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ME/CFS researcher Derya Unutmaz's hypothesis on cause of ME/CFS....

ljimbo423

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@ljimbo423 Just curious to know. What supplements do you take for your liver ? I am unable to tolerate silymarin or milk thistle the natural form. Any idea why ?
I don't know why you can't tolerate milk thistle. My first guess would be from it mobilizing toxins in the liver.

I take many supplements for my liver, dandelion root, curcumin, N-acetly-cysteine, Alpha lipoic acid, Trimethylglycine. Anything that increases Glutathione will help the liver process toxins.

Maybe one of these supplements will work in a different way than the milk thistle, so you don't get side effects from it.
 

debored13

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Here are some quotes from Ray Peat and selected studies about endotoxins.

http://www.functionalps.com/blog/2011/11/20/endotoxin-and-liver-health/

Of interest is:

"The liver serves as the key organ for the removal and detoxification of bacterial endotoxins that are continously absorbed in small amounts from the gastrointestinal tract. This paper postulates that liver injury impairs this detoxification process leading to further liver damage and systemic effects as well. Evidence is reviewed to support the contention that endotoxin may be a major common pathway for liver injury by a variety of agents, and methods of reducing endotoxicity of gut origin are proposed"

It's also interesting that endotoxins can interfere with glucose metabolism:

"These findings are consistent with down regulation of carbohydrate oxidation following LPS administration, which, based on the present data, may be due to PDC inactivation as a consequence of a rapid and marked increase in PDK4 mRNA and presumably protein expression."

http://www.physoc.org/proceedings/abstract/J Physiol 565PC99

So it seems that endotoxins stimulate the transcription of the enzyme that breaks down Pyruvate Dehydrogenase (PDK) and impair glucose oxidation.

If we assume that ME/CFS is a perpetual state of low-grade sepsis, PDH would appear to be inhibited in ME Blood studies, which it does!

The evidence keeps piling up...
If CFS was similar to low grade sepsis, that would explain why saline and thiamine have been shown to help
 

FMMM1

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If CFS was similar to low grade sepsis, that would explain why saline and thiamine have been shown to help
One of the authors of the above study is "Greenhaff, P L" from the University of Nottingham. Ron Tompkins OMF is planning to work with Paul Greenhaff, and Philip Atherton, from the University of Nottingham. Check out Ron's talk it starts at 4:55:32 [https://livestream.com/accounts/1973198/ME-CFS-2018/videos/180981460].

Your post also reminds me of Fluge's, and Mella's, paper "Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome". Here are two extracts from that paper:
1) The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes.
2) According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms.

So the "secondary rescue mechanisms" in ME/CFS, i.e. switch from producing cellular energy/ATP from glucose to amino acids, could be due to leaky gut [i.e. LPS entering the blood]. What causes/cures leaky gut -- you acquire ME/CFS --- can it be reversed?

LPS entering the bloodstream would (I assume) account for the effect on the immune cells, in the gut lining, observed by Unutmaz.

If you search for something like "Sirtuin pdk" you'll find a whole bunch of stuff that looks familiar; here's one random extract:
"Mitochondrial Sirtuin 4 Resolves Immune Tolerance in Monocytes by Rebalancing Glycolysis and Glucose Oxidation Homeostasis" [https://www.ncbi.nlm.nih.gov/pubmed/29593712].

Here's a potential blood based diagnostic test which measures the intracellular levels of phenylalanine it's one of the amino acids used for cellular energy/ATP production in ME/CFS [check out Fluge & Mella's paper] i.e. as an alternative to glucose:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

I've been trying to influence decision makers i.e. to try to get funding to develop a diagnostic test [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1003111]. Feel free to join in i.e. contact your elected representative and ask for funding for research and the development of a diagnostic test.
@Murph
 
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S-VV

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Indeed, LPS are a problem. D-lactic acid is another. Ammonia could be added to the list as well. The list of potentially harmful metabolites produced by the microbiome is quite extensive. Is leaky gut in the mechanical sense a problem for CFS? To an extent, but I don't think its the core issue. Rather, dysbiosis triggering inflammation, which in turn leads to increased uptake of LPS et al seems a more likely scenario.

Evidence for this are the anecdotal reports of people with ME/CFS taking antibiotics. They reverse symptoms in a matter of 24-48 hours. This is not enough time to kill pathogens, but enough time to induce a profound microbiome shift.

On the other hand, there are also reports of long term antibiotic use being beneficial for ME/CFS and autoimmune conditions. For example the Jadin protocol for "occult" infections, or the successful *resolution* of early arthritis by a few years of minocycline:

https://www.healthline.com/health/rheumatoid-arthritis/minocycline#takeaway
 

FMMM1

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Indeed, LPS are a problem. D-lactic acid is another. Ammonia could be added to the list as well. The list of potentially harmful metabolites produced by the microbiome is quite extensive. Is leaky gut in the mechanical sense a problem for CFS? To an extent, but I don't think its the core issue. Rather, dysbiosis triggering inflammation, which in turn leads to increased uptake of LPS et al seems a more likely scenario.

Evidence for this are the anecdotal reports of people with ME/CFS taking antibiotics. They reverse symptoms in a matter of 24-48 hours. This is not enough time to kill pathogens, but enough time to induce a profound microbiome shift.

On the other hand, there are also reports of long term antibiotic use being beneficial for ME/CFS and autoimmune conditions. For example the Jadin protocol for "occult" infections, or the successful *resolution* of early arthritis by a few years of minocycline:

https://www.healthline.com/health/rheumatoid-arthritis/minocycline#takeaway
Chris Armstrong proposed that the gut dysbiosis (change to more pathogenic species) was caused by the change to using amino acids, rather than glucose, for cellular energy/ATP production - check out Chris's 2016(?) webinar for details.

Maureen Hanson's team demonstrated gut dysbiosis (change to more pathogenic species) and increased LPS in the bloodstream [Google "Hanson LPS ME/CFS" or something similar and you should find the paper/commentary]. Maureen's team are currently working with a Norwegian group on faecal transplants i.e. as a potential means of reversing gut dysbiosis.

It seems we either need to:
  • reverse the upstream cause i.e. if gut dysbiosis is a consequence [(Chris Armstrong etc or metabolic trap - Phair] @Murph; or
  • reverse the gut dysbiosis i.e. if gut dysbiosis is the cause or can assist in some way.


Some of the areas where there is a lack of clarity could be resolved by research.

Here's a potential blood based diagnostic test:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
It's based on the measurement of intracellular phenylalanine. Chris Armstrong, and Fluge and Mella, proposed that amino acids [including phenylalanine] were being used for cellular energy/ATP production in ME/CFS i.e. rather than the normal glucose.

I've written to the European Union Committee on the Environment, Public Health and Food Safety (ENVI) requesting that they lobby for funding for research into ME/CFS including the development of a diagnostic test [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1003111]. Why not contact your elected representative i.e. to request funding for research into ME/CFS including the development of a diagnostic test?
 
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