Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Bdeep86]

Interesting, I was always an angry child and had a ton of emotional trauma and stress before getting sick. I wouldn't be surprised if there was a connection in early sickness.

There is a strong connection, it is much more profound then you may realize. It has been demonstrated repeatedly that people who experience early life trauma and emotional issues are much more likely to develop disease later in life. Interestingly in TCM they feel that these emotions are held in the liver. Of course high cortisol is shown to cause fatty liver, essentially I believe people whom suffer from CFS all have a certain degree of fatty liver.

 

[eljefe19]

Can fatty liver be tested for?

 

[Bdeep86]

Can fatty liver be tested for?

The liver dysfunction that I feel is taking place is very difficult to test directly for. You have lots of other markers for this dysfunction of the liver like anemia, low ceruloplasmin, low glutathione...ect. The quickest way is to get an ultrasound. The liver is wildly complex. It controls so much of our body and brain activities. Even slight abnormalities can cause profound impact.

 

[Chocolove]

@alex3619 Small amounts of oxaloacetate have been shown to greatly improve mitochondrial functioning in the brain by enhancing the functionality of the pyruvate dehydrogenase enzyme by up to 300%.
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1988.tb02966.x/abstract

In studies, acute oxaloacetate exposure enhances resistance to fatigue by increasing NAD to NADH conversion and allowing lactic acid to get recycled and converted to glucose at a much higher rate
Nogueira, L., Hogan, D., & Hogan, M. (n.d.). Acute oxaloacetate exposure enhances resistance to fatigue in in vitro mouse soleus muscle. (2011). The FASEB Journel, (25), 1104.5.

 

[Snow Leopard]

There is a strong connection, it is much more profound then you may realize. It has been demonstrated repeatedly that people who experience early life trauma and emotional issues are much more likely to develop disease later in life. Interestingly in TCM they feel that these emotions are held in the liver. Of course high cortisol is shown to cause fatty liver, essentially I believe people whom suffer from CFS all have a certain degree of fatty liver.

It has not been demonstrated "repeatedly" with high quality prospective studies.

Almost all of the studies I have been of low quality - either retrospective studies, which have notorious biases or were low quality design (eg if the evidence is entirely based on self report questionnaire(s) with fairly nonspecific questions is not useful specific/enough).

If you have any strong evidence on the contrary, then please provide a link.

 

[Bdeep86]

It has not been demonstrated "repeatedly" with high quality prospective studies.

Almost all of the studies I have been of low quality - either retrospective studies, which have notorious biases or were low quality design (eg if the evidence is entirely based on self report questionnaire(s) with fairly nonspecific questions is not useful specific/enough).

If you have any strong evidence on the contrary, then please provide a link.

You are not comfortable with the notion that early life stresses can predispose you to illness? If I recall correctly the studies I had looked at were done in the context of cancer development and some in the development of Diabetes. I am fine with the notion of prolonged stress in early life events causes issues down the road. If you do not feel comfortable with this notion or do not except the studies than we will have to disagree. It was a simple side note and I am only trying to help.

 

[Snow Leopard]

You are not comfortable with the notion that early life stresses can predispose you to illness? If I recall correctly the studies I had looked at were done in the context of cancer development and some in the development of Diabetes. I am fine with the notion of prolonged stress in early life events causes issues down the road. If you do not feel comfortable with this notion or do not except the studies than we will have to disagree. It was a simple side note and I am only trying to help.

I'm not saying there isn't a possible association, I'm saying there is a lack of evidence to know the strength of the association and what mediates it.

I'm also saying I need to see strong evidence before I'm willing to believe something. Specifically, I mean prospective studies that measure biological markers that predict later illness development, alongside any psychological and social factors.

When you've read thousands of studies in multiple fields, you no longer believe something just because there was a statistical association* found in a single published study or two.

*(such findings usually have poor sensitivity and/or sensitivity, meaning much deeper evidence is needed to demonstrate causation)

 

[Bdeep86]

I'm not saying there isn't a possible association, I'm saying there is a lack of evidence to know the strength of the association and what mediates it.

I'm also saying I need to see strong evidence before I'm willing to believe something. Specifically, I mean prospective studies that measure biological markers that predict later illness development, alongside any psychological and social factors.

When you've read thousands of studies in multiple fields, you no longer believe something just because there was a statistical association* found in a single published study or two.

*(such findings usually have poor sensitivity and/or sensitivity, meaning much deeper evidence is needed to demonstrate causation)

Fair point, I suppose its been some time since I have looked at them. I guess I was very comfortable with accepting this at the time as it is something I have seen often in people who suffer from CFS. When you look at prolonged elevation of stress hormones and their influence on epigenetic expression I suppose that also allowed me to believe that concept easier.

 

[Snow Leopard]

Fair point, I suppose its been some time since I have looked at them. I guess I was very comfortable with accepting this at the time as it is something I have seen often in people who suffer from CFS. When you look at prolonged elevation of stress hormones and their influence on epigenetic expression I suppose that also allowed me to believe that concept easier.

