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Chronic Fatigue Syndrome Shows Distinct Metabolomic Signatures, UCSD Study Says


NEW YORK (GenomeWeb) – A new metabolomics study of patients with chronic fatigue syndrome suggests a breakthrough in the understanding of the condition, with potential to offer the first biomarker-based diagnostic test.

Metabolic profiles from blood plasma of CFS patients indicate that the condition, which has resisted characterization, looks a lot like a post-infection or post-stress metabolic state that has failed to return to normal.

Led by Professor Robert Naviaux, scientists from the University of California, San Diego compared metabolomic profiles of 39 total men and women with matched controls, targeting 612 specific metabolites from 63 biochemical pathways.

Patients with CFS exhibited a measurable decrease in 80 percent of those 612 analytes and abnormalities in 20 pathways, including lipid, purine, cholesterol, and mitochondrial metabolism. CFS also appeared to affect patient microbiota. Moreover, a flexible classifier set of 15 of the top metabolites was sufficient to identify patients with CFS at an accuracy rate of more than 90 percent.

"The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, [gastrointestinal] function, the microbiome, the autonomic nervous system, [and] neuroendocrine and other brain functions," Naviaux said in a statement.

While metabolite signatures were highly individualized — 75 percent of the abnormalities were specific to a patient — they were all indicative of the same cellular response, Naviaux said. "It's chemically similar to the dauer state you see in some organisms, which kicks in when environmental stresses trigger a slow-down in metabolism to permit survival under conditions that might otherwise cause cell death. In CFS, this slow-down comes at the cost of long-term pain and disability."

The scientists published their study this week in the Proceedings of the National Academy of Sciences.

Mary Ann Fletcher, a researcher at Nova Southeastern University who studies CFS and immunology, said the UCSD team's ideas were "certainly in the realm of possibility. Metabolomics are an important area to examine," she said. Her own data suggest that mitochondrial function, which is related to metabolism, is adversely affected in patients with the disease.

Conceptualizing CFS as a state where cellular metabolism has failed to reboot following response to stress may help bring clarity and relief for patients whose condition has been dismissed by some as psychosomatic. Also called myalgic encephalomyelitis (ME) and described under the umbrella term ME/CFS, the condition affects as many as 2.5 million people in the US, 70 percent of whom are women.

Getting a diagnosis is its own challenge, since ME/CFS affects multiple systems in the body, and symptoms can vary and are often similar to those of other diseases. Currently, there is no single diagnostic test for the condition. "Many patients undergo a diagnostic odyssey that results in substantial personal expenditures that can exceed $100,000 over years of searching, absence from the workplace, and significant reductions in quality of life," the authors noted in their study.

While there have been other attempts to find biomarkers for ME/CFS, none have yielded anything of clinical value. Currently, Stanford University Professor Ron Davis is leading a large coalition using genomics to study ME/CFS, and Fletcher is using a $2 million grant from the National Institutes of Health to study biomarkers for the disease in men.

Just last year, an NIH panel called for even more funding for research on ME/CFS. Now, the UCSD team may have opened up a promising line of research to pour money into.

A metabolomics analysis offers the ability to "represent the functional interaction of genes and environment," the authors wrote, and "may provide a more technically and bioinformatically tractable, physiologically relevant, chemically comprehensive, and cost-effective method of diagnosis of complex chronic diseases."

Using mass spectrometry-based targeted metabolomics, the scientists showed that metabolite signatures could be used to diagnose patients with CFS, as determined by criteria defined by several authorities, including the National Academy of Medicine. Specifically, they used an AB Sciex Qtrap 5500 triple-quadrupole mass spectrometer in multiple reaction monitoring mode with Turbo V electrospray ionization.

Compared to controls, certain metabolic pathways were disrupted in CFS patients. Sphingo- and glycosphingolipid levels decreased the most. Purines, phospholipids, fatty acids, and cholesterol were also decreased, among other metabolite species. Some pathways were disrupted primarily in men (i.e., threonine metabolism) or women (i.e., fatty acid oxidation). Almost half of all the metabolites had a differential measurement in women than in men, the authors said.

The results helped the scientists show that ME/CFS is comparable to other conditions where metabolism is not performing normally.

"Despite the heterogeneity of CFS, the diversity of factors that lead to this condition, our findings show that the cellular metabolic response is the same in patients," Naviaux said.

The response is related to fundamental cell processes to deal with environmental stresses, in particular the response to bacterial, viral, or fungal infection and physical or psychological trauma, which Naviaux called the "cell danger response" (CDR).

"Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat," including regulation of innate immunity and inflammation, he said. "In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months."

But if normal metabolism isn't restored, the cell perpetuates the CDR and enters "a kind of siege metabolism," he said.

Resources are diverted from mitochondria and key metabolites are sequestered or jettisoned, Naviaux said. "This has the effect of further consolidating the hypometabolic state. When the hypometabolic response to threat persists for more than six months, it can cause CFS and lead to chronic pain and disability. Metabolomics now gives us a way to characterize this response objectively, and a way to follow the chemical response to new treatments in systematic clinical trials," he said.

The results might help explain why a small percent of people who are infected with pathogens implicated in CFS — such as Epstein-Barr virus or Borrelia burgdorferi, the bacterium that causes Lyme disease — develop symptoms of chronic fatigue.

Naviaux also said that the research has implications for understanding epigenetics and gene expression. "All of these metabolites that regulate epigenetics and gene expression are controlled primarily by mitochondrial metabolism," he said. "This makes sense because all cellular activities must be responsive to local resource availability and remain flexible to respond to potential threats that alter cellular health, and mitochondria are the prime monitors and regulators of cellular metabolism."

The authors said their study could provide a path forward for research on therapies and "helps to remove diagnostic uncertainty." However, Naviaux did not respond to GenomeWeb's request for comment on whether the metabolite signatures could form the basis for a mass spec-based clinical diagnostic assay or whether his lab is working on such an assay.

"I'm not convinced we will have that one, definitive test to find the disease," Fletcher said. "But what's much more possible is to have a menu of tests that enables clinicians to say, 'It's highly likely [to be ME/CFS].'" She added that ME/CFS diagnosis is "poorly covered," even in contemporary medical training, though that's also improving.

The Naviaux lab's website said the next steps are to validate their results in a larger population of North American ME/CFS patients and compare the results with genomics data in collaboration with Stanford's Ron Davis.