A Metabolic Trap for ME/CFS?

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According to the metabolic trap theory, excess tryptophan is converted to serotonin and when serotonin level gets high, the body adjusts itself to high serotonin environment reducing serotonin receptor numbers to reduce sensitivity to serotonin.
Serotonin receptor abnormality is at the centre of irritable bowel syndrome.
https://www.ncbi.nlm.nih.gov/pubmed/24425100
Just as a quick aside question regarding the Serotonin issues - after 5 years of seriously severe bloating 24/7 my gastro finally found a pill that works to combat it - it's called Prucalopride. It's a high affinity serotonin (5-HT4) receptor agonist. It's supposed to be a last hope med for those with incurable constipation. It works wonders for my bloating, but I've noticed my energy levels getting worse since I started taking it, with crashes coming way more frequently and easily and my overall condition getting quite a bit worse. Does anyone know if this medicine would be contraindicated with the Serotonin hypothesis with ME/CFS?

Thanks in advance
 

Moof

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I've noticed my energy levels getting worse since I started taking it, with crashes coming way more frequently and easily and my overall condition getting quite a bit worse. Does anyone know if this medicine would be contraindicated with the Serotonin hypothesis with ME/CFS?
I can't answer for the serotonin hypothesis, but getting your bowel working uses up a surprising amount of energy. I only 'go' every few days, but on the day it happens, I'm good for nothing else! It could just be that; if it is, your body may adjust to it, given time.
 

nandixon

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@nandixon

very interesting! I had a Il6 dosage done years ago, and it was low.
Plasma/serum IL-6 levels don't appear to be useful in this context because, as the article on juvenile type 1 diabetes I cited mentioned, the degradation of IDO1 is influenced by IL-6 concentrations in the local microenvironment.

I had also made a related post on a different thread:

I made a post a couple of days ago related to an interesting possibility regarding the use of Actemra (tocilizumab) in ME/CFS:

https://forums.phoenixrising.me/ind...ic-trap-for-me-cfs.58606/page-18#post-1012430

One of the references I cite, a very well-funded study in juvenile type 1 diabetes, found that IL-6 cytokine levels have generally been found to be normal in that disease as well, yet the IL-6 axis is in fact most definitely dysregulated in that disease - due at least partly to overexpression of the IL-6 receptor, if I remember correctly - and tocilizumab is a treatment for a subset of those patients.

After reading that study I realized that many of the cytokine studies in ME/CFS may have been for naught, because not only might various cytokine levels appear normal while their axes are actually dysregulated but that cytokine levels in the local microenvironment of the cell may be higher or lower than what serum/plasma levels might show as well.

But I have another concern. According to this study IDO2 has an inhibition effect on IDO1, so I don't see a big impact on IDO2 deficiency, unless in some cells that may be more dependant on IDO2 than on IDO1.
Without reading the full text of the journal article (which I normally always do), the abstract for the study appears to be indicating that Dr Phair might have obtained the opposite results from what he did in the 6 patient tracer experiment because the abstract suggests that a non-functional IDO2 (presumed to be present in the patients) should lead to an increased catabolism of tryptophan. Phair found the opposite, so I can only assume the study isn't applicable (for which there might be many reasons) or that the effect described is offset in the patients.
 

pattismith

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Plasma/serum IL-6 levels don't appear to be useful in this context because, as the article on juvenile type 1 diabetes I cited mentioned, the degradation of IDO1 is influenced by IL-6 concentrations in the local microenvironment.

I had also made a related post on a different thread:

Without reading the full text of the journal article (which I normally always do), the abstract for the study appears to be indicating that Dr Phair might have obtained the opposite results from what he did in the 6 patient tracer experiment because the abstract suggests that a non-functional IDO2 (presumed to be present in the patients) should lead to an increased catabolism of tryptophan. Phair found the opposite, so I can only assume the study isn't applicable (for which there might be many reasons) or that the effect described is offset in the patients.
Thank you for your reply!

Apart from Tocilizumab, is there any other way to increase IL6?

Also, I would like to know if IDO2 polymorphism produces inactivation of the enzyme or decrease expression.

In the first case, I would like to know if this inability to metabolize tryptophan is associated with an equal inability to inactivate IDO1, which may or may not be the case.
 