Prolonged elevation of stress hormones prior to most illnesses hasn't been demonstrated in prospective trials (eg measured at multiple time points.. correct me if I'm wrong). Secondly, measuring cortisol on its own is not sufficient and is usually a sign of a junk/speculative study if that is all they bothered to measure biologically.

Lastly, I believe the equivocal cortisol findings (eg flattened cortisol awakening curve, and slightly low cortisol in a minority of patients) is almost entirely due to altered sleep-wake rhythms and reduced metabolic* demands due to lower levels of intensive activity compared to healthy people. There is no meaningful HPA dysfunction in most patients, perhaps with an exception of a minority that may have Addison's Disease-like pathology.

*Cortisol is first and foremost a metabolic hormone, rather than a "stress hormone".

 

[Bdeep86]

Prolonged elevation of stress hormones prior to most illnesses hasn't been demonstrated in prospective trials (eg measured at multiple time points.. correct me if I'm wrong). Secondly, measuring cortisol on its own is not sufficient and is usually a sign of a junk/speculative study if that is all they bothered to measure biologically.

Lastly, I believe the equivocal cortisol findings (eg flattened cortisol awakening curve, and slightly low cortisol in a minority of patients) is almost entirely due to altered sleep-wake rhythms and reduced metabolic* demands due to lower levels of intensive activity compared to healthy people. There is no meaningful HPA dysfunction in most patients, perhaps with an exception of a minority that may have Addison's Disease-like pathology.

*Cortisol is first and foremost a metabolic hormone, rather than a "stress hormone".

Have you ever investigated PPAR signaling in regards to circadian rhythm and energy metabolism?

 

[FMMM1]

[QUOTE="It is not a potential diagnostic test because the findings are not sensitive enough.[/QUOTE]

Thanks snow leopard.

I found the mRNA data for "PDK1 (P = 0.002)" [Figure 3, A] but not the data for the enzyme. The data for the controls and people with ME/CFS overlap; the P value reflects the difference between the groups not individuals. Therefore, the data does not indicate that measuring the mRNA level can be used to diagnose individuals.

Fluge et al used the Canadian consensus criteria to select participants.

Yamano et al stated in their paper (2016 Oct 11) that "These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma". I.e. a mass spectrometry test, based on the measurement of TCA and urea cycles markers, could be used as a diagnostic test.

What about testing the the mRNA PDK1/PDK1 enzyme levels in people with ME/CFS who have dysfunction of TCA and urea cycles (Yamano et al) rather than using the Canadian consensus criteria (Fluge et al). Would the mRNA/enzyme levels then be sufficient to separate all of the people with ME/CFS from the controls?

What's the advantage of mRNA based diagnostic testing compared to mass spectrometry (Yamano et al). Mass spectrometry based testing is deliverable. £200 per sample is what the Government laboratories get here in the United Kingdom (FERA & AFBI labs.) but I haven't been able to get support for testing people as well as the food samples they currently test; something readers may wish to raise with your elected representative (MP/MEP etc) and the All-Party Parliamentary Group on ME. I've heard of laboratories running approximately 70-80 mass spectrometers for a single test (24 hours a day -- 365 per year) so it can be up scaled. However, mRNA based testing would appear to be easier to up scale; not clear that we're there yet i.e. with mRNA testing. Any news re Griffiths University groups work on a miRNA test?

The signalling compound (or whatever it is) in plasma from people with ME/CFS, which turned the muscle cells from health people into ME/CFS muscle cells - now that would be a discovery.

 

[paolo]

I took my first sodium dichloroacetate 200 mg oral dose yesterday. It seemed to make me sleepy for a few hours (increased fatigue is apparently one of the side effects of DCA), rather than boosting energy.

Then today I noticed I felt a bit depressed (another side effect of DCA). But I did not feel depressed yesterday while taking DCA, so this depression could just be a coincidence (since I get depression which comes and goes).

I am not going to take any DCA today, but may try again tomorrow, perhaps with 300 mg.

Hi @Hip,

any news from your one-man trial with DCA?

 

[Hip]

any news from your one-man trial with DCA?

Unfortunately either the DCA or the interferon suppositories (more likely) that I just started taking last week triggered a bout of neurologically-caused depression (which I often suffer from anyway), and I am trying to get over this before trying any more DCA. I don't like to test new drugs or supplements when I am in any way feeling less healthy than normal, just as a precaution.

Someone I know who's been trying DCA over the last few days has seen no positive effects so far on her ME/CFS.

 

[paolo]

@Hip I am sorry for your depression. Take care.

Thank you for the update. Very kind, as always.

 

[JES]

Regarding DCA dosage and side effects, this website has some interesting information, which suggests that DCA works better with vitamin B1 and caffeinated tea. I will probably order as well and experiment with it soon.

