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

[A.B.]

Then there's the issue of cause and effect. You test a group of people who spend a lot of time in a state of semi-hibernation and their metabolic profile is suggestive of a state of hibernation. Did they use healthy but sedentary controls?

One only needs to look at PACE or FINE to see that behaviour doesn't play any significant part. People don't improve even when they are assigned a therapist that tries to get them to do more.

 

[user9876]

Being highly conserved suggests a temporary state (to be conserved you have to pass on your genes so have either bred prior to hibernation and are still able to protect/raise your offspring during hibernation (unlikely) or the hibernation state passes once the environmental stressor is gone. The more interesting question is why PWME enter this state (if they do) and why they don't leave it. As an evolutionary conserved mechanism we all should be susceptible so why just PWME. Genetic vulnerability? If so why don't we all develop ME/CFS as infants when we first encounter environmental stresssors?

Then there's the issue of cause and effect. You test a group of people who spend a lot of time in a state of semi-hibernation and their metabolic profile is suggestive of a state of hibernation. Did they use healthy but sedentary controls?

I've yet to read the full paper - maybe they address these issues so apologies if they do.

I was assuming that they are suggesting it is an evolutionary mechanism that should have gone or not be triggered. The question for me is if they are correct and results are replicated then what is the 'environmental stressor' that is triggering the state (and keeping it in that state). Could an antibody be a trigger and hence the effectiveness of Rituximab. In that was the trigger would be encountered at random when the antibody is created rather than being a direct environmental thing?

 

[lansbergen]

A state of resistance in harsh conditions.

That is a much better term than Hibernation.

 

[Gingergrrl]

Could an antibody be a trigger and hence the effectiveness of Rituximab.

For me I don't think the antibody was the trigger versus the end result. For me the trigger was a series of events (neurotoxic reaction to a medication, followed by a severe virus, followed by toxic mold exposure). I believe my immune system couldn't fight these back to back triggers and flipped into autoimmunity. So in the beginning I don't think RTX would have been right for me, but now after reaching the autoimmune phase, I think it is.

 

[hixxy]

That is a much better term than Hibernation.

Well one tells you more about what's happening (hibernation) the other tells you more about why it's happening (resisting harsh conditions).

 

[adreno]

Been away from PR for a day and then I login and find this! Really exciting news. But we need confirmation before the party begins. Replication, replication, replication...

 

[Simon]

I've been trying to understand "dauer" and Googled it but still not sure exactly what it means. What would be the best translation or most similar word in English?

The key point is that Dauer is a state in the nematode worm C elegans - all the paper's references are on this. It's got nothing to do with mammalian hibernation, AFAIK. So how relevant it is to us is a big questions - we are a long way from nematode worms.

I'm still reading the paper - it looks very interesting, and the stats seem pretty robust, given the small sample size. Obviouslyy a lot will hang on replication, but that's what's so good about this team: the replication work has already started (hope someone can add a link to their fundraising).

 

[Marco]

One only needs to look at PACE or FINE to see that behaviour doesn't play any significant part. People don't improve even when they are assigned a therapist that tries to get them to do more.

The point I'm making is that activity is curtailed in PWME so some downregulation in metabolism might be expected as a consequence.

 

[A.B.]

Despite the heterogeneity of CFS, [and] the diversity of factors that lead to this condition, our findings show that the cellular metabolic response is the same in patients,” Robert K. Naviaux, PhD, professor of medicine, pediatrics and pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego School of Medicine, said in a press release. “And interestingly, it is 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.

http://www.healio.com/rheumatology/fibromyalgia/news/online/{adf536b1-65bc-4607-b71b-1d9b153a67fa}/researchers-identify-metabolite-disturbances-in-patients-with-chronic-fatigue-syndrome

So Naviaux thinks that the body is trying to prevent cell death by slowing metabolism.

 

[adreno]

The low sphingolipid profile in CFS appears to be an adaptive response that is opposite to the increased sphingolipids observed in metabolic syndrome (11) and the acute cell danger response (CDR) (7) and ultimately may represent a fundamental response to oppose the spread of persistent viral and intracellular bacterial infections.

