Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain

Abstract

BackgroundFatigue 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 methodsUntargeted 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.ResultsWhile 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%).ConclusionThe 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.

Multi-OMICS analyses of frailty and chronic widespread musculoskeletal pain suggest involvement of shared neurological pathways

“…Our previous studies suggested involvement of neurological pathways in aetiology of CWP, 14 and showed that its appearance significantly correlates with neuropathic pain features, 20 and with fatigue and depression. 3 , 9 This study further suggests that steroid pathways are involved in the mechanism of interaction between frailty and pain.…”

Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia

“…4B). We could not discriminate between these two metabolites as they are structurally similar and have the same molecular mass and fragmentation pattern in LC-MS. We also analysed the metabolites described in the literature, such as creatinine [31,55], platelet activating factor [11] and acetylcarnitine [25]. To infer alterations in the biological processes and metabolic and functional pathways associated with the differentially expressed metabolites, we used MetScape [44] and Ingenuity Pathway Analysis® (QIAGEN) (IPA).…”

Multi-omics Examination of Q Fever Fatigue Syndrome Identifies Similarities with Chronic Fatigue Syndrome

“…Investigations of the metabolome (16)(17)(18)(19)(20) and (gut) microbiome (21)(22)(23)(24)(25) in CFS, both aspects that are inadvertently linked with in ammation (16,26), showed interesting, albeit inconsistent, results (23,25). Up until this moment, no such studies were conducted in QFS.…”

“…Comparing CFS patients to HC, studies on metabolomic pro les consistently found differences between these groups (17)(18)(19)(20). Armstrong et al found that CFS patients show lower levels of glutamine and ornithine compared to HC (20).…”