Metabolic Trap In ME/CFS

[energyandstruct]

Robert Phair releases details on metabolic trap hypothesis. Early data supports the hypothesis! • r/cfs

A reddit thread isn't the best way of presenting it, but these findings and theory are very important I think.


This is all based on Phair's presentation in this video: (i'll get exact time etc soon)

ME/CFS Symposium at Stanford 2018 on Livestream

 

[energyandstruct]

"Okay. Some concepts in this are new to me and I will happily yield the floor to anyone with proper expertise, but here's my take:

TWO WORKER BEES

There is an important job in the body that needs to be done: turning an amino acid called tryptophan into another molecule called kynurenine.

Two enzymes work hard at doing that. One (IDO1) is good when there are low levels of tryptophan but totally gives up when levels get high. The other enzyme (IDO2) is good when we have high levels of tryptophan.

Robert Phair suggests IDO2 is not working.

THE TRAP

The trap here is due to the special feature of IDO1. It doesn't keep trying when Tryptohan is high - it throws up its arms in despair and weeps. So what happens if Trytophan gets really high? If you've got no functioning IDO2 and IDO1 is sitting in the corner drinking whiskey, you have no good way to turn tryptophan into kynurenine. Tryptophan just accumulates and accumulates. Things get worse.

(This process happens inside the cell, but not inside the mitochondria, just in the common and/or general area they call cytosol.)

The theory is that MECFS kicks in if you have a broken IDO2 (predisposition to disease) and then somehow (often during an infection) you get to the level of tryptophan that causes IDO1 to quit and walk off the job. There's no (easy) way back.

GENETICS

So, is IDO2 broken in CFS patients? Phair had a look in the genetic data from the Severely Ill Patients Study and found that on average, they had 1.7 genetic mutations in the gene that makes this enzyme. [However, he says these mutations are actually very common in humans. So it is unclear to me if this finding is especially relevant. Maybe it's not solely genetic? I don't find this part very satisfying.]

The metabolic trap can be demonstrated in various computer models though: If people without a working IDO2 get high tryptophan for long enough, they get stuck with it for basically ever.

EXPERIMENTAL SUPPORT

The rubber really hits the road when he tests patients. (n=6, so very preliminary. Data in the graph above.) Experiments in me/cfs patients cells comapared to healthy controls show tryptophan is high, kynurenine is low, and the ratio of the two is high, just like the metabolic trap hypothesis would predict.

(This is not the whole story, much has been omitted for simplicity, but it is, I think, the key parts.)

The end.

FINAL WORD:

Ron Davis himself issues a big warning on not trying to manipulate your own cellular tryptophan. You could give yourself brain damage or die. They think there could be an easy cure but they want to test it properly and are very worried about patients hurting themselves."

 

[energyandstruct]

IDO2 in Immunomodulation and Autoimmune Disease


this is a detailed review/study on Ido2's role in general, and especially in immunomodulation

 

[energyandstruct]

@haidut figured you may be interested in this discussion, given that you've kept up with the quality research on hypometabolism in CFS.

@Travis and @SB4 you may be interested too

 

[energyandstruct]

Obviously Peat doesn't really believe in the primacy of genetics, and Phair is speculating about the role of genetic mutations in this disease, but it also involves tryptophan metabolism, so I figured it would be very relevant to people interested in Peat's work

 

[energyandstruct]

This is a screenshot of a diff. part of Robert Phair's presentation, where he is discussing bistability in CFS... e.g. an alternative to the idea of homeostasis, suggesting that it is possible for one to get stuck in a steady state that is an ill state.

 

[energyandstruct]

Here are timestamps for the vid I posted:
IDO metabolic trap:
intro 6:42:44
details 6:48:36

chart of IDO2 mutations 6:52:58

 

[energyandstruct]

For anybody interested, this video has a ton of presentations of other promising research in general, but a lot of people were most excited about this "metabolic trap" hypothesis, so this is the one I was focusing on.

 

[SB4]

Huh, I've already got that paper bookmarked, will read it soon.

