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Naviaux et. al.: Metabolic features of chronic fatigue syndrome

M Paine

Senior Member
Auckland, New Zealand
The differences observed between men and women is quite something. And really, the paper clearly demonstrates that there are different genetic pathways involved in hypometabolic state between men and women. Perhaps there is a difference in susceptibility between these genetic pathways which can account for the prevalence of disease in women compared to men?

It almost seems like women are genetically predisposed to enter this state in a protective way, in a functionally different way to men. Could men be less likely to enter this state, to their detriment at the hands of environmental stressors? Could women be entering this state in a way which is more protective/less harmful to an unborn fetus?


Senior Member
Logan, Queensland, Australia
This is my first pass review, though I would love to see further discussion and checking by someone with a stronger stats background than I have, particularly with regard to checking for false positives:

Metabolic features of chronic fatigue syndrome
Naviaux et. al. , published in PNAS Plus.

22 males and 23 females met Fukuda, CCC and IOM criteria. There were 18 and 21 controls respectively.

The data clustering appears to be non-overlapping between controls and patients. (Figure 1), though this might not be an accurately reflection given that ranges are not shown.

A heading in the results section summarizes the paper in one line: Homogeneous Metabolic Response to Heterogeneous Triggers. You can find detailed discussion of those findings in the appendix here: http://www.pnas.org/content/suppl/2016/08/24/1607571113.DCSupplemental/pnas.1607571113.sapp.pdf

This is exciting for me because many of the speculations about biochemistry that I was debating with people in the late 90s and early 2000s touched on these things from time to time. They identified over 60 candidate metabolites, and later looked at which were most diagnostic.

The next heading is particularly important: Metabolites Correlated with the Clinical Severity of CFS. They have attempted to control for false discovery, though I have not looked at that level of detail in the appendix just yet. They conclude:

These findings were consistent with the notion that CFS is a coordinated hypometabolic state.

I am not going to discuss all findings, just the ones I currently find interesting. Its a really long list, and I don't want to just quote huge lists of issues and hypothesized issues.

The decreased sphingolipid and glycosphingolipid findings are different from found in the metabolic syndrome and the acute cell danger response, and it looks like CFS is the opposite of an acute cell danger response. I found this bit very interesting, and might indicate that the ME or CFS response is a conserved evolutionary response:

Decreased octenoic acid is also known to inhibit the susceptibility to Herpes virus infections ...

Later on they said as much, here:

These facts suggest that CFS is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life.

This is one of the things I recall being discussed in the 90s. Indeed, I have commented many many times that CFS might be triggered in an attempt to combat potentially life threatening infections, especially in heart and brain.

Cholesterol synthesis is lowered? This is surprising to me.

Uric acid was low in males, and adenosine in females. I wonder what this implies for me as my uric acid is always high.

Two of the amino acid findings are not what you would expect from acute inflammation or infection. However other findings in the paper suggest otherwise. Its not a clear issue.

FAD, or flavin adenine dinucleotide, appears to be low, and so you might expect B vitamin issues and especially problems with lipoic acid and glutathione.

Increased arginine, which I think is suspected in susceptibility to herpes virus infections, seems to be associated with decreased post operative infection as well. Hmmmmm ...

HICA, or 2-Hydoxyisocaproic acid, was low, which might mean suseptibility to bacterial and fungal infection.

There is an interesting quote that reflects possible treatments:

Our clinical experience suggests that symptom improvements can be achieved more reliably by addressing the personalized abnormalities rather than by assuming a chemical abnormality without actual measurement.

They write about similarities to the dauer state, a type of hibernation, but in a fast look at some literature it appears to be more about dormant nematodes (worms) and not bears. They survive hostile conditions this way. They say this:

Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes that are triggered by exposure to adverse environmental conditions.

This I found very interesting given my personal health:

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 (37), but at the cost of significant long-term disability, pain, and suffering.

One long term therapeutic research direction is to investigate the role of NADPH.

The importance of this study is summed up near the end:

The finding of an objective chemical signature in CFS helps to remove diagnostic uncertainty, will help clinicians monitor individualized responses to treatment, and will facilitate multicenter clinical trials.

If validated I think these findings will change ME research forever. I really hope they can be shown to be accurate, and that further studies will expand on these findings, lead to better patient cohort selection, and selected biochemical targets for intervention. Exciting times ...
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Senior Member
We don't know that. For all we know, we could all be dead right now without it.

Oh, I do agree our activity limitations might well be protective. I was thinking in terms of this state being an adaptive response to an environmental threat, which makes it seem like more of a throwback than a useful tool.


Senior Member
I don't follow you. Yes this notion was speculated about before the study came out, but they in fact found the opposite. There is a hypometabolic state, not the hypermetabolic state of CDR; the study explicitly rule outs an activated CDR.

not quite. it rules out an acute CDR. Leave CDR on and you might see the opposite, perhaps. Not saying I believe that is the case, just that the study doesn't rule out CDR being the problem.


Senior Member