The trigger right there?

It has recently been shown that mitochondrial MTHFD2L is responsible for producing 20–40% of cellular NADPH by the oxidation of methylene tetrahydrofolic acid to 10-formyl tetrahydrofolate (51). These data show that folates are important not only in methylation reactions but also in regulating intracellular redox and NADPH levels

Folate is one on the few things that I find consistently helpful and can pull me out of a crash.

Rich Vank was onto NADPH as a central factor, btw. See:
http://forums.phoenixrising.me/inde...fs-nadph-measurement-at-riordan-clinic.15641/

 

[charles shepherd]

UK media coverage in The Times + a short note on the PACE trial and QMUL:

Chronic fatigue syndrome could be the body trying to hibernate
Tom Whipple, Science Editor

August 30 2016, 12:01am, The Times
An estimated 250,000 people have CFS in Britain. The disease, which is difficult to diagnose, causes people to suffer from persistent exhaustionGetty Images

Chronic fatigue syndrome may be caused by the body mistakenly going into a semi-hibernation state, a study has suggested.

An estimated 250,000 people have CFS, also known as ME, in Britain. The mysterious disease, which is difficult to diagnose, causes people to suffer from persistent exhaustion and can strike with no obvious cause. Theories about the cause have ranged from a bacterial or viral infection to psychiatric issues, and there are few effective treatments.

A previous major study suggesting the best treatments involved cognitive behaviour therapy or exercise angered those suffering from ME, with many saying that it trivialised their disease and ignored possible biological causes.

Now US scientists have found a chemical signature of the disease in the blood of sufferers. They claim that it is similar to a state found in nematode worms called dauer. In this state, the metabolism adjusts to a difficult environment by slowing down — enabling existence, but not much more.

Writing in the journal Proceedings of the National Academy of Sciences, the researchers said that dauer “permits survival and persistence under conditions of environmental stress, but at the cost of severely curtailed function and quality of life”. For many ME sufferers that is an apt description of their condition.

All animals have ways of responding to changes in environmental conditions that threaten survival

For their study, scientists screened the blood plasma of 85 people for metabolites. These are by-products of the chemical reactions in cells, including the breakdown of molecules to release energy. More than half of those screened had been told they had ME.

The aim of the study was to come up with a simple way to diagnose ME. At present, there is no blood test, so doctors have to judge if a patient’s lifestyle and behaviour fit the criteria.

However, as well as finding 20 markers that were indicative of the disease, Robert Naviaux, from the University of California, San Diego, found that these matched markers that would be expected in invertebrates in the dauer state.

This suggested that the condition could be a misfiring response to the environment, with the body mistakenly entering a state designed for survival in harsh conditions. Under this theory, just as allergies are overactive immune responses, ME could be an overactive response of the metabolic system.

“All animals have ways of responding to changes in environmental conditions that threaten survival,” Professor Naviaux said. “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 these conditions.”

Other scientists welcomed the research, but cautioned that it was too early to say what was going on. Andrew McIntosh, from the University of Edinburgh, said: “It is difficult to know whether the changes reported are a cause or an effect of CFS.”

Disease worsened by stigma
A complex disease biologically, ME is equally fraught politically (Tom Whipple writes). For many sufferers this latest study is more than just an insight into a disease — it adds weight to their battle against another piece of research that was published in 2011.

The Pace trial, run by UK researchers, remains one of the most comprehensive investigations into treatment for ME. It concluded that cognitive behavioural therapy and exercise could treat it.

Some sufferers took this as implying that their condition was all in the mind. They questioned the methodology and amid bitter arguments have sought to gain access to the full data. Academics involved in the trial said they had received abuse just for doing their jobs.

Now, after a legal battle, Alem Matthees, who has ME, has succeeded in forcing Queen Mary, University of London to release data from the trial. He said: “There is a growing chorus of academics . . . speaking out about the methodological problems with the Pace trial, yet for many years patients were left to speak out alone.”

