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

nandixon

nandixon

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One of the more interesting things I found while researching sphingosine-1-phosphate (S1P) is a great explanation for why many people with ME/CFS seem to become sensitive to the effects of alcohol (at least judging from the poll here).

In two early references, from 2003 and 2004:

Sphingosine-1-phosphate stimulates cortisol secretion

Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion

The authors found that in order for S1P to stimulate cortisol and aldosterone secretion, that it must first activate a critical enzyme called phospholipase D (PLD) which makes phosphatidic acid (PA).

Alcohol (ethanol) reduces the levels of PA by reacting with PA to form a phosphatidylalcohol (a reaction which PLD itself actually catalyzes).

If S1P signaling is already impaired (e.g., due to low levels or autoantibodies against its receptors) then this additional interference with PLD by alcohol is likely to be problematic for properly making cortisol and aldosterone.

Also, just a note here about the potential importance of S1P and aldosterone from the second reference above:
Secretion of aldosterone is critical for the transport of Na+, K+, and water in the organism; therefore, this novel action of S1P places it as a central metabolite for controlling fluid and electrolyte balance and blood pressure homeostasis.
Click to expand...
 
deleder2k

deleder2k

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@nandixon, thank you so much. It looks great. I don't understand much of it, but I am sure they'll reply. You can also send the e-mail to dr. Mella.


Some are sensitive to alcohol, but why do I almost feel 100% recovered when drinking a lot of alcohol? Less dizzy, lactic acid is gone, significantly reduced pain, less cracking in my joints. It looks like alcohol effects all my symptoms. Haukeland says that some can't drink alcohol at all. A glass of wine is enough to make them feel poisoned. I need to drink a bottle of wine to feel better. A few years ago, when my ME wasn't that bad 2-3 glasses of wine improved my symptoms. Now I need more to get the same effect.

I do suffer from some sort of endothelial dysfunction. I am also 99% certain that my flow-mediated dilatation test will show reduced blood flow under stress.
 
A

ash0787

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I started to wonder how one maintains a sterile uncontaminated environment for these experiments,
if what you are looking at is a single cell then any of the bacteria from your skin or the air could easily outweigh
the thing you are trying to measure, they must have standard practices for it, possibly helped a lot by machinery
but it must add a lot to the cost of performing the experiments and how long it takes compared to a typical chemical test on the macro scale.
 
nandixon

nandixon

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deleder2k said:
Some are sensitive to alcohol, but why do I almost feel 100% recovered when drinking a lot of alcohol? Less dizzy, lactic acid is gone, significantly reduced pain, less cracking in my joints. It looks like alcohol effects all my symptoms. Haukeland says that some can't drink alcohol at all. A glass of wine is enough to make them feel poisoned. I need to drink a bottle of wine to feel better. A few years ago, when my ME wasn't that bad 2-3 glasses of wine improved my symptoms. Now I need more to get the same effect.
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That's very interesting. I'm not sure, but have you seen this study from 2013? I'm not sure it's applicable and it's just a small study so not sure how well it can be trusted, but under their theory apparently some people can derive extra energy from the acetate that alcohol is converted into:

Increased brain uptake and oxidation of acetate in heavy drinkers

There are also a couple of layperson articles on that study:

Heavy alcohol consumption gives brain extra energy: study

Heavy drinkers get extra brain fuel from alcohol

I didn't check to see if there is newer research on this.
 
Sing

Sing

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nandixon said:
One of the more interesting things I found while researching sphingosine-1-phosphate (S1P) is a great explanation for why many people with ME/CFS seem to become sensitive to the effects of alcohol (at least judging from the poll here).

In two early references, from 2003 and 2004:

Sphingosine-1-phosphate stimulates cortisol secretion

Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion

The authors found that in order for S1P to stimulate cortisol and aldosterone secretion, that it must first activate a critical enzyme called phospholipase D (PLD) which makes phosphatidic acid (PA).

Alcohol (ethanol) reduces the levels of PA by reacting with PA to form a phosphatidylalcohol (a reaction which PLD itself actually catalyzes).

If S1P signaling is already impaired (e.g., due to low levels or autoantibodies against its receptors) then this additional interference with PLD by alcohol is likely to be problematic for properly making cortisol and aldosterone.

Also, just a note here about the potential importance of S1P and aldosterone from the second reference above:
Click to expand...

Does S1P also stimulate adrenaline secretion--meaning all the adrenal hormones?

I expect it would from my own experience. 20 years ago when my illness progressed to a disabling level, I lost a normal capacity for fight or flight and instead would go into a feeling of exhaustion. I also had PEM and started into very frequent thirst and way excessive urination. I also had serious cognitive and memory problems.

But 15 years before that I had lost a normal tolerance for alcohol down to zero tolerance, and developed continual insomnia problems, muscle aching and a tendency to pick up infections very easily. My mind still worked though and ! still seemed to have normal adrenal function during that earlier period.

