characterized by immune-mediated demyelination, gliosis, axonal injury, and progressive neurodegeneration. Although magnetic resonance imaging and histopathology can identify lesion location and inflammatory activity, these approaches provide only an incomplete account of the biochemical processes occurring within diseased tissue. Previous metabolomic investigations have demonstrated systemic metabolic abnormalities in the blood and cerebrospinal fluid of people with MS; however, the molecular composition of the lesions themselves has remained comparatively underexplored. Ladakis and colleagues addressed this gap by examining the metabolome of postmortem white-matter tissue from individuals with secondary progressive MS. Their study is particularly significant because it integrates metabolomic measurements with single-nucleus RNA sequencing from spatially corresponding tissue samples. This multiomic design enables metabolic changes to be interpreted alongside alterations in cellular abundance and gene expression, thereby connecting biochemical disturbances with specific inflammatory, glial, and myelinating cell states. Rather than treating MS lesions as structurally homogeneous areas of tissue damage, the study presents them as metabolically organized microenvironments whose molecular characteristics vary according to lesion stage and anatomical position.
Spatially Resolved Metabolomic and Transcriptomic Profiling
The investigators analysed 25 brain-tissue samples, including 17 specimens obtained from five individuals with secondary progressive MS and eight control white-matter specimens from six neurologically unaffected donors. MS tissue was sampled from several pathological compartments: the edges of chronic active lesions, the edges of chronic inactive lesions, demyelinated lesion cores, and periplaque white matter surrounding established lesions. This sampling strategy was important because lesion edges may contain ongoing inflammatory activity, whereas lesion cores generally represent areas of advanced demyelination, oligodendrocyte depletion, and tissue destruction. Metabolites were quantified using liquid- and gas-chromatography platforms coupled to mass spectrometry, producing an initial dataset of 783 identified compounds. After quality control, missing-value filtering, normalization, imputation, logarithmic transformation, and scaling, the investigators used generalized estimating equations to compare tissue groups while accounting for repeated samples from the same donors, age, and sex. Weighted gene correlation network analysis was then applied to organize correlated metabolites into 16 biologically interpretable modules. Finally, metabolite set enrichment analysis and Multiomics Factor Analysis were used to connect metabolic pathways with cell-type abundance and transcriptomic programs measured in adjacent tissue.
Sphingolipid Accumulation Defines the MS Lesion Metabolome
The most prominent metabolic feature of MS lesions was an increase in sphingolipid-related molecules, particularly sphingosines, sphingomyelins, and ceramides. Compared with control white matter, MS lesions exhibited significantly elevated sphingosines and a strongly increased module containing sphingomyelins and ceramides. These changes were not restricted to visibly demyelinated lesions: periplaque white matter also demonstrated increased sphingomyelin and ceramide levels, suggesting that metabolically abnormal tissue extends beyond conventional lesion boundaries. Spatial analysis further revealed a pathological gradient, with the highest sphingomyelin and ceramide module scores occurring in lesion cores. Sphingolipids are essential structural constituents of cellular membranes and myelin, but they also function as bioactive signalling molecules. Ceramides can promote oxidative stress, mitochondrial dysfunction, inflammatory signalling, autophagy, necroptosis, and apoptosis, whereas sphingosine-1-phosphate commonly supports cell survival and immune-cell trafficking. Notably, sphingosine-1-phosphate was not significantly altered despite the increase in ceramides and sphingosines. This imbalance may indicate that lesion tissue is shifted toward cytotoxic and proinflammatory sphingolipid signalling rather than protective sphingosine-1-phosphate activity. Nevertheless, the observed accumulation may reflect both active lipid metabolism and the release of membrane components during myelin degradation.
Depletion of Protective Lipids and Cellular Energy Resources
In parallel with sphingolipid accumulation, MS lesions displayed substantial reductions in several metabolite classes associated with membrane remodelling, anti-inflammatory signalling, myelin maintenance, and cellular energy production. Lysophospholipids were decreased across all MS-derived tissue categories, including periplaque white matter, chronic active and inactive lesion edges, and lesion cores. Monoacylglycerols were also reduced, while a broader module containing unsaturated fatty acids, endocannabinoids, and lysophospholipids was especially diminished in lesion cores. Polyunsaturated fatty acids and endocannabinoids can modulate immune-cell activation, cytokine production, oxidative stress, glutamate excitotoxicity, and leukocyte migration. Their depletion may therefore weaken endogenous mechanisms that normally restrict neuroinflammation and support tissue repair. The investigators additionally identified lower nucleotide and energy-metabolite levels in MS lesions, with particularly pronounced reductions in lesion cores. These findings are compatible with mitochondrial impairment, altered cellular energetics, increased cell death, or reduced metabolic activity in oligodendrocyte-depleted tissue. Importantly, energy metabolites were also decreased in periplaque white matter, indicating that biochemical dysfunction may precede overt demyelination or contribute to progressive lesion expansion. Collectively, the results suggest that advanced MS pathology involves not only an excess of potentially damaging lipid mediators but also a loss of metabolites associated with metabolic resilience and remyelination.
