From Ron Davis, "This is the most important and groundbreaking study of ME/CFS to date"
From Dr. Ron Davis:
"The publication, “Metabolic Features of Chronic Fatigue Syndrome” by Naviaux RK, et al. is a landmark in ME/CFS research. It is the most important and groundbreaking study of ME/CFS to date.
Extending recent indications of metabolic alterations in ME/CFS, this study provides the first comprehensive, quantitative demonstration of the metabolomic deficiencies that characterize the disease. They define a clear metabolic ‘signature’ that accurately distinguishes patients from healthy individuals.
This signature was consistent even among patients with different symptoms or disease-initiating events. These findings are exciting news for both patients and researchers. Not only do they substantiate the biological reality of this stigmatized disease, but they also point to the most promising ME/CFS biomarker candidate the field has seen. An ME/CFS biomarker – long awaited by scientists – would allow the precise and objective diagnostics that have never been possible for this disease. In addition, it would accelerate the search for treatments.
Dr. Naviaux’s study suggests that both of these endeavors could be designed in a way that will benefit all patients, regardless of their symptoms and initiating events (which are not always known).
In addition to a common metabolomic response, patients show a variety of individual responses. These individual responses may contribute to the symptomatic differences, and may be caused in part by genetic differences. Similarly, effectively treating ME/CFS might require two components: a common treatment for all patients and a personalized treatment. Interestingly, this might explain the plethora of treatments that have helped individual patients but only rarely work on other patients.
Another important finding from this study is that the metabolomic response observed in ME/CFS is opposite to the pattern seen in acute infection and metabolic syndrome. This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness. What is important to note is that in the absence of evidence of an active infection, it is plausible that the long-term antimicrobial treatments often used for ME/CFS patients are doing more harm than good.
This breakthrough study thus presents several new findings of great importance to the ME/CFS patient, medical, and research communities – and perhaps most importantly, to the search for treatments. For these findings to have an impact on patient care, further investigation and validation via independent studies are crucial. Because of this, the Open Medicine Foundation has funded the next study of a larger patient cohort, in which Dr. Naviaux will validate the ME/CFS metabolomic signature in a larger, geographically diverse sample, and I will explore the role of genetics in the individual responses. These studies are already underway. We appointed Dr. Naviaux to the Scientific Advisory Board of OMF earlier this year, and we are grateful for his expertise in helping to unravel the metabolic mysteries of this debilitating disease.
We are finally on the right path to understanding ME/CFS. We and many of our collaborators are working hard to translate this new understanding into general and personalized treatments. "
Added to this is a Q and A with Dr Naviaux expanding some key aspects of the study:
Q1. Some people still argue that CFS is not a real illness but all in the mind. Does your
discovery of a chemical signature help shatter this myth?
Yes. The chemical signature that we discovered is evidence that CFS is an objective
metabolic disorder that affects mitochondrial energy metabolism, immune function, GI
function, the microbiome, the autonomic nervous system, neuroendocrine, and other
brain functions. These 7 systems are all connected in a network that is in constant
communication. While it is true that you cannot change one of these 7 systems without
producing compensatory changes in the others, it is the language of chemistry and
metabolism that interconnects them all.
Q2. How does chronic fatigue syndrome fit in with other kinds of hypometabolic states
All animals have ways of responding to changes in environmental conditions that
threaten survival. We discovered that there is a remarkable uniformity to this cellular
response, regardless of the many triggers that can produce it. We have used the term,
the cell danger response (CDR) to describe the chemical features that underlie this
response. Historical changes in the seasonal availability of calories, microbial
pathogens, water stress, and other environmental stresses have ensured that we all
have inherited hundreds to thousands of genes that our ancestors used to survive all of
The body responds differently to the absence of resources (eg, caloric restriction or
famine) than to the presence of pathogens and toxins. We can classify two responses: a
single-step response to the absence of resources, and a two-step process in response
to the presence of a threat. Both responses are completed by a return to normal
metabolism and function. When resources are severely curtailed or absent, the full CDR
is bypassed, and the flow of nutrients through metabolism is decreased to conserve
limited resources in an effort to “outlive” the famine. This is often called a caloric
On the other hand, when the cell is faced with an active viral,
bacterial, or fungal attack, or certain kinds of parasitic infection, severe physical trauma,
or even chronic psychological trauma (which produces a similar chemical change in
metabolism), this activates the two-step response. The first step is to acutely activate
the CDR. Innate immunity and inflammation are regulated by the metabolic features of
the CDR. Activation of the CDR sets in motion a powerful sequence of reactions that are
tightly choreographed to fight the threat. These are tailored to defend the cell against
either intracellular or extracellular pathogens, kill and dismantle the pathogen,
circumscribe and repair the damage, remember the encounter by metabolic and
immunologic memory, shut down the CDR, and to heal.
