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

[Jenny TipsforME]

I've been playing a bit with pictoral, metaphorical examples discussed here but posting on Twitter eg
https://t.co/fsJ4xH9clX">pic.twitter.com/fsJ4xH9clX</a></p>&mdash; Jenny Tips for ME (@TweetTipsforME) <a href="

https://twitter.com/i/web/status/770639885942263808

">August 30, 2016

 

[Marco]

Does anyone know if they give a full list of the metabolites tested?

 

[Simon]

I don't think it being inappropriately switched on is necessarily the conclusion from the paper. There are certainly other alternatives, namely that it is appropriately switched on in reaction to an ongoing infection.

Then it really would be expected to be well studied, given the number of chronic human infections. The authors argue against the ongoing use of antivirals/antibiotics on the basis of their results.

There are certain changes in the nematod metabolism which involve some genes for which their are human orthologs. DAF-16 is the nematode ortholog of the FOXO human genes. DAF-2 is the ortholog of IGF1R (Insulin-like Growth Factor 1 Receptor).

Interesting. I was actually about to suggest that given dauer is well studied, it must be possible to look for the same genes in humans and at least taake an eductated guess if they were functional. You were ahead of the game!

But would be good to see if the whole pathway is intact, since obviously those genes in humans don't normally lead to dauer.

 

[Nielk]

The paper argues multiple triggers, including initial virus/infection, lead to a common hypometabolomic state, perhaps as a stuck defence mechanism (so not a "coincidence").

I'm not a scientist and I'm trying to understand this hypo metabolic state. The way I understand it from this study, it's a defense mechanism following some type of hit - whether viral, infectious, environmental or other. Something goes wrong in the body and it stays in this stuck position? The reason this happens might be genetic. Certainly, this is not the norm for individuals experiencing this type of "hit".

What are the odds that a large group of people in a specific location, all develop this hypo metabolic state following an epidemic hit?

 

[AndyPR]

I've been playing a bit with pictoral, metaphorical examples discussed here but posting on Twitter

How about describing it as a computer that is in a power save mode? I appreciate that technically there is more to it than that but as a metaphor perhaps it's good enough?

 

[Valentijn]

But would be good to see if the whole pathway is intact, since obviously those genes in humans don't normally lead to dauer.

The other thing that happens is that some genes stop functioning entirely, but their remnants are sitting around in the genome as pseudogenes. So an alternative to a normally functioning normal gene, or a normally functioning rarer variation of that gene, could be the genetically-induced re-activation of a pseudogene.

This is pretty theoretical stuff, however. On the one hand, mutations tend to happen in one direction (certain nucleobases degrade into other nucleobases, but not vice-versa), so it seems like it should be harder for any mutations to revert to an earlier state. On the other hand, it sounds like otherwise inactive pseudogenes often still undergo transcription.

 

[Valentijn]

What are the odds that a large group of people in a specific location, all develop this hypo metabolic state following an epidemic hit?

It might depend on the intensity of the hit. Normal hit = sporadic cases in people who are especially predisposed. Uber hit = epidemic outbreak including people would have been able to handle a normal hit.

 

[duncan]

Does cancer count as a stressor?

One would imagine a significant and reliable/repeatable portion of cancer survivors would develop CFS. I'm not sure we have any stats linking cancer and ME/CFS.

 

[Tuha]

They say that cholesterol is low in ME patients. My experiences are that my cholesterol was also lower but I had high level of triglycerides. Then I tried ketogenic diet (almost after few days my energy level increased 20 %) and my cholesterol level got a bit higher than the recommended limits and triglycerides were perfect. But after some months I had to add more carbohydrates because I felt a bit strange (I think hypoglycemic) but the energy level stayed. Now I will do the lipid tests again so I will see if it changed with diet again.
Does this fit somehow with the picture?

 

[Valentijn]

One would imagine a significant and reliable portion of cancer survivors would develop CFS. I'm not sure we have any reliable stats linking cancer and ME/CFS.

There's been research into post-treatment fatigue in cancer patients. But that's been linked to the chemo or radiation therapies, not to the cancer itself.

