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

[AndyPR]

We need to keep saying nice things about the study, this thread was just linked to on The Microbe Discovery Project's Facebook page
https://www.facebook.com/microbediscovery/posts/1091245727611127

 

[Biarritz13]

Seeing as phospholipids seem to be important in all of this, perhaps those who bashed Prof. Garth Nicholson might like to revisit their views of him?

And maybe Radio wasn't that wrong :

http://forums.phoenixrising.me/index.php?threads/reverse-mitochondrial-damage-101.28175/

 

[msf]

I read the last paper the other day:

Plasma chenodeoxycholic acid (CDCA) was decreased in females (Table 3, Females). CDCA is a primary bile acid made from cholesterol. Decreased cholesterol flux can result in decreased substrate for bile acid synthesis needed for normal fat digestion and microbiome signaling (24). The absence of adequate bile acid delivery can lead to a loss in intestinal mucosal integrity and leaky gut via a cascade of events stemming in part from disrupted farnesoid X receptor signaling (25).

I have had some problems with bile synthesis after a course of Metronidazole, so perhaps women in particular should be cautious about using nitroimidazoles. Also, perhaps using a choleretic (I found artichoke leaf tea works well for my problem) might help.

 

[Cheshire]

How weird that there are so many UK newspaper articles and none from the US... Maybe we can thank the SMC after all, in their haste to downplay the results they have alerted the media.

 

[alex3619]

How weird that there are so many UK newspaper articles and none from the US... Maybe we can thank the SMC after all, in their haste to downplay the results they have alerted the media.

Is that ironic?

 

[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/

 

[frog_in_the_fog]

This news will be hard to ignore in the U.K.

http://www.dailymail.co.uk/health/a...ebilitating-illness-telltale-signs-blood.html

 

[wastwater]

Good stuff

 

[Countrygirl]

Thanks @JaimeS

Great work!

 

[Simon]

Thus far, it's mostly been for worms, but more broadly, it's simply a normal genetic reaction to certain stimuli which results in energy-conserving behavior.

Um, got a reference for that? The paper gives 4 or 5 Dauer refs, all on worms. A quick google also brought up a ton of worm stuff. It would be very helpufl to see any evidence that this applies directly to humans, or even mammals.

 

[alex3619]

Um, got a reference for that? The paper gives 4 or 5 Dauer refs, all on worms. A quick google also brought up a ton of worm stuff. It would be very helpufl to see any evidence that this applies directly to humans, or even mammals.

I have seen references to insects and fish and other animals, which can have similar profiles. I would want to know if hibernating mammals like bears have a similar mechanism, but I doubt it.

 

[Gijs]

I have seen references to insects and fish and other animals, which can have similar profiles. I would want to know if hibernating mammals like bears have a similar mechanism, but I doubt it.

''
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 studied (...)'', Naviaux.

 

[Valentijn]

Um, got a reference for that? The paper gives 4 or 5 Dauer refs, all on worms. A quick google also brought up a ton of worm stuff. It would be very helpufl to see any evidence that this applies directly to humans, or even mammals.

"Torpor" and "aestivation" are similar concepts, and happen in mammals. Hibernation was recently discovered in a primate, the fat-tailed dwarf lemur, in response to high temperatures.

I think the lack of prior documentation of similar behavior in humans is what makes the similarity especially interesting. It suggests that humans in general (or maybe just some with whacky genes) might be geared to undergo a similar process when exposed to certain stimuli. In which case, this finding goes far beyond ME or illness.

 

[alex3619]

''
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 studied (...)'', Naviaux.

We are not hibernating, but if the biochemistry is the same we need to study it, no matter what its called.

 

[Simon]

"Torpor" and "aestivation" are similar concepts, and happen in mammals.

But that's not the same thing.

Much research has been done on the hypometabolic phenotype in other biologic
systems, including dauer (35), diapause (40), hibernation (41), estivation (42), torpor (43), ischemic preconditioning (44), ER stress (45), the unfolded protein response (46), autophagy (47, 48), and caloric restriction (49).

So they looked at a load of hypometabolomic states, but only picked out dauer, only referenced in worms, as comparable to what's happening in this study. Which is very interesting, but would be even more so with examples a bit closer to us on the evolutionary tree. And I presume if there were any, the paper would have quoted them.

added

I think the lack of prior documentation of similar behavior in humans is what makes the similarity especially interesting. It suggests that humans in general (or maybe just some with whacky genes) might be geared to undergo a similar process when exposed to certain stimuli. In which case, this finding goes far beyond ME or illness.