@debored13 Have you got 23andme or similar done? For this one rs10109853 I am heterozygous which apparently reduces IDO2 by 90%. There are like 4 or 5 main ones however you only need 1 or 2 of them to be bad to get a very slow or not working IDO2. If this is the case I would imagine that IDO2 would be not working well at all in the vast majority of Europeans since rs10109853 alone is only like 25% wildtype.

I am pretty skeptical about this hypothesis but also quite intrigued. It could explain why people with CFS generally don't tolerate carbs very well; as insulin increases tryptophan influx to the brain.

I would be quite interested in hearing what @Travis thinks of this hypothesis.

 

[energyandstruct]

Huh, I've already got that paper bookmarked, will read it soon.

@debored13 Have you got 23andme or similar done? For this one rs10109853 I am heterozygous which apparently reduces IDO2 by 90%. There are like 4 or 5 main ones however you only need 1 or 2 of them to be bad to get a very slow or not working IDO2. If this is the case I would imagine that IDO2 would be not working well at all in the vast majority of Europeans since rs10109853 alone is only like 25% wildtype.

I am pretty skeptical about this hypothesis but also quite intrigued. It could explain why people with CFS generally don't tolerate carbs very well; as insulin increases tryptophan influx to the brain.

I would be quite interested in hearing what @Travis thinks of this hypothesis.

I have not gotten 23andme done. I was on the fence due to limited money and I saw some stuff about the rate of false positives and then had skepticism toward genetic explanations in general, so I didn't pull the trigger on it.


Anecdotally, I've had good results from a combo BCAA high dose (two teaspoons) and tyrosine, a few times in a row. But they don't last extremely long and aren't curative.
apparently the BCAAs compete with tryptophan and help it not be converted into serotonin? or something?

 

[Diokine]

IDO and tryptophan metabolism in general is hyooge deal in this context. I think that chronic fungal infections are precipitated by various genetic differences, may be initiated by systemic immune activation, and are maintained by fungal adaptations to immune activation leading to immune fatigue.

Niacin (nicotinic acid) may be helpful in some of the aspects of immune fatigue.

 

[energyandstruct]

Anyway I'm not well-versed enough in this specific enzyme/gene to know if this is all plausible or likely, but increased tryptophan seems plausible in CFS people. And his idea of "bistability" seems very interesting too

 

[olive]

If this is true why aren’t more CFS sufferers developing pallegra, fasting is very common in those circles and dietary niacin doesn’t stick around for long AFAIK.

 

[SB4]

Anecdotally, I've had good results from a combo BCAA high dose (two teaspoons) and tyrosine, a few times in a row. But they don't last extremely long and aren't curative.
apparently the BCAAs compete with tryptophan and help it not be converted into serotonin? or something?

Yeah I think that's how it works. I have a tub of BCAA sitting behind me now that I will try out at some point.

IDO and tryptophan metabolism in general is hyooge deal in this context. I think that chronic fungal infections are precipitated by various genetic differences, may be initiated by systemic immune activation, and are maintained by fungal adaptations to immune activation leading to immune fatigue.

Could you go into more detail on how fungal infections interact with Tryptophan, etc?

If this is true why aren’t more CFS sufferers developing pallegra, fasting is very common in those circles and dietary niacin doesn’t stick around for long AFAIK

Interesting point. I did a 30 day fast with CFS and didn't seem to develop this. I think IDO1 doesn't entirely shut off when Tryptophan gets to high, so there will still be some conversion to Kynurenine and then niacin. Perhaps this is enough?

 

[energyandstruct]

Naviaux discussed the IDO pathway a couple times in his paper on the Cell Danger Response (not his paper on CFS)

I think his work is good, but I also wonder about the inconsistencies between this and his

statement in paper on CFS that possible interventions could be aimed at increasing B6. is it definite that lower B6 leads to increased kynurenine/tryptophan ratio?
Anyway, he has also said that the acute CDR is the opposite of CFS in some ways. iirc B6 is important for at least one other metabolic pathway, producing acetylcoa.

https://www.sciencedirect.com/science/article/pii/S1567724913002390

 

[energyandstruct]