 

[serg1942]

Hoy folks, wow, there are a lot of posts to read already! Well, without having read the previous messages, I just wanted to share my analysis on the paper that I have made in Spanish:

http://www.sfc-em-investigacion.com/viewtopic.php?p=31521#p31521

Maybe my view is shared by some of you. What I wrote in Spanish after reading the paper is essentially, that these results are mostly a confirmation of the altered metabolic/biochemical pathways already published and therefore known on ME/CFS, such as the mitochondrial failure, oxidative damage, catabolism, altered redox status, problems in the methylation cycle and adjacent pathways such as nucleotides metabolism, etc. There are some things I think are new, such as the lipid metabolism, although it is something we already knew--indirectly from the lipid oxidation, unbalanced omega 3-6 ratio, lipid peroxidation, etc.

Those of us who studied in depth the Yasko’s protocol for autism ,years ago , and its application the ME/CFS proposed by Richard A. Van Konynenburg, do know many of the found abnormalities--and it's great that they are confirmed and published!.

As for the hypometabolic state, well, I remember having read this several times years ago,from for example Dr. Myhill in her book. It is great that this study actually points out this fact, giving to it a grade of evidence it didn’t have before.

I would also like to remember that the concept of putting together some metabolites in order to draw a diagnostic tool is not new, and has been carried out various times in the past, with even better sensibilities than this paper finds: Dr. Myhill made it with 5 parameters; I think it was Dr Klimas who published the potencial diagnostic value of a few cytokines put together, and in the same vein, recently, Dr. De Meirleir and his team published how more than 400 SNPs (12 of these in the “transcriptional region” of the DNA) with a very low P value, could also distinguish between patients and controls.

For me, and in my very humble opinion, the most relevant part of this study are the following assertions:

(…)ultimately may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections. (…)This pattern is also opposite of what is found during acute inflammation and infection (…) Plasma FAD was decreased in both males and females with CFS (...)FAD is mobilized from tissues, increased in the plasma, and renal secretion is increased under conditions of stress or infection (…) Hydroxyproline was increased(...)Another metabolic fate of hydroxyproline is glyoxylate, which can be transaminated in mitochondria to produce glycine and metabolized in peroxisomes to oxalate and peroxide for cell defense and innate and antiviral immunity (…) Arg levels were also increased in chronic fatigue(...)Increased Arg is associated with a decreased risk of infection after operative stress and is used to synthesize the antimicrobial molecule agmatine under conditions of active infection (…) HICA was decreased in both males and females with CFS.(..)HICA has antibacterial and antifungal activity.(…)

In short, no matter if papers look at the immune system, or at the biochemical/metabolic signature of ME/CFS—like this one does--, they find the same: multiple aetiological events lead to a similar state of chronic inflammation, immune activation and immune-suppression (yes, at the same time), probably caused by intracellular viral or bacterial infections… Well, this sounds quite familiar, doesn't it!

I just wanted to share my 2 cents!
Best,
Sergio

 

[ghosalb]

25% general and 75% unique abnormalities.....wish it was 75/25, treatment would have been easier...unless if one can fix 25% general abnormalities, that will take care of the other 75% unique abnormalities.

 

[JaimeS]

I cannot keep up with this conversation -- you guys are amazing!

The article will be out at 10am this morning, ET -- in an hour, in other words. This WILL BE the url, as in, it won't lead to anything if you click on it now:

http://www.meaction.net/2016/08/30/naviauxs-metabolism-paper-is-about-as-big-as-you-think/

Live now!

 

[frog_in_the_fog]

https://twitter.com/i/web/status/770639885942263808

For me it is like a computer that hibernates ever few hours, which also crashes and restarts.

 

[Marco]

I keep dipping in and out of this thread. Just a few thoughts.

Assuming these results are meaningful :

Exogenous administration of leptin (e.g. for obesity) is eventually unsuccessful because as well as curbing appetite, leptin also results in hypometabolism;

Younger found that elevated leptin levels (within normal range) in ME/CFS correlated with high fatigue days;

Also according to Younger, leptin sensitises microglia making them potentially more reactive to stimuli;

Following traumatic brain injury there is an acute phase of hypermetabolism (in terms of brain glucose uptake) followed by hypometabolism (likewise). It's not clear if this hypometabolism extends to the periphery or if brain hypometabolism metabolites is detected in serum.

