Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation
Pavan Bhargava, Kathryn C. Fitzgerald, Peter A. Calabresi, Ellen M. Mowry
Pavan Bhargava, Kathryn C. Fitzgerald, Peter A. Calabresi, Ellen M. Mowry
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Clinical Research and Public Health Immunology Neuroscience

Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Abstract

BACKGROUND. Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls. METHODS. We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation. RESULTS. Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03). CONCLUSIONS. Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities. TRIAL REGISTRATION. ClinicalTrials.gov NCT01667796. FUNDING. This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.

Authors

Pavan Bhargava, Kathryn C. Fitzgerald, Peter A. Calabresi, Ellen M. Mowry

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Figure 4

Vitamin D supplementation cohort — results of pathway analyses using weighted correlation network analysis.

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Vitamin D supplementation cohort — results of pathway analyses using wei...
Difference in average green metabolite module (A) and red metabolite module (B) changes occurring between multiple sclerosis (MS) cases and healthy controls (HCs). P values are derived from tests of 3-way cross-product between vitamin D status, time, and disease status in generalized estimating equations (GEE) models. (C) Correlations between metabolites belonging to the green and red modules. Each pie represents one metabolite within each of these modules, where darker or brighter green or red hues denote how strongly metabolites changed over time between MS patients and HCs following vitamin D supplementation. The length of each pie is proportional to the number of correlations a given metabolite has with other metabolites in the green or red modules that exceed 0.45. A connecting line is drawn between the metabolite pies if the metabolite-metabolite correlation is at least 0.45. For example, weighted correlation network analysis (WGCNA) classifies the metabolite γ-glutamyl histidine into the green module, and its correlation with γ-glutamyl valine (classified by WGCNA into the green module) is ≥0.45. As a result, there is a line connecting the γ-glutamyl valine and γ-glutamyl histidine pies. In contrast to the modules derived in the cross-sectional cohort (B), we observe no intermodular correlation between green and red modules (Pearson’s r = 0.03; P = 0.71). The contents of these modules are listed in Table 4 and Supplemental Table 2. (D) Relation between metabolite module-membership scores and difference in change in means between MS patients and HCs for the individual metabolite models. The hue of green or red color denotes the degree of significance for a test of differences in the change between MS patients and HCs occurring after vitamin D supplementation for a given metabolite. The darker the red or green hue, the more strongly the metabolite changes differently between MS patients and HCs following vitamin D supplementation. Metabolite module-membership scores are derived as the correlation between the overall metabolite module eigen-metabolite score and that of the individual metabolite.