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

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Bdeep86

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@nandixon has brought up some great points. I originally started looking into this theory as an underactivation of FXR in the gut as the FXR activation relates to PPAR-a signaling in the liver which was my original focus. I found FXR through what I felt was dysfunctional PPAR-a signaling (I still believe this is happening but that its DNA binding capacity has been diminished by NF-Kappa-B p65). I suppose the sticking point to where I felt it could be overactivation was because of decreases bile synthesis is usually the result of activating the intestinal FXR receptor activation.

Both scenarios are plausible so I decided to change my theory to state that FXR dysfunction is taking place. Regardless, this phenomena is taking place because of what is going on around the receptors. I still maintain that this is an issue of liver-gut disharmony. That the communication from the intestines back to the liver has become dysfunctional and resulting in stagnant liver dysfunction. FXR under activation seems to fit in tighter with nandixon's viewpoint and I have no objection of this notion that underactivation could absolutely be happening. It doesn't really matter in my opinion because even this is a downstream effect and the therapies that I have in mind correct either issue.
 
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jump44

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Bdeep86 said:
Careful with those, depending on how severe your case and what is going on in your gut these could cause some issues. You need to support both at the same time.
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Is there a reason you say be careful with these? For me the bile acids caused severe nausea, but TUDCA has always treated me well.

Im currently taking enteragam as part of a multi therapy from my doctors and am thinking its helping. I was going to add Tudca back in soon.
 
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PDXhausted

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I have tried Ox bile previously, and it made me feel quite a bit worse, though it did help my sluggish gut to move things through. Would that indicate a particular pattern one way or another?
 
nandixon

nandixon

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Bdeep86 said:
FXR under activation seems to fit in tighter with nandixon's viewpoint and I have no objection of this notion that underactivation could absolutely be happening.
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I wanted to clarify for other people, that I'm just trying to investigate potential upstream causes for why the S1P signaling pathways seem to be impaired in ME/CFS. FXR is just one possibility because of how some people seem to improve or are made worse when the microbiome is modified in different ways by antibiotics, bile acids, foods, probiotics, etc.

But equally likely might be that the S1PR2 receptor (which is also in the intestinal tract and liver) is being dysregulated, because S1PR2 can also act as a bile acid receptor in addition to FXR. The difference is that S1PR2 is activated by conjugated bile acids (in addition to S1P) whereas FXR is activated by deconjugated bile acids. Note that those S1PR2 receptors, when activated, also activate the Akt/mTOR (mTORC1) pathway.

Bottom line: I'm trying to figure out now whether a low S1P problem could be caused by FXR, or simply exacerbated by S1PR2. (I'm hoping to apply some of the information I mentioned earlier here to help sort this out.)
 
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Bdeep86

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nandixon said:
I wanted to clarify for other people, that I'm just trying to investigate potential upstream causes for why the S1P signaling pathways seem to be impaired in ME/CFS. FXR is just one possibility because of how some people seem to improve or are made worse when the microbiome is modified in different ways by antibiotics, bile acids, foods, probiotics, etc.

But equally likely might be that the S1PR2 receptor (which is also in the intestinal tract and liver) is being dysregulated, because S1PR2 can also act as a bile acid receptor in addition to FXR. The difference is that S1PR2 is activated by conjugated bile acids (in addition to S1P) whereas FXR is activated by deconjugated bile acids. Note that those S1PR2 receptors, when activated, also activate the Akt/mTOR (mTORC1) pathway.

Bottom line: I'm trying to figure out now whether a low S1P problem could be caused by FXR, or simply exacerbated by S1PR2. (I'm hoping to apply some of the information I mentioned earlier here to help sort this out.)
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OK yes not to put words in your mouth. I was trying to point out where our two theories maybe overlapping. Will be interesting to see where the bile and liver interactions with this receptor take you. Have you ever supplemented with conjugated bile acids?
 
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Bdeep86

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278
jump44 said:
Is there a reason you say be careful with these? For me the bile acids caused severe nausea, but TUDCA has always treated me well.

Im currently taking enteragam as part of a multi therapy from my doctors and am thinking its helping. I was going to add Tudca back in soon.
Click to expand...

Add it in later in the day, start off using it every other day. You may need other gut support in place. TUDCA is one of the best agents for CFS so long as you can handle it.
 