I can provide refs/links but not right now.

I'm wondering if neuroinflammation could be the stressor that maintains the hypometabolic state?

I'm also interested if they tested for metabolites from the tryptophan catabolism pathway such as quinolinic acid - a marker of 'neuroinflammation'? If I recall correctly this metabolite has been found to be elevated recently by Lipkin/Hornig? The Naviaux paper doesn't mention it from what I've read.

 

[JaimeS]

Does cancer count as a stressor?

One would imagine a significant and reliable/repeatable portion of cancer survivors would develop CFS. I'm not sure we have any stats linking cancer and ME/CFS.

see my article --- there is increased incidence of cancer in ME.

They say that cholesterol is low in ME patients. My experiences are that my cholesterol was also lower but I had high level of triglycerides.

My cholesterol used to be perfect, but the sicker I got, the lower it dropped. 45 points or so. I've also been on a far more fat-rich diet, but it hasn't shifted, actually.

-J

 

[MikeJackmin]

If this is right we are dealing with deep metabolic and genetic issues that are beyond any prior expertise in medicine. That implies caution is mandatory, which will clash with our huge need for solutions as soon as possible.

If these new insights help explain the mechanism of action of rituximab, I wonder if they imply a greater risk than we might have appreciated.

 

[Bob]

Personally, I don't think 'hibernation' would be a helpful term for us to use, for various reasons:
1. It's not accurate.
2. It could mislead the public and researchers.
3. It suggests that we are simply 'sleepy', and it doesn't clearly describe our other symptoms such as flu-like symptoms, pain, PEM, neurological issues, gut issues, OI, etc.
4. People would say to us: "oh, you're so lucky... I'd love to have an excuse to sleep through winter and wake up in the summer".

Also, remember that ME/CFS hasn't been described as the same as dauer, but only that there are similar metabolic pathways. (Would 'dauer' explain all symptoms in ME/CFS such as the worse type of neurological symptoms?) And, seeing as dauer is a phenomena generally seen in invertebrates and not humans (as far as I understand it), we don't know what it means for humans to enter a similar state, in terms of 'why', 'how' etc.

ME/CFS doesn't seem like a particularly adaptive process to me, but who knows. Could it be a dysfunctional genetic throwback or a genetic disease? Could it be caused by an activated endogenous retrovirus? There are many opportunities to speculate here.

I'd be interested to know if there are metabolic similarities between ME/CFS and people who have an acute infection with associated symptoms, such as flu. Some flu symptoms (i.e. lethargy, weakness, exhaustion) seem like a type of dauer-state in humans, and are also very similar to ME/CFS; and the biological reaction to acute infection might better explain a dauer-type state of health in humans. Flu also has other symptoms very similar to ME/CFS (e.g. joint pain, cognitive dysfunction etc). (I'm not suggesting that flu viruses are causing ME/CFS but I mean that the cellular response to flu viruses might be at fault.) (Or would the body's reaction to viruses be better defined by the "cell danger response" rather than dauer? I'm not familiar with either phenomenum.)

 

[Tuha]

My cholesterol used to be perfect, but the sicker I got, the lower it dropped. 45 points or so. I've also been on a far more fat-rich diet, but it hasn't shifted, actually.

-J

Maybe the severity is important . It will be interesting to see the data from moderate/mild patients.

 

[Bob]

How is this any different though to the idea of depression being an adaptive (useful) state for dealing with life's hardships? (see for example http://www.scientificamerican.com/article/depressions-evolutionary/ ).Isn't that just what the psych lobby will say?

Interesting question. But I think the psychs who focus on ME/CFS wouldn't be the type to describe depression as adaptive, but would describe it as a maladaptive psychological reaction to ordinary life-events.

How does this finding explain the many incidences of ME outbreaks? Did all these patients' coincidentally develop a hypometabolic state after their initial virus/infection?

Good question; we can only speculate at this point. I think this research doesn't really change our understanding or interpretation of outbreaks. (Just my personal thoughts, of course.) Perhaps specific viruses or specific toxins elicit a specific protective cellular response that becomes irreversible in some people vulnerable to a particular genetic disease process?