 

[eljefe19]

Regarding DCA dosage and side effects, this website has some interesting information, which suggests that DCA works better with vitamin B1 and caffeinated tea. I will probably order as well and experiment with it soon.

My DCA is on the way and I will be experimenting on myself as well.

 

[Sidereal]

I wouldn't take DCA without allithiamine or sulbutiamine, personally. I think the risk of nerve damage is too great. In this study (coauthored by Naviaux) they used regular thiamine (which is totally useless in my experience) and the results were not good:

Muscle Nerve. 2001 Jul;24(7):916-24.
Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate.
Spruijt L1, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH, Barshop BA.
Author information

Abstract
Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment.

https://www.ncbi.nlm.nih.gov/pubmed/11410919

 

[JES]

Thanks for the warning. That is a massive dosage of DCA though, around 4 g per day for me, which is AFAIK what they use for cancer. It's anyway impractical/costly to supplement at this dosage long term. I'll start with a much lower dosage and see if it has any effects, which should eliminate the risk of nerve damage.

 

[Bdeep86]

That's the first seeming inconsistency I've seen in the many dozens of papers I've read related to the hypothesis in my signature.

I noticed the same effect years later from the antibiotic Xifaxin (rifaximin), which supposedly has negligible systemic absorption and only acts in the gastrointestinal tract, suggesting that both it and AZM might be having a beneficial effect on the gut microbiome. Not sure though, of course.

It may have been inhibiting bacteria which causes too much de-conjugation of bile acids which would increase Tauro-Beta-Muricholic Acid. This acting as an FXR antagonist would allow normal function and bile circulation to resume in the liver. I think this is what is happening in CFS and that positive effects from antibiotics are due to adjustments in the gut.

 

[nandixon]

It may have been inhibiting bacteria which causes too much de-conjugation of bile acids which would increase Tauro-Beta-Muricholic Acid. This acting as an FXR antagonist would allow normal function and bile circulation to resume in the liver. I think this is what is happening in CFS and that positive effects from antibiotics are due to adjustments in the gut.

@Bdeep86 I think your very interesting idea may be based on this study. Note that tauro-beta-muricholic acid is a conjugated bile acid found primarily in mice and rats, and humans would seemingly only have very low levels of this that could potentially be increased from antibiotic treatment. ["Humans synthesize cholic acid (CA) and chenodeoxycholic acid (CDCA), whereas mice synthesize CA and β-muricholic acid (βMCA) (Russell, 2003)."]

So I'm not sure how much of an effect that increasing any endogenous tauro-βMCA might have, although that compound does have a fairly potent IC50 of 40 microM as a farnesoid X receptor (FXR) antagonist.

There are two very interesting additional things that I found from researching your idea, though:

The first, which is related to the hypothesis in my signature, is that there is a sphingosine-1-phosphate (S1P) receptor, S1PR2, in liver cells that is not only activated by S1P but also by conjugated bile acids including, for example, tauroursodeoxycholic acid (TUDCA). Reference - this is a mouse study but the authors believe it applies to humans:

Conjugates of UDCA have been shown to activate the ERK1/2 and AKT signaling pathways in primary hepatocytes in culture (36, 37). The current data suggest that activation of these signaling pathways by TUDCA may be via the S1P2 [aka S1PR2] in primary hepatocytes (Fig. 4).

So the favorable antibiotic effect sometimes seen in ME/CFS, assuming it's due to an increase in conjugated bile acids, might actually potentially be due to increased agonism of the S1PR2 receptor.

Either S1PR2 agonism or FXR antagonism might theoretically increase mTORC1 activity and seemingly be favorable for the PDH complex impairment Fluge & Mella found.

However, the second thing I came across is that FXR appears to be very intimately involved with the production of ceramides. (See, for example, reference #1 and reference #2.) (Note: The second reference also mentions the use of caffeic acid phenethyl ester (CAPE), which might be a potential alternative to antibiotics for increasing levels of conjugated bile acids since it inhibits bacterial de-conjugation.)

Using FXR antagonists (or increasing their endogenous levels) would actually lower ceramide levels, and these have already been found to be low in ME/CFS in the Naviaux study. So this would not seem compatible and not appear to be a good idea at first glance - unless the low ceramide levels are actually a favorable adaptation in ME/CFS.

Lastly, I haven't looked at it closely, but there is at least one interdependent relationship that has been found between FXR and S1PR2, and in this case activating FXR decreased the expression of S1PR2. (Reference) I'm not sure how applicable this particular situation is to ME/CFS, though.

In sum, I'm not sure whether antagonism of FXR would be a good thing or not, I'm guessing not but who knows. In any event, I don't believe it would be occurring due to endogenous tauro-βMCA because this bile acid is probably not found in humans in large enough amounts to affect FXR. On the other hand, I suspect your idea about inhibition of bacterial de-conjugation being behind the favorable response to antibiotics seen in ME/CFS is probably correct.