Abstract:
More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS.
We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21-67 y). Females were 52 (±2.5) y old (range, 20-67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females.
We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism.
Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84-100%] in males using eight metabolites and 96% (95% CI, 86-100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.
Source: Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80. doi: 10.1073/pnas.1607571113. Epub 2016 Aug 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027464/ (Full article)
Comment
G L Francis 2016 Sep 19 04:58 a.m.
I have read your publication in PNAS titled ‘Metabolic features of chronic fatigue syndrome’ with much interest, this significant contribution has at last provided a definitive publication of a realistic evidence based diagnostic test based on a panel of blood metabolites – this could provide a more robust diagnostic base for future rational treatment studies in ‘CFS’.
Athough there are many more complex and critical questions to be asked, I will keep mine simple. I took particular note of the authors comments “When MTHFD2L is turned down in differentiated cells, less mitochondrial formate is produced and one-carbon units are directed through Methylene-THF toward increased SAM synthesis and increased DNA methylation” (from Figure S6. Mitochondrial Control of Redox, NADPH, Nucleotide, and Methylation Pathways legend). I recently read the paper, ‘Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and Endothelial Cell Dysfunction’ Shiran A et al. IMAJ 2015; 17: 288–292, and wondered whether the gene variations in the individuals described within that publication, could be over represented in your subjects, mind you the size of your study population probably answers my own question; and no doubt many mechanisms that lead to a perturbation of this pathway exist, of which this could conceivable be just one of many, even if a minor contributor. Moreover, there does seem to be a difference between the two papers in terms of the particular pertubations on incidence of cardiovascular disease and outcomes?