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Chronic fatigue syndrome is a multisystem disease that causes long-term pain and disability. It is difficult to diagnose because of its protean symptoms and the lack of a diagnostic laboratory test. We report that targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology.
Metabolomics showed that chronic fatigue syndrome is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer. This discovery opens a fresh path for the rational development of new therapeutics and identifies metabolomics as a powerful tool to identify the chemical differences that contribute to health and disease.
Metabolomics has several advantages over genomics for the diagnosis of complex chronic disease and for the growing interest in precision medicine. First, fewer than 2,000 metabolites constitute the majority of the parent molecules in the blood that are used for cell-to-cell communication and metabolism, compared with 6 billion bases in the diploid human genome. Second, metabolites reflect the current functional state of the individual.
Collective cellular chemistry represents the functional interaction of genes and environment. This is metabolism. In contrast, the genome represents an admixture of ancestral genotypes that were selected for fitness in ancestral environments. The metabolic state of an individual at the time of illness is produced by both current conditions, age, and the aggregate history, timing, and magnitude of exposures to physical and emotional stress, trauma, diet, exercise, infections, and the microbiome recorded as metabolic memory.
Analysis of metabolites may provide a more technically and bioinformatically tractable, physiologically relevant, chemically comprehensive, and cost-effective method of diagnosis of complex chronic diseases. In addition, because metabolomics provides direct small-molecule information, the results can provide immediately actionable treatment information using readily available small-molecule nutrients, cofactors, and lifestyle interventions. Our results show that CFS has an objectively identifiable chemical signature in both men and women and that targeted metabolomics can be used to uncover biological insights that may prove useful for both diagnosis and personalized treatment.
Dr. Naviaux is the founder and co-director of the Mitochondrial and Metabolic Disease Center (MMDC), and Professor of Medicine, Pediatrics, Pathology, and Genetics at UCSD. He directs a core laboratory for metabolomics at UCSD. He is the co-founder and a former president of the Mitochondrial Medicine Society (MMS), and a founding associate editor of the journal Mitochondrion. He is an internationally known expert in human genetics, inborn errors of metabolism, metabolomics, and mitochondrial medicine. He is the discoverer of the cause of Alpers syndrome---the oldest Mendelian form of mitochondrial disease---and the developer of the first DNA test to diagnose it. Dr. Naviaux's lab has developed a number of advanced technologies like biocavity laser spectroscopy and mtDNA mutation detection by mass spectrometry.
Hypometabolism, Dauer, and CFS.
Our results show that the metabolic features of CFS are consistent with a hypometabolic state. Sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid and branch chain amino acid metabolites, FAD, and lathosterol were decreased. The decreases in these metabolites correlated with disease severity as measured by Karnofsky scores.
Much research has been done on the hypometabolic phenotype in other biologic systems, including dauer, diapause, hibernation, estivation, torpor, ischemic preconditioning, ER stress, the unfolded protein response, autophagy, and caloric restriction. Dauer, which means persistence or long-lived in German, is an example of one well-studied system.
The developmental stage of dauer is a hypometabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical features. Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes that are triggered by exposure to adverse environmental conditions. Entry into dauer confers a survival advantage in harsh conditions.
When the dauer response is blocked by certain mutations (dauer defectives), animals are short-lived when exposed to environmental stress. These mutations show that the latent ability to enter into a hypometabolic state during times of environmental threat is adaptive, even though it comes at the cost of decreasing the optimal functional capacity. Similar to dauer, CFS appears to represent a hypometabolic survival state that is triggered by environmental stress.
The metabolic features of CFS and dauer correspond to the same pathways that characterize the acute CDR and metabolic syndrome but are regulated in the opposite direction. For example, cholesterol, phospholipids, and uric acid are often elevated in the acute CDR and metabolic syndrome, but these metabolites were decreased in CFS patients. A prediction based on these findings is that patients with CFS would be more resistant to the constellation of hypertension, dyslipidemia, central obesity, and insulin resistance that increase all-cause mortality associated with metabolic syndrome, but at the cost of significant long-term disability, pain, and suffering.
I wonder if treatment of metabolism would be considered for CFS to overcome the environmental stress.
To produce ATP, mitochondria need certain essential raw materials, namely Coenzyme Q10 (CoQ10), D-ribose, L-carnitine, magnesium and vitamin B-3.
In a normal healthy person, CoQ10 can be synthesized, but it requires the amino acid tyrosine, at least eight vitamins, and several trace elements. The vitamins include folic acid, vitamin C, B-12, B-6 and B-5.
Synthesis of CoQ10 is inhibited by environmental toxins and chronic disease.
I am coming to the view that many of my CFS patients are metabolically “dyslexic” - that is to say, even when all the raw materials are available, they cannot make their own CoQ10 in sufficient amounts, and therefore levels need to be measured and supplemented.
Indeed a recent study showed a close correlation between levels of CoQ10 and severity of CFS. (“Coenzyme Q10 Deficiency in ME/CFS” by Michael Maes, et al.)
Metabolite dynamics in skeletal muscles are simulated during high intensity exercise. We take into account exercise induced purine nucleotide loss and de novo synthesis. A reduced mitochondrial capacity is assumed for CFS patients. CFS simulations exhibit critically low levels of ATP and a prolonged recovery time. Additionally an increased acidosis and lactate accumulation is observed in CFS.