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nandixon

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Apart from Tocilizumab, is there any other way to increase IL6?
We'd actually want the opposite. The idea behind the use of tocilizumab (Actemra) I mentioned here is to block the IL-6 receptor. This is in order to attempt to reduce the effects of the extra increase in IL-6 which it appears a non-functional IDO2 may cause during an immune activation process such as exposure to LPS or whatever might be driving ME/CFS. By reducing the effect of IL-6 (in the local microenvironment), that may increase the amount of IDO1 (by reducing its degradation) and thus improve the conversion of tryptophan to kynurenine (assuming the results Dr Phair found are not actually normal, as I mentioned previously).
 

pattismith

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We'd actually want the opposite. The idea behind the use of tocilizumab (Actemra) I mentioned here is to block the IL-6 receptor. This is in order to attempt to reduce the effects of the extra increase in IL-6 which it appears a non-functional IDO2 may cause during an immune activation process such as exposure to LPS or whatever might be driving ME/CFS. By reducing the effect of IL-6 (in the local microenvironment), that may increase the amount of IDO1 (by reducing its degradation) and thus improve the conversion of tryptophan to kynurenine (assuming the results Dr Phair found are not actually normal, as I mentioned previously).
Yes thank you, I meant to decrease IL6, sorry!

Tocilizumab is far from being soon available for ME/CFS, so i wondered.

I found some answers in selfhacked

https://www.selfhacked.com/blog/interleukin-6/
 

Belbyr

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I went digging through some older videos of Nancy Klimas's researcher, Dr Gordon Broderick and he spoke about phenylalanine in his computation models. I wonder if someone here can triangulate that to Ron Davis's trap theory???
It appears that these 2 research groups are digging around the HPA axis in a similar fashion.
 
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I went digging through some older videos of Nancy Klimas's researcher, Dr Gordon Broderick and he spoke about phenylalanine in his computation models. I wonder if someone here can triangulate that to Ron Davis's trap theory???
From 2011 PR blog. Quite amazing this was discussed in 2011 in an article about Gordon Broderick
Link : https://phoenixrising.me/archives/5396
A Metabolic Pathway Gone Awry in ME/CFS? Five pathways were particularly significant and he picked out phenylalanine metabolism as a pathway that may have awry in one group of CFS patients. Phenylalanine is a pretty nice fit because it’s a precursor for tyrosine, dopamine and the two big autonomic nervous system factors, norepinephrine and epinephrine.
From NOVA article
Link : https://www.nova.edu/nim/broderick-and-craddock-article-in-intl-innovation.pdf
Significantly down-regulated in the more severe cases and less so in patients who might be getting better, the phenylalanine pathway provides a signpost for distinguishing among post-infectious ME/CFS sufferers the level of care that needs to be delivered and when.
Presenting a completely different cohort to the ME/CFS study, Gulf War veterans suffering GWI ...... Looking primarily at the immune signalling and detoxification pathways, they were eventually able to achieve 90 per cent accuracy in distinguishing between the groups. As with the post-infectious ME/CFS patients, phenylalanine suppression was found to be the characteristic factor.
In 2012 and 2015 papers Armstrong et al also pointed out phenylalanine was decreased in the blood.
Link : https://minerva-access.unimelb.edu.au/bitstream/handle/11343/121955/2015 Armstrong Metabolomics CFS.pdf?sequence=5&isAllowed=y

However this year Karl Morten et al research paper indicated that phenylalanine levels were the result of mitochondrial dysfunction and were increased inside cells..
Link : https://pubs.rsc.org/en/Content/ArticleLanding/2018/AN/C8AN01437J#!divAbstract

So unclear how all this relates to the try-trap.........

P.S. It's a shame Dr Gordon Broderick has left NOVA about a year ago and is now at RIT. From the recent NOVA GWI funding press release it does seem he is still involved with modelling the disease though.
 
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Okay, I did find this. I'm not a boffin but it seems the presence of phenylalanine can reduce the transportation of Tryptophan into cells.
INDOLEAMINE 2,3-DIOXYGENASE INDUCES EXPRESSION OF A NOVEL TRYPTOPHAN TRANSPORTER IN MOUSE AND HUMAN TUMOR CELLS
Other than L-tryptophan, the only amino acid that had any detectable effect on tryptophan uptake in both IFN-?-treated and IDO transduced Hela cells was phenylalanine, which inhibited tryptophan uptake by over 50%.
Both phenylalanine and L-Dopa inhibited the glutamine-insensitive tryptophan flux in IDO positive cells, while tyrosine had little additional effect, suggesting that the induced tryptophan transporter has specificity for more hydrophobic, aromatic amino acids, although qualitatively the effect of tryptophan was of significantly higher affinity.
Could this mean conversely that if we have decreased phenylalanine in the blood as indicated by Broderick and Armstrong maybe more Tryptophan is transported into IDO positive cells? As I mentioned I'm not a boffin.......
 