I was one of the people with a gradual, somewhat "staged" onset of ME/CFS. Now I have even a wider variety of serious symptoms than I've mentioned. It seems to me that whatever is the "wrench that got thrown into the works", it causes worsening and widening symptoms over time, as one deficiency or imbalance causes more. The old idea that ME/CFS is not progressive has not been my experience.
 
Murph

Murph

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Following on from comments about alcohol above, I've had some thoughts about why I have a problem with it.

I feel okay sometimes drinking it but afterwards it gives me PEM, just like exercise, and with about the same time delay. Furthermore, the problems seemed to multiple: Alcohol+activity is especially bad for me, even with a day of rest in the middle. At one point I developed the following theory (which I wrote up at the time and have copied below):

Everything that made me get PEM was also a known cause of vasodilation: alcohol, stress and exercise. This also served to back-up my fear of hot water - I have a vivid memory of a relaxing onsen that, to my utter surprise, made me go straight to PEM town.

I began to believe what was happening was my veins were getting baggy and saggy from vasodilation, then, presumably, not springing back. In response, my immune system was calling in a full shut down in a desperate attempt to prevent me doing more exercise, and to maintain homeostasis. It was a simple theory but one that explained everything I was feeling.

In that context, I was excited to hear about Fluge and Mella's nitric oxide patent. But I came away disappointed. They patented something that *causes* vasodilation. That would be no good to me, I concluded.

Time passed. I tried eating different things. Saw various medical professionals. Added and subtracted supplements.

Eventually I came back to the topic and began doing yet more research on vasodilation and vasconstriction. There has been rather a large amount written about CFS and nitric oxide (NO).

What slowly became clear to me was that endothelial cells, in charge of regulating vasoconstriction and vasodilation, release nitric oxide in response to feeling stress in the blood vessel. As blood flow speeds up turbulence increases, and in response they release NO to relax the blood vessel.

Or at least they should.

I began to wonder: what would happen if in my body, the ability of these cells to react was for some reason broken? What if I was never getting actual vasodilation in response to these theoretically vasodilatory activities like exercise? What if my veins were never getting loose and relaxed at all?

How would the endothelium react if it tried to make and release NO in response to the stress, and still couldn't make the stress go away? The question may be important, because endothelial cells are a major part of the immune system, and play a role in regulating the metabolism.

If they feel constant stress that they can't alleviate, might they trigger an immune response? Could they even send signalling molecules that trigger a hypometabolic state? There is not yet evidence that they do... But no evidence that they couldn't, either... The body uses arginine to make NO. Naviaux found arginine levels were increased in the bodies of CFS patients compared to controls. Perhaps a compensatory mechanism? It was not clear.

--

Anyway, I tried taking arginine to see if I could make more NO and solve my problems. Didn't seem to do anything much. The above is speculation based on snippets of evidence really, so I'm not too surprised.

I'm interested in hearing whether other people experience 'problems with alcohol' in the same way, i.e. as a direct cause of PEM.
 
deleder2k

deleder2k

Senior Member
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1,129
nandixon said:
That's very interesting. I'm not sure, but have you seen this study from 2013? I'm not sure it's applicable and it's just a small study so not sure how well it can be trusted, but under their theory apparently some people can derive extra energy from the acetate that alcohol is converted into:

Increased brain uptake and oxidation of acetate in heavy drinkers

There are also a couple of layperson articles on that study:

Heavy alcohol consumption gives brain extra energy: study

Heavy drinkers get extra brain fuel from alcohol

I didn't check to see if there is newer research on this.
Click to expand...


Thanks I'll look into it. Haukeland is aware that some say they improve drastically after alcohol intake. As far as I know they are working on some gene analysis' with regards to this in the lab.


Mechanisms of alcohol-induced suppression of B-cell response.


I was noticed of this, but it doesn't seem to explain why I feel better within an hour or two. It think it has something to do with FMD...

@Murph, how much l-arginine did you take? Did you combine it with citrulline?
 
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Jonathan Edwards

Jonathan Edwards

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Sasha said:
@Jonathan Edwards - do you think that researchers are aware that a possible reason for some studies not replicating might be this issue (which I don't trust myself to summarise)? I wonder if it's worth a bit of a re-review of past work.
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I actually think it is the first thing any serious researcher would think of - so I do not think we need to worry it is being missed.
 
eljefe19

eljefe19

Senior Member
Messages
483
deleder2k said:
Thanks I'll look into it. Haukeland is aware that some say they improve drastically after alcohol intake. As far as I know they are working on some gene analysis' with regards to this in the lab.


Mechanisms of alcohol-induced suppression of B-cell response.


I was noticed of this, but it doesn't seem to explain why I feel better within an hour or two. It think it has something to do with FMD...

@Murph, how much l-arginine did you take? Did you combine it with citrulline?
Click to expand...

I'm my early days of illness I could drink heavily but now cannot handle more than 1-2 drinks. I have never considered supplemental alcohol lol but may after reading this.
 
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