Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics

Dorottya Nagy-Szakal,Jose G Montoya,Mady Hornig,Joy E Ukaigwe,Bohyun Lee,Anthony L Komaroff,Brent L Williams,W Ian Lipkin,Dinesh K Barupal,Bruce Levin,Daniel L Peterson,Nancy G Klimas,Ellie J R Kahn,Susan Levine,Xiaoyu Che,Lucinda Bateman,Oliver Fiehn

doi:10.1038/s41598-018-28477-9

Abstract

The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.

Highlights

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder of more than six months duration comprising unexplained fatigue, post-exertional malaise, unrefreshing sleep and either cognitive dysfunction or orthostatic intolerance[1]
We have reported fecal microbiome analyses and proposed a model wherein intestinal dysbiosis may contribute to bacterial metabolic disturbances that are distinct between ME/CFS subgroups defined by the presence or absence of IBS14
We recently reported that ME/CFS patients with irritable bowel syndrome (IBS), ME/CFS patients without IBS and normal control subjects have group-specific differences in fecal microflora[11]

Summary

Introduction

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder of more than six months duration comprising unexplained fatigue, post-exertional malaise, unrefreshing sleep and either cognitive dysfunction or orthostatic intolerance[1]. In a study of 67 ME/CFS patients and 66 healthy controls, Yamano and colleagues assayed 144 metabolites and reported abnormalities in levels of metabolites related to glycolysis, the tricarboxylic acid cycle and the urea cycle, but not in glutamine metabolism[9]. Nuclear magnetic resonance (NMR) spectroscopy has revealed metabolomic abnormalities consistent with altered gluconeogenesis, potential inhibition of glycolysis and impaired oxidative stress response[11]. Another NMR study found that, as compared with controls, glutamine and ornithine serum levels in ME/CFS were lower, and correlated with metabolites linked to the urea cycle[12]. As in our previously reported metagenomic analyses, we found that metabolomic profiles differ between ME/CFS patients and controls and between ME/CFS patients who do or do not have IBS

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Results

Conclusion