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nandixon

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@wigglethemouse, I believe that study is talking about an amino acid transporter that is apparently only found in tumor cells and which seems to have much different properties than the conventional tryptophan transporter, System-L, they compare it to found in healthy cells.(I think other non-tumor-related tryptophan transporters have been found besides system-L, though.)
 

HTester

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Can anyone tell my naive thinking how the tryp trap fits in with gut symptoms? Please. As my gut is by far the worst area I have to suffer.
Theoretical specifics: As you know tryptophan is the precursor for both kynurenine and serotonin. We often think of serotonin as important in the brain, but it is also extremely important in the gut. Indeed, most of the serotonin in the body is actually in the gut. So if the gut cells making serotonin are in the trap, the gut's function will be impaired.

Predicting exactly how it will be impaired is complicated by the enzymology of the first enzyme in the pathway from Trp to serotonin. That enzyme is tryptophan hydroxylase and it has at least two isoforms, TPH1 and TPH2. The dogma is that TPH1 is the peripheral isoform and TPH2 is the brain isoform. So if the dogma is correct, then we'd expect serotonergic nerves in the midbrain to express TPH2 and serotonin-producing cells in the gut to express TPH1. This matters because TPH1 is reportedly substrate inhibited, just like IDO1, and TPH2 is not substrate inhibited.

So with all those reported results taken as facts, we'd predict too much serotonin in the brain and too little serotonin in the gut.
 

bertiedog

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Theoretical specifics: As you know tryptophan is the precursor for both kynurenine and serotonin. We often think of serotonin as important in the brain, but it is also extremely important in the gut. Indeed, most of the serotonin in the body is actually in the gut. So if the gut cells making serotonin are in the trap, the gut's function will be impaired.

Predicting exactly how it will be impaired is complicated by the enzymology of the first enzyme in the pathway from Trp to serotonin. That enzyme is tryptophan hydroxylase and it has at least two isoforms, TPH1 and TPH2. The dogma is that TPH1 is the peripheral isoform and TPH2 is the brain isoform. So if the dogma is correct, then we'd expect serotonergic nerves in the midbrain to express TPH2 and serotonin-producing cells in the gut to express TPH1. This matters because TPH1 is reportedly substrate inhibited, just like IDO1, and TPH2 is not substrate inhibited.

So with all those reported results taken as facts, we'd predict too much serotonin in the brain and too little serotonin in the gut.
Dr Phair thank you so much for researching our illness. I find it very interesting what you have written here because I think it is exactly what I experience and I also have many genetic changes in all of the genes you have mentioned, several of them I have homozygous mutations. My brain and my gut appear to cause most of my issues!

BTW you do have my data!

Pam
 

FMMM1

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From 2011 PR blog. Quite amazing this was discussed in 2011 in an article about Gordon Broderick
Link : https://phoenixrising.me/archives/5396


From NOVA article
Link : https://www.nova.edu/nim/broderick-and-craddock-article-in-intl-innovation.pdf



In 2012 and 2015 papers Armstrong et al also pointed out phenylalanine was decreased in the blood.
Link : https://minerva-access.unimelb.edu.au/bitstream/handle/11343/121955/2015 Armstrong Metabolomics CFS.pdf?sequence=5&isAllowed=y

However this year Karl Morten et al research paper indicated that phenylalanine levels were the result of mitochondrial dysfunction and were increased inside cells..
Link : https://pubs.rsc.org/en/Content/ArticleLanding/2018/AN/C8AN01437J#!divAbstract

So unclear how all this relates to the try-trap.........

P.S. It's a shame Dr Gordon Broderick has left NOVA about a year ago and is now at RIT. From the recent NOVA GWI funding press release it does seem he is still involved with modelling the disease though.
Only briefly glanced at your post.
Two papers to check out one by Chris Armstrong (2015 - probably one you refer to + 2015? Webinar) and the other by Fluge and Mella (December 2017?). Basically, as you are aware, these amino acids are being used for cellular energy production (even though glucose is available); I assume that is why the intracellular levels increase i.e. they're imported for energy production (and the plasma/blood levels decrease).
 

