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A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Fredrik Hoel, August Hoel, Ina K.N. Pettersen, Ingrid G. Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Alexander Fosså, Katarina Lien, Ingrid Herder, Hanne L. Thürmer, Merete E. Gotaas, Christoph Schäfer, Rolf K. Berge, Kristian Sommerfelt, Hans-Peter Marti, Olav Dahl, Olav Mella, Øystein Fluge, Karl J. Tronstad
Fredrik Hoel, August Hoel, Ina K.N. Pettersen, Ingrid G. Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Alexander Fosså, Katarina Lien, Ingrid Herder, Hanne L. Thürmer, Merete E. Gotaas, Christoph Schäfer, Rolf K. Berge, Kristian Sommerfelt, Hans-Peter Marti, Olav Dahl, Olav Mella, Øystein Fluge, Karl J. Tronstad
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Research Article Immunology Metabolism

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

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Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Authors

Fredrik Hoel, August Hoel, Ina K.N. Pettersen, Ingrid G. Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Alexander Fosså, Katarina Lien, Ingrid Herder, Hanne L. Thürmer, Merete E. Gotaas, Christoph Schäfer, Rolf K. Berge, Kristian Sommerfelt, Hans-Peter Marti, Olav Dahl, Olav Mella, Øystein Fluge, Karl J. Tronstad

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Figure 2

Clustering analysis of global metabolite data.

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Clustering analysis of global metabolite data.
Untargeted global metabol...
Untargeted global metabolome analysis in serum from 35 healthy controls (HC) and 83 patients with ME/CFS (ME). Initial analyses identified 159 metabolites significantly different in patients with ME/CFS compared with the HC group (2-tailed Welch’s test, P < 0.05). (A) The graph illustrates the coefficient of variation (CV) for all the significantly altered metabolites. The metabolites are organized along the x axis according to their CV in the ME/CFS group, with increasing CV from left to right. (B) Linear regression of the data in A to assess the overall difference in data heterogeneity between the 2 groups. (C) Heatmap based on k-means clustering using the 159 significantly different metabolites. The heatmap shows the autoscaled levels of each metabolite in each sample, colored blue for decline and red for elevation as indicated on the vertical bar. The patients with ME/CFS clustered into 3 subsets with different metabolic phenotypes, here referred to as metabotypes (M1–M3). The M1 and M2 subsets contained the majority of patients with ME/CFS, and only 1 HC subject clustered with each of them. The third cluster contained the majority of HC subjects and the remaining patients with ME/CFS (M3; separated from HC with a gray line). The heatmap split the 159 metabolites into 3 blocks, or “signatures,” for which the involved metabolite classes are indicated (color-coded) underneath the heatmap. (D) “Tree map” illustrating the relative contributions (box sizes) of the metabolite classes in each metabolite block. The colors indicate the metabolite class, while the abbreviated subclasses are written inside the boxes (see Supplemental Data Set 1 for full names).

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ISSN 2379-3708

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