Yes, it's curious, but if this is some inappropriate reaction being switched on, which is the proposal, I'm a bit surprised it hasn't been seen in higher organisms. Of course, it being so hidden might be why mecfs has been so hard to crack. But it also suggests that dauer has survided through hundreds of millions of years of evolution since we split from our nematode friends, unused but functioning - and that itself might be a bit surprising.

 

[mermaid]

I see according to this study that women had disturbed fatty acid metabolism?

I have literally just written to my GP to ask if I could have a blood test done re Fatty Acid Oxidation Disorder for Carnitine,(Acylcarnitine profile) because when I was at my worst with ME (shortly after having whooping cough but had already been diagnosed with ME at that point), I had a Carnitine blood test which according to Dr Myhill was the lowest score she had ever recorded in anyone. Since then, I retested 4 years on and it did rise, (without Carnitine supplements as taking by gut caused me severe pain), but was still under the range.
I did think that I possibly have a genetic disorder as I had some issues as a young child which indicate to me now that maybe a Fatty Acid disorder was behind them but interesting to see this as part of the study.

 

[Esther12]

Yes, it's curious, but if this is some inappropriate reaction being switched on, which is the proposal, I'm a bit surprised it hasn't been seen in higher organisms. Of course, it being so hidden might be why mecfs has been so hard to crack. But it also suggests that dauer has survided through hundreds of millions of years of evolution since we split from our nematode friends, unused but functioning - and that itself might be a bit surprising.

If 0.5% of other species sometimes ended up with symptoms like CFS, would we even have noticed? I don't know how much attention we pay to unusual symptoms/behavior in small numbers of animals.

 

[Nielk]

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?

 

[Simon]

If 0.5% of other species sometimes ended up with symptoms like CFS, would we even have noticed? I don't know how much attention we pay to unusual symptoms/behavior in small numbers of animals.

Dauer in worms is quite dramatic so we might have seen it in other animals, or humans given that hypometabolomic states generally have been studied. As I said, it might just never have been seen - maybe for the reasons you mention, but the sheer distance between us and the only known example bugs me a bit - I think it deserves further explanation.

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?

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").

 

[Valentijn]

So they looked at a load of hypometabolomic states, but only picked out dauer, only referenced in worms, as comparable to what's happening in this study. Which is very interesting, but would be even more so with examples a bit closer to us on the evolutionary tree.

They might have chosen the nematodes as an example due to the dauer state being extremely well researched in them on the cellular level. Whereas with hibernation and other states, most information is regarding the behavioral changes.

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).

Yes, it's curious, but if this is some inappropriate reaction being switched on, which is the proposal, I'm a bit surprised it hasn't been seen in higher organisms.

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.

There is also a great deal of variety in the human genes in the immune system, in regard to responding to different infections, and those mutations are usually beneficial in some situations and detrimental in others. Hence it may be that ME patients have a somewhat rare genetic mutation which is beneficial in some situations, while causing problems in other situations.

But it also suggests that dauer has survided through hundreds of millions of years of evolution since we split from our nematode friends, unused but functioning - and that itself might be a bit surprising.

Regarding the pathway involved in the dauer state:

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.[6] DAF-2 is the only member of the insulin receptor family in C. elegans [a nematode] but it corresponds, in form and function, to multiple pathways in humans. The protein predicted from DAF-2's sequence is 35% identical to the human insulin receptor, which regulates metabolism; 34% identical to the IGF-1 receptor, which regulates growth; and 33% identical to the human insulin receptor–related receptor.[7][8] In C. elegans, the insulin/IGF-1/FOXO pathway is initiated by changes in IGF-1 levels which cause IGF-1 receptors to start a phosphorylation cascade that deactivates the FOXO transcription factor, DAF-16. When not phosphorylated, DAF-16 is active and present in the nucleus. DAF-16 is responsible for up-regulating transcription of about 100 genes that code for cell protecting products such as heat shock proteins and antioxidants.[9] Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.[10] By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.[6] In most eukaryotes, insulin activates DAF-2 signaling. However, both human insulin and insulin coded for by orthologous genes in C. elegans inhibit DAF-2 receptors in C. elegans.[11]