Belbyr

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Gordon Broderick seems to be very intelligent in his talks. I believe he is a Canadian resident. I would love for him and Dr. Phair to visit each other.
 

Hopeful1976

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Theoretical specifics: As you know tryptophan is the precursor for both kynurenine and serotonin. We often think of serotonin as important in the brain, but it is also extremely important in the gut. Indeed, most of the serotonin in the body is actually in the gut. So if the gut cells making serotonin are in the trap, the gut's function will be impaired.

Predicting exactly how it will be impaired is complicated by the enzymology of the first enzyme in the pathway from Trp to serotonin. That enzyme is tryptophan hydroxylase and it has at least two isoforms, TPH1 and TPH2. The dogma is that TPH1 is the peripheral isoform and TPH2 is the brain isoform. So if the dogma is correct, then we'd expect serotonergic nerves in the midbrain to express TPH2 and serotonin-producing cells in the gut to express TPH1. This matters because TPH1 is reportedly substrate inhibited, just like IDO1, and TPH2 is not substrate inhibited.

So with all those reported results taken as facts, we'd predict too much serotonin in the brain and too little serotonin in the gut.
I feel I have to write that I’ve had some success with Betaine Hcl with pepsin and my gut symptoms, and in consequence, my improved m.e symptoms (good gut = better m.e symptoms). I’ve read how gut acid has a lot of impact on histimine... strangely, a big effect of taking the hcl is I’m very wakeful at night; yet I feel better... there’s clues everywhere to this illness. I wanted to let you know this experience in case it resonated with anything else.. thank you for everything you are doing. It really does mean so much to us. More than people could ever know.
 
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Theoretical specifics: As you know tryptophan is the precursor for both kynurenine and serotonin. We often think of serotonin as important in the brain, but it is also extremely important in the gut. Indeed, most of the serotonin in the body is actually in the gut. So if the gut cells making serotonin are in the trap, the gut's function will be impaired.

Predicting exactly how it will be impaired is complicated by the enzymology of the first enzyme in the pathway from Trp to serotonin. That enzyme is tryptophan hydroxylase and it has at least two isoforms, TPH1 and TPH2. The dogma is that TPH1 is the peripheral isoform and TPH2 is the brain isoform. So if the dogma is correct, then we'd expect serotonergic nerves in the midbrain to express TPH2 and serotonin-producing cells in the gut to express TPH1. This matters because TPH1 is reportedly substrate inhibited, just like IDO1, and TPH2 is not substrate inhibited.

So with all those reported results taken as facts, we'd predict too much serotonin in the brain and too little serotonin in the gut.
Great response, thanks so much!

Any thoughts on why Cymbalta seems to help ME pain? It removes 95% of my pain, and improves my quality of life massively.

It’s an SNRI.
 

Aroa

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However this year Karl Morten et al research paper indicated that phenylalanine levels were the result of mitochondrial dysfunction and were increased inside cells..
Link : https://pubs.rsc.org/en/Content/ArticleLanding/2018/AN/C8AN01437J#!divAbstract

So unclear how all this relates to the try-trap.........
This paper is interesting because it may be linked to the second Metabolic Trap hypothesis studied by Dr. Phair : “Tyrosine” since phenylanine can be converted into it, and because of the use of a new technology.

These are Karl Morten´s words provided by MEA in a Research summary :

“It is becoming clear that metabolic/energetic dysfunction plays a role in ME/CFS. More information is required to determine if these differences are driving the illness or are a consequence of having ME/CFS.

Single Cell Raman Spectroscopy is an exciting new tool which can give a readout on aspects of intracellular metabolism. Live cells/tissue are not required, which if the approach is successful, will be a major benefit in developing a diagnostic test.”

https://www.meassociation.org.uk/2018/09/mea-research-summary-the-search-for-biomarkers-in-me-cfs-using-raman-spectroscopy-06-september-2018/

I would love if anyone could give us some insights about the use of the Single Cell Raman Spectroscopy compared to Mass Spectometry

Thank you Dr. Phair for your research and for participating in this forum, although I wouldn´t like to distract you too much.

Big thanks to the super team : Julie, Curt, Sundari and Ryan :heart:
 

Belbyr

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