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Bdeep86

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nandixon said:
Just TUDCA so far, using 250 mg after breakfast. I do notice some improvement in energy from that. I'll be trying some other bile acids later this week.
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How long have you been on it. Its actually best to take it later in the day towards dinner time.
 
nandixon

nandixon

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I previously posted, about a year and a half ago, that the drug that has helped me the most with my ME/CFS symptoms is cimetidine (available OTC in the US as Tagamet). (See this search string: http://forums.phoenixrising.me/index.php?search/34758570/&q=cimetidine&o=date&c[user][0]=6966)

It's been known for many years that cimetidine, which is usually thought of as an H2 histamine "blocker," decreases regulatory T cell (Treg) activity, i.e. relieves immunosuppression and is immunostimulatory, but the exact mechanism wasn't discovered until a few months ago, and I wasn't aware of this research until yesterday.

Remarkably, cimetidine degrades Treg activity by increasing the levels of a protein called STUB1 and as part of that process it activates the Akt/mTOR (mTORC1) pathway. (Reference)

So that fits exceptionally well with the impaired S1P signaling hypothesis, since S1P activates Akt (through S1PR receptors) by increasing the phosphorylation of that enzyme, and that's what cimetidine does as well.(!)

I found that only a narrow therapeutic window works with cimetidine (too much makes me worse) and that it is best taken twice a day roughly 12 hours apart. And this is perfectly consistent with what the researchers found to be optimal for the best effect from cimetidine in vitro in the study I referenced (in the full paper). I take only 1/4 tablet (= 50 mg) about 1 hour after breakfast and at least 2 hours after dinner to avoid interference with stomach acid secretion.

This confirms, for me anyway, that the Fluge & Mella results are likely explained by:

??--> Low ceramides--> Low S1P--> Impaired S1P signaling--> Under-activated Akt--> Under-activated mTORC1--> Increased PDKs & SIRT4--> Inhibited PDH complex

(Note that I know that cimetidine's effect for me is not related to any H2 histamine receptor activity because the other major H2 blockers, ranitidine and famotidine, either had no effect or made me worse.)
 
Murph

Murph

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nandixon said:
This confirms, for me anyway, that the Fluge & Mella results are likely explained by:

??--> Low ceramides--> Low S1P--> Impaired S1P signaling--> Under-activated Akt--> Under-activated mTORC1--> Increased PDKs & SIRT4--> Inhibited PDH complex
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I like this theory! It is clear and fits the evidence. The thoughts I have are:

1. (This is for me so I don't fall into the trap of thinking the answer is simple) The steps above are obviously a model, representing a linear path through a quite dimensional world of biochemistry. At each step, compensatory mechanisms will be in play, and feedback loops, that could be relevant.

here's a nice little map of Mtor activation from the paper 'mtor at a glance' (Laplante and Sabatini, 2009)

Screen Shot 2017-01-31 at 10.48.48 PM.png



2. I'm wondering if there is a bigger role for AMPK! It seems closely linked to MTORC, as this snippet from "mtor at a glance suggests"

"The energy status of the cell is signaled to mTORC1 through AMP-activated protein kinase (AMPK), a master sensor of intracellular energy status (reviewed by Hardie, 2007). In response to energy depletion (low ATP:ADP ratio), AMPK is activated and phosphorylates TSC2, which increases the GAP activity of TSC2 towards Rheb and reduces mTORC1 activation (Inoki et al., 2003). Additionally, AMPK can reduce mTORC1 activity in response to energy depletion by directly phosphorylating Raptor (Gwinn et al., 2008)."

and, furthermore, it has a range of very important roles in the body that seem extremely relevant. Here's a snippet of a paper on AMPK that hits so many MECFS buzzwords it seems like it can't not be involved!

"... its importance in many critical cellular processes is well established. For cells it is critical that energy supply and demand are closely matched. AMPK is recognized as a critical integrator of this balance. It is known to be allosterically activated by an increased AMP:ATP ratio. Activation of the kinase switches on catabolic pathways while switching off anabolic ones. It also acts as a redox sensor in endothelial cells where oxidative stress can disturb NO signaling. Abnormal NO signaling leads to disturbed vasodilatory responses..."
 
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