Vitamin D Supplementation Reduces Markers of Oxidative Stress Measured by Untargeted Metabolomics in Healthy Controls but Not in Multiple Sclerosis Patients

Objective: To utilize untargeted metabolomics to investigate the change in metabolic profiles in multiple sclerosis (MS) and healthy controls (HCs) following high-dose vitamin D supplementation. Background: Vitamin D deficiency is linked to increased risk for MS and MS disease activity. Whether the metabolic effects of vitamin D are similar in MS and HCs is not known. Methods: were white women, aged 18-60 years, with screening 25-hydroxyvitamin D (25(OH)D) levels ≤30 ng/ml and were HCs or had MS. Participants received 5000 IU vitamin-D3 daily for 90 days. Blood was collected at baseline and end of study. Metabolomics analysis was performed by liquid/gas chromatography with mass-spectrometry at Metabolon Inc. Serum 25(OH)D levels were measured in a single batch. Metabolomics data were pre-processed and weighted correlation network analysis (WGCNA) was performed to summarize the data as metabolite modules. The module eigen-metabolite values were utilized in a generalized estimating equations to correlate change in metabolite modules to change in 25(OH)D levels, adjusting for clinical traits (case status, BMI, age). Results: 24 MS and 27 HC study completers were evaluated. Demographic characteristics were similar between groups. 612 metabolites were measured; WGCNA analysis identified 10 metabolite modules. The change in eigen-metabolite correlated with the change in serum 25(OH)D for one module, the constituents of which included markers of oxidative stress (gamma-glutamyl amino acids, 5-oxoproline, bilirubin), lipid peroxidation (13-HODE and 9-HODE), and protein oxidation (cysteine-sulfinic acid and methionine-sulfoxide). The change in this module was different between MS and HCs (p=0.016), with the HCs showing a significant decrease with vitamin D supplementation and the MS group showing no change. Conclusions: Untargeted metabolomics demonstrated reductions in oxidative stress markers with vitamin D supplementation in HCs but not in MS patients. Whether this effect is related to differences in downstream vitamin D metabolism, signaling, or ongoing inflammation is unclear. Disclosure: Dr. Bhargava has nothing to disclose. Dr. Fitzgerald has nothing to disclose. Dr. Steele has nothing to disclose. Dr. Cassard has nothing to disclose. Dr. Waubant has received personal compensation for activities with Roche Diagnostics Corporation, Genzyme Corporation, and Novartis. Dr. Waubant has received research support from Roche Diagnostics Corporation, Biogen Idec, and Novartis. Dr. Peter A. Calabresi has received personal compensation for activities with Abbott and Vertex as a consultant. Dr. Calabresi has received research support from Novartis, MedImmune and Biogen. Dr. Mowry has received research support from Teva Pharmaceuticals and Biogen Idec.