Those with ME often feel they are being judged, that people think they are lazy or “faking it”. In that context, yesterday’s study will be seen as a victory.

 

[Marco]

I was assuming that they are suggesting it is an evolutionary mechanism that should have gone or not be triggered. The question for me is if they are correct and results are replicated then what is the 'environmental stressor' that is triggering the state (and keeping it in that state). Could an antibody be a trigger and hence the effectiveness of Rituximab. In that was the trigger would be encountered at random when the antibody is created rather than being a direct environmental thing?

Indeed. In which case whether the state is one of prolonged hibernation or sickness behaviour or whatever is somewhat incidental (not in terms of the effects of course) compared to the autoimmune process.

 

[Ben H]

The key point is that Dauer is a state in the nematode worm C elegans - all the paper's references are on this. It's got nothing to do with mammalian hibernation, AFAIK. So how relevant it is to us is a big questions - we are a long way from nematode worms.

I'm still reading the paper - it looks very interesting, and the stats seem pretty robust, given the small sample size. Obviouslyy a lot will hang on replication, but that's what's so good about this team: the replication work has already started (hope someone can add a link to their fundraising).

Thanks Simon. Replication is already underway with a larger sample size, and the next stage is to compare findings against other diseased states/illnesses. Including the moderately ill-to see if the same potential biomarkers exist.

I will take the opportunity to link to the donation page for OMF, who are relying solely on donations to fund this research (Dr Naviaux's above study was seperate, but he is now on the OMF research team as many of you know, actively working with OMF).

So, if you'd like to donate to further this line of research

http://www.openmedicinefoundation.org/donate-to-the-end-mecfs-project/

It makes a huge difference, and I believe the best investment in our health and hope.

Thanks!


B

 

[PDXhausted]

Re: the microbiome-- I wonder if there could be something to do with leaky gut or bacterial translocation that could account for the persistence of this state and why a pathogen has been difficult to detect.

This might be a stupid question-- but I wonder if there are resident organisms in our gut that are intracellular?

 

[Stewart]

Ian Lipkin said at the end of last year that he had a paper coming that showed metabolic changes (and immune protein changes) in people with ME -- that hasn't been published yet has it?

It'll be interesting to see whether it fits with/corroborates Naviaux's research...

 

[A.B.]

Chronic fatigue syndrome may be caused by the body mistakenly going into a semi-hibernation state, a study has suggested.

It's disappointing that people immediately jump to the conclusion that this altered state must be a mistake.

 

[lansbergen]

It's disappointing that people immediately jump to the conclusion that this altered state must be a mistake.

I do not think it is a mistake but a evolutonary develped way to survive.

 

[Stewart]

It's disappointing that people immediately jump to the conclusion that this altered state must be a mistake. If research continues to view it as mistake, we might never discover the actual cause.

I'm sure that the SMC will have issued a press release yesterday, probably with a helpful quote from Professor McIntosh, gently suggesting that people shouldn't put too much faith in one unreplicated piece of research...

If only they'd done the same when PACE was published.

 

[user9876]

Indeed. In which case whether the state is one of prolonged hibernation or sickness behaviour or whatever is somewhat incidental (not in terms of the effects of course) compared to the autoimmune process.

But either could be treated? Also understanding the one process may point to an auto-antibody - if that theory is correct. I suspect it is more complex in that there also seems to be the need for something such as a virus to help trigger the condition. So there seems to be a multiple things to get into the state but given the results from norway perhaps only antibodies maintain the state.

 

[Simon]

Other scientists welcomed the research, but cautioned that it was too early to say what was going on. Andrew McIntosh, from the University of Edinburgh, said: “It is difficult to know whether the changes reported are a cause or an effect of CFS.”

I think that's an interesting point, given that the controls were healthy and much more active (Karnofsky scale ratings). As Ben says, looking at sick controls too would be useful.

However, it's a pity that the Times journalist went to a biological psychiatrist, Professor Andrew McIntosh, for comment rather than, say an expert in metabolomics/metabolism. Going to both would have been fine.