Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)
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nandixon
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The majority of people with ME/CFS do worse with alcohol after developing the disease. (See this poll, for example.) And I previously mentioned here one possibility for this which is related to S1P and phospholipase D (PLD).
Specifically with respect to acute alcohol ingestion, this is likely to be even worse for most people with ME/CFS and I personally wouldn't distinguish this. As far as your implication as to how a small subset of ME/CFS patients seem to benefit from this acute ingestion, I don't know.
With respect to FXR, since alcohol antagonizes this enzyme, and since inhibition of FXR leads to decreased synthesis of ceramides - from which S1P is made - then that seems consistent under a simplistic version of my model for alcohol making ME/CFS symptoms worse:
Inhibited FXR-->Low ceramides-->Low S1P/Impaired S1P signaling-->Under-activated Akt/mTORC1 pathway-->Impaired PDH complex (Fluge & Mella)
(It's getting too far off topic, but one research group in south Florida seems to be focused on how S1P can be useful with respect to protection or restoration of blood brain barrier (BBB) damage caused by alcohol, so the corollary for people with ME/CFS would be that not having enough S1P would make us more vulnerable to that damage. (E.g., reference.) So this might be an additional/alternative mechanism for the bad effects of alcohol in addition to what I mentioned about the PLD enzyme.)
Yes absolutely many do worse on alcohol as well. I view this again as a result of compromised liver function which went on to compromise gut function which is now feeding into each other. If the liver is already down and not functioning then administering alcohol would certainly make many cases worse. Especially when many peoples CYP450 system is out of whack and more alcohol gets through. However, even in this very thread, some have claimed to have a dramatic reduction in symptoms after alcohol consumption. It was just one of the biomarkers I had used.
Sing
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I wonder if people who drink a lot daily, especially older adults, have a similar lack of energy due to impaired PDH? My observation of such people is that they nap often. This may be due to hangovers and the body trying to detox but couldn't there also be a low energy state due to impaired PDH functioning?
nandixon
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Since conjugated bile acids might possibly be playing a helpful role in alleviating the symptoms of ME/CFS, one experiment perhaps to try is to see whether supplementing these in combination with a bacterial bile salt hydrolase (BSH) inhibitor might be helpful. The BSH inhibitor would slow the de-conjugation/degradation of those bile acids by the relevant bacteria (e.g., Lactobacillus species but also others) and give them a longer life in the intestinal tract. This might give a similar effect as an antibiotic but without the harsh effect on the microbiome.
Conjugated bile acids are the forms commonly sold as bile acid supplements. Taurocholic acid is the most abundant one in humans and is an activator of S1PR2. (Conjugation just means that the acid portion of the bile acid has been reacted with the amino portion of an amino acid like taurine or glycine to combine the two together as an amide.)
A couple of known BSH inhibitors are caffeic acid phenethyl ester (CAPE) and tempol (reference). Interestingly, riboflavin (vitamin B2) is a potent BSH inhibitor. (Reference)
The idea in simple terms:
Conjugated bile acids + BSH inhibitor = effect that antibiotics are having?
Well they definitely are contributing to sluggish liver function.
That is one route. Propolis has high amounts of CAPE. I have a few ideas on how to accomplish this. Certainly bile acid therapy will play a factor. Some have tried tempol and had mixed results I wonder if pairing this with a BSH inhibitor may provide better results. I bigger part of me feels that Propolis and riboflavin may not be strong enough.
I use propolis daily and if I take too much my belly hurts badly (around the spleen zone I think) and I get worse. But it is one of the best things I've found for Multiple Chemical Sensivity crisis.
Yes its a good supplement, it will help with this to some degree i'm just not sure it will be as profound as what would be needed to inhibit BSH to the level that you would need.
Fits in well with what I believe is happening. If you want there is another thread going with my theory i'm not sure how to link it, but if you want to discuss over there I would like to know more. I don't want to side track this thread too much.