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. For
example, only a small percent of people who are acutely infected with Epstein-Barr virus
(EBV) or human herpes virus 6 (HHV6), or Lyme disease go on to develop chronic
symptoms. If the CDR remains chronically active, many kinds of chronic complex
disease can occur. In the case of CFS, when the CDR gets stuck, or is unable to
overcome a danger, a second step kicks in that involves a kind of siege metabolism that
further diverts resources away from mitochondria and sequesters or jettisons key
metabolites and cofactors to make them unavailable to an invading pathogen, or acts to
sequester toxins to limit systemic exposure. This has the effect of further consolidating
the hypometabolic state. When the hypometabolic response to threat persists for more
than 6 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.
Q3. You talk about the chemical signature being similar to a state of hibernation. What
sort of animals exhibit a similar signature in hibernation?
I wouldn’t use the term hibernation to describe chronic fatigue syndrome. Humans do
not hibernate. Hibernation is just one of a handful of hypometabolic states that has been
studied in different animals. There are many others that go by names like dauer,
diapause, torpor, estivation, caloric restriction, etc. Many environmental stresses will
trigger hypometabolism in humans. In our experience, the metabolic signature of dauer
is more similar to CFS than some of the other hypometabolic states that have been
One of the main points of our metabolomics study of CFS was to give other
scientists a new tool to analyze all of these hypometabolic states, developmental stages,
and syndromes so that the similarities and differences can be objectively studied, and
rational new therapies developed.
Q4. Are men and women really that different in CFS?
Yes. About 40-50% of all the metabolites that we measure in our method have a
different normal concentration in males and females. This is not all related to
testosterone and estrogen. Literally hundreds of metabolites are tuned to different
concentrations in men and women. At the pathway level, we found that men and women
shared 9 (45%) of the 20 biochemical pathways that were disturbed in CFS patients.
Eleven pathways (55%) were more prominent in males or females. We find that to do
metabolomics properly, you need to have an adequate number of age- and sex-matched
controls. If healthy males and females are lumped together as controls, the power to
see metabolic differences in CFS and many other diseases is much decreased.
Likewise, the metabolism of a 25-year old male is different from a 35-year old male, and
categorically different from a 25-year old female. In each decade of life there are many
metabolic changes that occur as part of normal development and aging. When proper
age- and sex-matched controls are used, metabolomics is one of the most powerful new
tools available to physicians and scientists to study chronic complex disease.
Q5. How do the metabolic changes you identified in CFS relate to the recent interest in
epigenetics and methylation pathways?
All the covalent chemical modifications of DNA and histones that regulate gene
expression are the result of metabolic changes controlled by mitochondria. For
example, all DNA and histone methylation depends on the availability of SAdenosylmethionine
(SAMe). Phosphorylation reactions depend on the availability of
ATP. Acetylation depends on the availability of Acetyl-CoA. Demethylation depends on
the availability of oxygen and alpha-ketoglutarate. Other demethylation reactions require
the availability of FAD+ and generate peroxide. Deacetylation depends critically on the
availability of NAD+. DNA ADP-ribosylation also depends on the availability of NAD+.
The master fuel regulator AMP kinase (AMPK) activity depends on the build-up of AMP
or the de novo purine biosynthesis intermediate AICAR (aminoimidazole carboxamide
ribotide). mTOR is another key barometer of cellular fuel status. mTOR activity requires
the availability of leucine. All of these metabolites that regulate epigenetics and gene
expression are controlled primarily by mitochondrial metabolism. 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.
With regard to cytoplasmic methylation reactions that involve folate and B12 metabolism,
mitochondria also play a key role by regulating the release of formate, the balance of
NADPH to NADP+, NADH to NAD+, FADH2 to FAD+, propionyl-CoA to succinyl-CoA,
and glycine to serine. Ultimately, all of these mitochondrial reactions influence the tide
of substrates available for methionine, cysteine, glutathione, and taurine metabolism.
The ebb and flow of these metabolites determines the balance between cell survival and
death, controlling epigenetic modifications and gene expression. These reactions are
illustrated in supplemental online Figure S6 of our paper.
Q6. How might your results help with treatment of CFS?
This first paper was not focused on treatment. However, metabolomics reveals a new
window into the underlying biology of CFS that makes us very hopeful that effective
treatments will be developed soon and tested in well-controlled clinical trials.
Metabolomics will be an important component of any clinical trial of new treatments for
CFS. It will also play an important role in analyzing the similarities and differences of
classical laboratory models of hypometabolic states like dauer.
With hope for all,
Open Medicine Foundation
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