Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain .2017 Highlights • Fatigue is a debilitating condition of unknown aetiology associated with chronic pain. • Metabolome provides an agnostic tool to reveal mechanisms of complex diseases. • Decreased circulating levels of eicosapentoenoate (EPA) were associated with fatigue coupled with chronic pain. • The set of 15 circulating metabolites provide a diagnostic tool for fatigue associated with chronic pain. Abstract Background Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue. Material and methods Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue. Results While no association between fatigue and metabolites was identified in twins without CWP (n = 711), in participants with CWP (n = 395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (β = − 0.452 ± 0.116; p = 1.2 × 10− 4). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p = 1.5 × 10− 4 and p = 3.1 × 10− 4, respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC = 75%; 95% CI 69–80%). Conclusion The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP.