Integrative Multi-Omics in Multiple Sclerosis: Unifying Genomic, and Metabolic Signatures of Disease Pathology

While the nuclear genome has long been the primary focus of Multiple Sclerosis (MS) research, recent investigations suggest that the "missing heritability" of the disease—the portion of genetic risk not explained by standard genome-wide association studies—may lie in the complex interaction between nuclear and mitochondrial genomes. A study of the Russian population identified specific biallelic combinations that appear to confer a protective effect against MS, involving interactions between mitochondrial DNA variants (such as m.4580 and m.13708) and nuclear immune-related genes like CXCR5, TNFRSF1A, and CD86. Importantly, these interactions were found to be additive rather than epistatic, meaning the protective effects of these genetic components accumulate without mutually amplifying or suppressing one another. This highlights that an individual's susceptibility to MS is likely determined not just by independent nuclear risk factors, but by a specific chimerical context where mitochondrial and nuclear variants co-exist.

Epigenetics: The Environmental Interface The bridge between this genetic architecture and environmental triggers—such as diet, smoking, and vitamin D deficiency—is built upon epigenetic mechanisms, which regulate gene expression without altering the DNA sequence itself. Research indicates that environmental stimuli drive pathogenesis through DNA methylation, post-translational modification of histones, and non-coding RNAs. For instance, histone acetylation is critical for oligodendrocyte differentiation and myelination; however, aberrant deacetylation can inhibit myelin repair, a failure characteristic of MS lesions. Furthermore, specific microRNAs (miRNAs) like miR-155 and miR-326 act as "NeurimmiRs," modulating the cross-talk between the immune system and the brain, and their upregulation is associated with active lesions and disease severity. These epigenetic marks are cell-type specific, meaning the same environmental signal can trigger inflammation in immune cells while simultaneously impairing repair mechanisms in oligodendrocytes.

Transcriptional Hubs and Pathway Prioritization Moving from gene regulation to gene expression, advanced transcriptomic analyses using "vote-counting" strategies have prioritized genes that are consistently deregulated across multiple independent studies, filtering out noise to find true pathological signals. This rigorous approach identified 528 highly significant genes in MS white matter, revealing specific pathway dysfunctions such as folate metabolism in normal-appearing white matter (NAWM) and complement cascade activation in chronic active lesions. Network analysis of these genes pinpointed six major signaling hubs, including PTPRC (CD45), HLA-B, MYC, and MMP2, which likely drive the molecular mechanisms of tissue damage. Notably, the genes CASP1 and VIM were consistently upregulated across four independent studies, suggesting that inflammasome activation (mediated by CASP1) and astrocytic scarring (mediated by VIM) are central, sustained features of MS pathology.

The Critical Role of Liver X Receptors in Lipid Metabolism A crucial, yet often overlooked, aspect of MS pathogenesis involves disrupted lipid metabolism, particularly through the function of Liver X Receptors (LXRs). LXRs are nuclear transcription factors that integrate lipid metabolism with immune regulation; they are activated by oxysterols (oxidized cholesterol derivatives), the levels of which are altered in MS patients due to neurodegeneration and oxidative stress. In the central nervous system, LXR activation is vital for stimulating oligodendrocyte maturation and remyelination by promoting cholesterol efflux via transporters like ABCA1. Conversely, dysregulated LXR signaling in T-cells can drive inflammation, while its activation has been shown to inhibit the differentiation of pro-inflammatory Th17 cells. This duality positions LXRs as a promising therapeutic target, where modulation could simultaneously dampen autoimmunity and promote the repair of damaged myelin sheaths.

Metabolic Shifts: From Energy Crisis to Neurotoxicity Metabolomics profiling further elucidates the biochemical consequences of these upstream genetic and transcriptional changes, revealing profound shifts in energy production and tryptophan catabolism. A consistent finding across multiple cohorts is the dysregulation of the kynurenine pathway, characterized by a reduction in neuroprotective metabolites like kynurenic acid and an increase in neurotoxic compounds like quinolinic acid. Simultaneously, MS patients exhibit signs of an energy crisis; early disease stages are marked by upregulated glycolysis (elevated glucose and lactate), while progressive forms show a shift toward ketone body utilization, correlated with increased disability. These metabolic alterations are not merely byproducts of the disease but are actively involved in pathophysiology, with mitochondrial dysfunction leading to the accumulation of metabolites that may exacerbate neurodegeneration.

The Lipidomic and Microbial Nexus The metabolic disturbance in MS extends deeply into lipidomics, linking host metabolism with the gut microbiome. Patients exhibit widespread alterations in lipids, including reductions in short-chain fatty acids (SCFAs) like propionate, which are crucial for regulating T-regulatory cells. Lipidomic analysis reveals a shift toward pro-inflammatory arachidonic acid derivatives in progressive MS, correlating with brain atrophy, while protective polyunsaturated fatty acid (PUFA) derivatives are associated with preserved white matter integrity. Furthermore, the disease is characterized by a "microbial bottleneck," evidenced by reduced levels of gut-derived metabolites like indolelactate and myo-inositol. These findings suggest that the disruption of the gut-brain axis contributes to a systemic pro-inflammatory state, where the loss of beneficial microbial metabolites impairs the body's ability to regulate immune responses and maintain neuroprotection.

Toward Integrative Biomarkers and Therapeutics The convergence of these multi-omics findings—from mitochondrial-nuclear gene combinations to downstream metabolic readouts—points toward a future of personalized medicine in MS. The identification of specific molecular hubs like CCL2, which has shown both beneficial and detrimental effects in animal models depending on the context, underscores the need for precise therapeutic targeting. Moreover, metabolites such as serum neurofilament light chain (sNfL) and specific amino acid profiles are emerging as robust biomarkers for disease activity and progression, potentially outperforming traditional markers like oligoclonal bands in some contexts. By integrating these diverse biological layers, researchers are constructing a cohesive model of MS that transcends simple autoimmunity, viewing the disease instead as a complex failure of metabolic, genetic, and epigenetic homeostasis.

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:
Abbadessa, G., Nagano, A., Hametner, S., Howell, O., Owen, D., Papadaki, A., Srivastava, P., Bonavita, S., Magliozzi, R., Reynolds, R., Rizig, M., & Nicholas, R. (2025). Mapping molecular pathways of multiple sclerosis: A gene prioritization and network analysis of white matter pathology transcriptomics. Annals of Neurology, 1–13. Huynh, J. L., & Casaccia, P. (2013). Epigenetic mechanisms in multiple sclerosis: Implications for pathogenesis and treatment. The Lancet Neurology, 12(2), 195–206. Kozin, M. S., Kiselev, I. S., Boyko, A. N., Kulakova, O. G., & Favorova, O. O. (2020). The combined effect of nuclear and mitochondrial genomes on the risk of developing multiple sclerosis. Neurology, Neuropsychiatry, Psychosomatics, 12(Suppl. 1), 15–19. Pineda-Torra, I., Siddique, S., Waddington, K. E., Farrell, R., & Jury, E. C. (2021). Disrupted lipid metabolism in multiple sclerosis: A role for liver X receptors? Frontiers in Endocrinology, 12, 639757. Smusz, J., Mojsak, P., Matys, P., Mirończuk, A., Tarasiuk, J., Grubczak, K., Starosz, A., Kochanowicz, J., Kułakowska, A., & Kapica-Topczewska, K. (2025). Metabolomics in multiple sclerosis: Advances, challenges, and clinical perspectives—A systematic review. International Journal of Molecular Sciences, 26(18), 9207.