Metabolic Signatures Reflect the Cellular Composition of Lesions
Integration with single-nucleus RNA-sequencing data demonstrated that the metabolic profile of MS tissue was closely associated with its cellular architecture. Sphingolipids, diacylglycerols, phosphatidylcholines, phosphatidylethanolamines, and other membrane-related lipid metabolites were positively correlated with astrocytic and immune-cell populations, including inflammatory astrocytes, microglial populations, infiltrating immune cells, and immune-like oligodendrocyte progenitor cells. The same pathways were generally negatively correlated with mature oligodendrocytes and premyelinating progenitor populations. This pattern supports a relationship between sphingolipid-rich environments and inflammatory or gliotic tissue states. Conversely, long-chain fatty acids, endocannabinoids, monoacylglycerols, lysophospholipids, and pantothenate/coenzyme A metabolites were negatively associated with inflammatory astrocytes and immune cells but positively associated with oligodendrocytes and progenitor cells capable of contributing to remyelination. These reciprocal associations indicate that lesion metabolism may reflect a balance between two biological states: an inflammatory, demyelinating state dominated by immune and reactive glial cells, and a reparative state associated with oligodendrocyte survival, lipid synthesis, and myelin restoration. However, correlations between metabolite concentrations and cell populations cannot determine whether the metabolites drive cellular changes, arise as products of those cells, or accumulate secondarily following tissue injury.
Multiomic Analysis Reveals a Molecular Gradient of Lesion Severity
Multiomics Factor Analysis provided an independent, unsupervised assessment of the relationship between metabolic and transcriptional alterations. Of the four identified factors, the first factor accounted for approximately 40% of gene-expression variability and 12% of metabolomic variability. Its values followed a striking pathological gradient: they were lowest in control and periplaque white matter, increased at chronic inactive and chronic active lesion edges, and reached their highest levels in lesion cores. Metabolic pathways positively associated with this lesion-related factor included sphingomyelins, phosphatidylethanolamines, and dipeptides. In contrast, negatively weighted pathways included hexosylceramides, endocannabinoids, lysophospholipids, and monoacylglycerols. The corresponding transcriptomic component was enriched for genes involved in neuronal ensheathment, oligodendrocyte differentiation, lipid metabolism, phospholipid biosynthesis, and myelination. These coordinated changes indicate that the loss of myelinating cellular programs is accompanied by a reorganization of tissue lipid composition. The analysis also identified enrichment of vascular and circulatory-development pathways in lesion tissue, a finding that may be consistent with altered vascular density, angiogenesis, or blood–brain barrier remodelling in chronic MS lesions. Overall, the multiomic factor appears to capture a continuum from relatively preserved white matter to metabolically depleted, inflammatory, and severely demyelinated lesion cores.
Therapeutic Implications, Limitations, and Future Directions
The study identifies lipid metabolism as a potentially important therapeutic interface between neuroinflammation, oligodendrocyte biology, and tissue degeneration. Enzymes involved in ceramide synthesis or sphingomyelin breakdown, including ceramide synthases and neutral sphingomyelinase 2, may represent candidates for experimental intervention. Modulating these pathways could theoretically reduce cytotoxic sphingolipid accumulation, protect oligodendrocytes, and attenuate inflammatory astrocyte activation. However, translation will require caution. The study included a small number of donors, all MS cases had secondary progressive disease, and postmortem tissue provides only a static representation of a dynamic pathological process. Tissue homogenization also prevents precise determination of whether metabolites were intracellular, extracellular, myelin-derived, or produced by particular cell populations. Furthermore, the cross-sectional design cannot establish whether lipid abnormalities initiate inflammation, result from demyelination, or participate in a self-reinforcing cycle of tissue injury. Larger studies using spatial metabolomics, lipid imaging, isotope tracing, experimental demyelination models, and longitudinal human biomarkers will therefore be necessary. Despite these limitations, the investigation provides compelling evidence that MS lesions possess distinct and spatially organized metabolic states. By linking lipid disturbances to cellular and transcriptional profiles, it establishes a framework for understanding how metabolism may influence chronic inflammation, remyelination failure, and progressive neurological disability.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Ladakis, D. C., Pedrini, E., Reyes-Mantilla, M. I., Sanjayan, M., Smith, M. D., Fitzgerald, K. C., ... & Bhargava, P. (2024). Metabolomics of multiple sclerosis lesions demonstrates lipid changes linked to alterations in transcriptomics-based cellular profiles. Neurology: Neuroimmunology & Neuroinflammation, 11(3), e200219.
