Severe ME patients have 1.7 broken copies of IDO2

[pattismith]

The abstract isn't saying that IDO2 only depends on AhR receptors. It's saying that IDO2 is influenced by AhR receptors but that IDO1 apparently is not. IDO2 is certainly not just regulated only by AhR receptors.

oh really! I feel confused if I misanderstood this sentence!
However, I can't find much information about IDO2 regulation either...

 

[nandixon]

oh really! I feel confused if I misanderstood this sentence!

However, I can't find much information about IDO2 regulation either...

The authors wrote that sentence in a very imprecise way. I went ahead and looked at the full text for the study of the 2014 abstract (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238401/), and what the authors appear to actually be meaning is that IDO2 is regulated in a unique manner by AhR. Namely that AhR, which acts as a transcription factor, is sufficient by itself (alone) to stimulate gene expression of IDO2, but IDO2 is also regulated by other things (see below).

(I found another source from 2015 that indicates that IDO1 is also regulated by AhR. See: The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586474/)

In the 2014 full text the authors give other examples of how IDO2 is regulated:

IDO2 is also expressed like IDO1 in antigen-presenting cells but under somewhat different control. The IDO2 promoter includes a prominent binding site for the transcription factor IRF-7, a master regulator of dendritic cell maturation, suggesting a central role in these professional antigen-presenting cells (15). In this setting, IDO2 appears to be a mainly basally expressed gene, the levels of which vary little by comparison to IDO1 levels that are more robustly regulated. Current information suggests that at the RNA level IDO2 expression is regulated by various pro-inflammatory stimuli, but less robustly than IDO1, including in dendritic cells by interferon-γ (IFN-γ), IL-10, lipopolysaccharide, and prostaglandin E2 (3, 15–18). Interestingly, activation of the aryl hydrocarbon receptor (AhR), a transcription factor, which can serve as a physiological ligand for kynurenine (19), has been reported to upregulate IDO2 in dendritic cells (20, 21). Since activated IDO1 generates kynurenine, this observation presents the intriguing possibility of a downstream mechanism to elevate IDO2 levels in dendritic cells where IDO1 becomes upregulated, a prospect discussed further below.

(Note that that last sentence would fit with Phair's hypothesis about the role of IDO2.)

I don't really want to spend any more energy on this because until Dr Phair can reproduce the tracer study (with the controls properly matched for IDO2 genetic variations) this is likely to end up being what is known as a “wild goose chase.”

 

[wigglethemouse]

Tryptophan blood levels in established ME/CFS patients are more likely to be low, as you suggest.

This is the Tryptophan data from the Hanson metabolite study. The median and average values between patients and controls are within 5% so not much difference. I don't know the parameters of blood collection. I imagine TRP levels could be dependant on timing and type of last meal.

 

[nandixon]

@wigglethemouse
Didn't at least both Fluge & Mella and Chris Armstrong find lower tryptophan levels on average in their studies? I know that mine ran borderline low when tested.

Also, I may be mis-remembering, but the patients for Hanson's study may have all been supplied by Susan Levine. I'm not sure that I trust her assessment abilities.

 

[wigglethemouse]

Didn't at least both Fluge & Mella and Chris Armstrong find lower tryptophan levels on average in their studies? I know that mine ran borderline low when tested.

I did a quick scan of the papers. Seems similar to Hansons - no real difference
Armstrong 2012
Tryptophan ME/CFS 47.6±14.7
Tryptophan Control 48.1±9.0

Armstrong 2015
In non-ME/CFS subjects, relative abundance blood aspartate positively correlated with the blood BCAAs and tyrosine. In the ME/CFS cohort aspartate positively correlated with glutamine, threonine, tryptophan and total amino acids.

Fluge & Mella 2017
Tryptophan ME/CFS 73.4
Tryptophan Control 77.8

Also, I may be mis-remembering, but the patients for Hanson's study may have all been supplied by Susan Levine. I'm not sure that I trust her assessment abilities.

It was Susan Levine using Fukuda criteria. Sample handling method after blood draw is not specified explicitly. For metabolomics it is best to process the blood immediately and then freeze. Also timing of last meal before blood draw could be important.

 

[nandixon]

@wigglethemouse
Thanks. Fluge & Mella gave statistical significance (p=0.009) to the tryptophan difference between patients and controls, but there was only significance for women and not men. But I agree with you. I was probably biasing my memory of those studies with my own results.

 

[wigglethemouse]

Thanks. Fluge & Mella gave statistical significance (p=0.009) to the tryptophan difference between patients and controls, but there was only significance for women and not men.

FYI - The Hanson study was women only.

 

[Inara]

In order for outbreaks to occur, there must be a common predisposing factor among the population, so any rare mutations can automatically be discarded.

I understand this is part of Dr. Phair's hypothesis, but I do not agree with this. I think many people, including scientists, agree now that ME is most possibly heterogenous, meaning (as I understood it) different reasons could lead to ME (which results in "subsets"). What you may need is a predespisition to ME, and this is not only given if there is a common genetic variant, but is - theoretically - also possible if there are rare variants. I don't think rare variants should be discarded per se.

 

[Inara]

"Gene expression studies indicate that IDO2 is a basally and more narrowly expressed gene than IDO1 and that IDO2 is uniquely regulated by AhR, which serves as a physiological receptor for the tryptophan catabolite kynurenine. In the established KRN transgenic mouse model of rheumatoid arthritis, where IDO1 gene deletion has no effect, IDO2 deletion selectively blunts responses to autoantigen but has no effect on responses to neoantigen challenge"

I always wondered if Vitamin B6 may play a role re. kynurine and tryptophan? Does someone know this?