That's what Ken Lassesen believes as well. Mitochondrial problems -- in his view -- come as a result of a microbiome shift.
https://cfsremission.com/2017/01/09/cfs-is-not-a-mitochondrial-dysfunction/
Yes that microbiome shift starts to alter liver function in my viewpoint. This is at the core of what is happening in CFS, it can get much more technical but as I put in my theory it starts a disharmony between the gut and liver.
Michelle
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Hope this isn't too off-topic, but I just wanted to make sure that Tunguska's post way up thread linking to a paper suggesting that opioids increase mTOR signalling didn't get lost in such a long thread given the substantial subgroup of us who find opioids improve functional capacity. Would think it would be of particular interest to @nandixon @Hip and maybe @Marco
To be sure, my biochem knowledge is far too limited to know if the mu opioid receptor pathway activating mTOR is relevant to S1P. Or if their methods are sound.
To be sure, my biochem knowledge is far too limited to know if the mu opioid receptor pathway activating mTOR is relevant to S1P. Or if their methods are sound.
Snow Leopard
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If only they'd criticise the psychological research with the same zeal! (double standards much?)
Hip
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Thanks for reminding us of @Tunguska's post, Michelle. The first time I saw Tunguska's post, I immediately thought of the opioids thread that you linked to, where as you say, many people reported that opioid pain killer drugs temporarily reduced their brain fog and other neurological symptoms. Opioid pain killer drugs usually work by agonising the mu-opioid receptor.
I also myself observed large improvements in brain fog after taking the potent mu-opioid agonist dermorphin (see this thread). Had it not been for the side effects triggered by dermorphin, it would have been a viable ME/CFS treatment for me.
So it seems that mu-opioid receptor agonism can activate mTOR. Another paper on this here:
Modulation of mTOR Activity by μ-Opioid Receptor is Dependent upon the Association of Receptor and FK506-Binding Protein 12
nandixon
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@Michelle Thanks, I'd forgotten to look to see if that fit with impaired S1P activity.
My own experience with opioids is that my most significant (but still only partial) remission from many years of ME/CFS came during a period when I had to use a fentanyl patch due to an arm injury.
For 8 months while using it, and another 3 months afterwards, I had much more energy and much less PEM. I couldn't fully enjoy that because of the pain but it was very apparent. (I went off the fentanyl with almost no tapering - a few days, so there was obviously no addiction present.)
Quickly looking at the literature, opioids (morphine) have been found to increase S1P levels or activity in multiple ways, at least in animal studies, so that does seem consistent. (Sample reference.)
Because there are not only many pathways leading to mTORC1, but also many more pathways and metabolic processes that use S1P, it will probably ultimately be best to address what's actually causing the low levels of S1P (if they are low, for example) as far upstream as possible, e.g., perhaps by fixing an inhibited/under-activated farnesoid X receptor (FXR) (this is one possible explanation for the low ceramides that Naviaux found in his study, and S1P is made from ceramides).
My own experience with opioids is that my most significant (but still only partial) remission from many years of ME/CFS came during a period when I had to use a fentanyl patch due to an arm injury.
For 8 months while using it, and another 3 months afterwards, I had much more energy and much less PEM. I couldn't fully enjoy that because of the pain but it was very apparent. (I went off the fentanyl with almost no tapering - a few days, so there was obviously no addiction present.)
Quickly looking at the literature, opioids (morphine) have been found to increase S1P levels or activity in multiple ways, at least in animal studies, so that does seem consistent. (Sample reference.)
Because there are not only many pathways leading to mTORC1, but also many more pathways and metabolic processes that use S1P, it will probably ultimately be best to address what's actually causing the low levels of S1P (if they are low, for example) as far upstream as possible, e.g., perhaps by fixing an inhibited/under-activated farnesoid X receptor (FXR) (this is one possible explanation for the low ceramides that Naviaux found in his study, and S1P is made from ceramides).
Hip
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You can actually buy phytoceramides (plant based ceramides) as a supplement. Perhaps this is worth experimenting with.
Oral phytoceramide supplements apparently can create younger looking skin.