Naviaux discussed the IDO pathway a couple times in his paper on the Cell Danger Response (not his paper on CFS)

I think his work is good, but I also wonder about the inconsistencies between this and his

statement in paper on CFS that possible interventions could be aimed at increasing B6. is it definite that lower B6 leads to increased kynurenine/tryptophan ratio?
Anyway, he has also said that the acute CDR is the opposite of CFS in some ways. iirc B6 is important for at least one other metabolic pathway, producing acetylcoa.

https://www.sciencedirect.com/science/article/pii/S1567724913002390

screenshot refuses to load but here's the quote:
"
4.16. Vitamin B6

Low plasma levels of the active metabolite of vitamin B6, pyridoxal 5′-phosphate (PLP) are a common feature of inflammation and the CDR (Paul et al., 2013). PLP is a cofactor in 4 reactions in the dioxygenase (IDO) pathway of tryptophan metabolism, after the formation of kynurenine, leading to the synthesis of quinolinic acid and NAD+ and NADP+. PLP is also required by the enzyme S1P lyase for inactivating the lymphocyte chemoattractant sphingosine-1-phosphate (S1P). Low systemic levels of PLP have the effect of increasing the kynurenine/ tryptophan ratio, and increase S1P in inflamed tissues, thereby sustaining an active CDR.

 

[energyandstruct]

@haidut I've seen you post Naviaux's work on autism and CFS, but did you ever read his paper on the Cell Danger Response, that's earlier, but goes through a lot of details of these pathways?


There's some stuff that seems very on point and some stuff that seems possibly/probably wrong at least from Peat's perspective, on lipids, but it's a very detailed overview of theories of stress on the cell and metabolism.

the stuff that I thought peat wouldn't agree with is descriptions of the roles of lipids in the cell wall and stress. He also says the CDR involves an overly oxidized redox state. But also CFS is supposed to be the opposite of the acute CDR in some ways, so a paradigm of reductive stress still makes sense for CFS

 

[DesertRat]

There is high ROS as oxidative damage in CFS even with low cellular oxidative metabolism.

 

[DesertRat]

Out of curiosity, I checked my lab results from Jan 2007 when I was feeling 80% recovered and could exercise, and then compared them with the same test (different lab though) in May 2010, just under 3 years after I relapsed. In 2007, the kynurenate was 1.4, at the high side of normal; in 2010, as kynurenic acid, it was 0.9, the low side of normal. This would 'fit' his thesis; but the odd thing is that when I felt like crap and could barely walk in 2010, all the test results were normal, although all consistently low. When I felt great in 2007, so many metabolities were out of range, that it was clear there were some major issues with BCAA and tryptophan metabolism, fatty acid oxidation, hepatic conjugation, glutathione wasting, and intestinal dysbiosis. The overwhelming fatigue is a compensatory mechanism to slow things down, which is why most attempts to speed up the metabolism (whether with cortisol, or thyroid, or methyline blue) backfire.

 

[energyandstruct]

Out of curiosity, I checked my lab results from Jan 2007 when I was feeling 80% recovered and could exercise, and then compared them with the same test (different lab though) in May 2010, just under 3 years after I relapsed. In 2007, the kynurenate was 1.4, at the high side of normal; in 2010, as kynurenic acid, it was 0.9, the low side of normal. This would 'fit' his thesis; but the odd thing is that when I felt like crap and could barely walk in 2010, all the test results were normal, although all consistently low. When I felt great in 2007, so many metabolities were out of range, that it was clear there were some major issues with BCAA and tryptophan metabolism, fatty acid oxidation, hepatic conjugation, glutathione wasting, and intestinal dysbiosis. The overwhelming fatigue is a compensatory mechanism to slow things down, which is why most attempts to speed up the metabolism (whether with cortisol, or thyroid, or methyline blue) backfire.

he's talking about intracellular kynurenine, serum levels wouldn't reflect this.

As far as the bolded part, I hope that's not true. I do think CFS is more complicated than peat makes it out to be, but I hope that the state can be exited out of through some kind of stimulus. Even worms with dauer can exit that state with the right nutrient.

That said, what do you think works?