Decoding MS Through Metabolites: What Your Blood Reveals About Disease Risk
Multiple sclerosis (MS) has long puzzled scientists. What triggers the immune system to attack the brain and spinal cord? Beyond genetics and environment, researchers have increasingly turned their attention to the metabolome—the constellation of small molecules circulating in our blood. A remarkable new study published in the Journal of Neuroimmunology offers the most comprehensive look yet at whether specific metabolites may cause MS, not just correlate with it. Using advanced Mendelian randomization, the authors sifted through 571 metabolites to identify which ones play a causal role in disease risk.
Mendelian Randomization: Nature’s Randomized Trial
One of the challenges of metabolomics research is separating cause from consequence. Do metabolite changes trigger MS, or does MS change the metabolome? The study harnesses a powerful statistical tool—Mendelian randomization (MR)—which uses naturally occurring genetic variations as proxies for metabolite levels. Because these genetic variants are randomly assigned at conception, they allow researchers to infer whether high or low metabolite levels directly increase MS risk. This approach bypasses the biases of traditional observational studies, such as lifestyle confounding or reverse causation.
A Massive Analysis Across Three Metabolomics Datasets
To ensure robustness, the team drew genetic data from three major metabolomics GWAS, representing over 140,000 participants. They then cross-referenced these data with one of the largest MS genetic studies available—14,802 MS cases and 26,703 controls. After strict quality filtering, 571 metabolites were tested for their causal influence on MS risk. The result? Twenty-nine metabolites emerged as likely causal, spanning amino acids, lipids, lipoproteins, ketone bodies, and nucleotides. This is one of the most exhaustive metabolome-wide MR analyses ever performed for MS.
Amino Acids Take Center Stage—Especially Serine and Lysine
Among the striking findings were several amino acids. Genetically higher levels of serine, lysine, and O-sulfo-L-tyrosine were all linked to an increased risk of MS. Serine is particularly fascinating: although its measured blood levels vary across MS subtypes, this study shows that individuals genetically predisposed to higher serine levels face a significantly higher MS risk (OR = 1.56). Serine also fuels lipid synthesis in myelin-forming cells—potentially linking it to the demyelination hallmark of MS. Meanwhile, gamma-glutamyl amino acids revealed a split personality: gamma-glutamylleucine was protective, while gamma-glutamylphenylalanine increased risk.
Lipids and Lipoproteins: A Tale of Two Directions
Not all fats are equal—especially in the realm of MS risk. The study uncovered a nuanced pattern:
Large VLDL particles (very-low-density lipoproteins) were associated with lower MS risk when they carried more cholesterol, triglycerides, or phospholipids.
In contrast, very large HDL particles (high-density lipoproteins) showed the opposite effect—higher lipid content increased MS risk (OR up to 1.20).
This challenges the common belief that HDL is always “good” and VLDL always “bad.” In the context of MS biology, lipid transport and immune signaling appear far more complex than traditional cardiometabolic models suggest.
Ketone Bodies and Energy Metabolism Join the Story
The study also flagged two key ketone bodies—acetoacetate and acetone—as potentially increasing MS risk. Both showed strong and consistent MR associations. This is intriguing because MS patients often show elevated ketone levels, and ketogenic diets have gained popularity as experimental therapies. Whether ketone bodies directly promote MS or simply reflect metabolic compensation remains an open question—but this study provides a compelling push to explore the metabolic underpinnings of neuroinflammation more deeply.
What This Means for the Future of MS Research
This metabolome-wide MR study marks a milestone: it identifies serine, lysine, key lipids, ketone bodies, and uridine as promising causal candidates for MS risk. These findings could guide the development of biomarkers for early detection, new therapeutic targets, or even metabolite-modifying interventions. While more work is needed—especially across diverse populations and MS subtypes—the study provides a roadmap for how genetic and metabolomic data can reshape our understanding of autoimmune diseases. In the ongoing quest to unravel MS, the metabolome may be one of our most powerful allies yet
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:
Ge, A., Sun, Y., Kiker, T., Zhou, Y., & Ye, K. (2023). A metabolome-wide Mendelian randomization study prioritizes potential causal circulating metabolites for multiple sclerosis. Journal of neuroimmunology, 379, 578105.