 

[JES]

I always wondered if Vitamin B6 may play a role re. kynurine and tryptophan? Does someone know this?

It does work as cofactor in some of the steps in the tryptophan-kynurenine pathway:

As a side note, the only blood test that came back abnormal for me was serum vitamin B6, which was elevated outside the reference range. I had not been supplementing and I always thought it was a curious result and it's apparently something that is seen in autism as well.

I have trialed supplementing with B6 as well several times. What happens is an initial positive response for around 2-3 days, after which the effect wears off. I have been thinking that B6 might have temporarily helped some of these pathways, but if the core problem is elsewhere, e.g. in the microbiome, it's likely that the body will attempt to self-regulate tryptophan metabolism back to baseline.

 

[frozenborderline]

This is not what Phair thinks is casing the trap. The hypothesis of Phair, which was simulated in a computer model, predicts that if tryptophan concentrations remain high for a certain period of time, the patient gets stuck in a trap, a bistable state, where there is no easy way out from. This happens because of the unusual enzyme kinetics of IDO1, according to which IDO1 gets inhibited at high concentrations of tryptophan. Hence the patient would need a working IDO2 to get out of the trap.

The interesting thing about Phair's model is that it would potentially explain both ME/CFS outbreaks and also account for why only certain people get hit by the illness. In order for outbreaks to occur, there must be a common predisposing factor among the population, so any rare mutations can automatically be discarded. According to the model, the predisposition to the disease would be common, but the penetrance would be low, due to the fact that only certain set of condition could trigger the trap.

It could of course also be that something else inhibits IDO1, and as you say, the cause could potentially be in the microbiome. However, I'm not sure if it would as elegantly explain ME/CFS outbreaks or the fact that many people get ill overnight and cannot seem to return back to a healthy state.

The ido1/ido2 metabolic trap theory still seems sort of implausible to me for a couple reasons —-it just seems too fragile to have a system with so little redundancy that a simple viral infection can activate this. This becomes especially true if the mutation is common and the triggers are heterogeneous. Like are most people really prone to get me/cfs any time they get a significant infection that lasts x long ? It could be true, after all with many environmental factors a lot of chronic illnesses seem to be increasing in prevalence. Apparently there are lots of woodsman/hunter types that get lyme all the time and don’t even have a reaction to it. But unless we’re talking about a mutation that was somehow selected for recently despite being maladaptive idk about this.

 

[Inara]

As a side note, the only blood test that came back abnormal for me was serum vitamin B6, which was elevated outside the reference range.

Thanks for that graph. So if Vit. B6 would be low (in the cells, see below), tryptophan could accumulate?
If so, I wonder if there are other pwME who have this.

[My serum B6 was always elevated even without taking it. Since I found that strange I tested for some metabolic products, which showed a B6 deficiency. At the same time I can't substitute B6 - even lowest doses lead to over-dosage symptoms. Nobody knows what this is. (It's not hypophosphatasia or the like...) And it seems I can't fix the deficiency.]

 

[nandixon]

As a side note, the only blood test that came back abnormal for me was serum vitamin B6, which was elevated outside the reference range. I had not been supplementing and I always thought it was a curious result and it's apparently something that is seen in autism as well.

I have trialed supplementing with B6 as well several times. What happens is an initial positive response for around 2-3 days, after which the effect wears off. I have been thinking that B6 might have temporarily helped some of these pathways, but if the core problem is elsewhere, e.g. in the microbiome, it's likely that the body will attempt to self-regulate tryptophan metabolism back to baseline.

[My serum B6 was always elevated even without taking it. Since I found that strange I tested for some metabolic products, which showed a B6 deficiency. At the same time I can't substitute B6 - even lowest doses lead to over-dosage symptoms. Nobody knows what this is. (It's not hypophosphatasia or the like...) And it seems I can't fix the deficiency.]

I have the elevated B6 finding as well. If your alkaline phosphatase (ALP or Alk Phos, aka tissue-nonspecific ALP or TNSALP) tends to run at the bottom of the normal range, like mine does, then it may be due to that.

There's apparently a common genetic variation(s) in the ALPL gene that results in lower ALP levels, and ALP seems to be involved in the disposal of excess B6 (pyridoxal-5'-phosphate or PLP).

So the high B6 probably isn't reflecting an inability to use the B6. It's been shown in infants with actual frank hypophosphatasia and extremely elevated B6 levels due to deficient ALP that their tissue levels of B6 are actually pretty normal. (See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC329654/)

The practical consequences of this, for me anyway, is that it puts a lower cap on how much B6 I can take to try to over drive energy metabolism, and there's a very narrow therapeutic window: Taking less than 25 mg B6 I have worse fatigue, whereas at just 50 mg I start developing peripheral neuropathy symptoms after several days.

 

[wigglethemouse]

There's apparently a common genetic variation(s) in the ALPL gene that results in lower ALP levels, and ALP seems to be involved in the disposal of excess B6 (pyridoxal-5'-phosphate or PLP).

I am another that cannot supplement B6 without it going way high. @nandixon do you have any more details on if there is a specific mutation or any mutation? My 23andMe shows 8 variations at 5 locations in the ALPL gene. Enlis shows unknown clinical significance.

EDIT : Apparently 300 mutations can have an effect. I couldn't find a list of which ones.
EDIT : My Alkaline Phosphatase levels are fine. Don't know why low B6 supplementation causes elevated levels of B6. Maybe the supplement was the wrong form of B6.

 

[wigglethemouse]

This post is interesting. Perhaps those of us with low cortisol and low ALP pre-illness due to ALPL gene mutations have a double whammy that prevents utilization of B6 in cells. Most studies I found with a quick search were on pets with elevated ALP where corticosteroids were found elevated

Most people on PR who have high B6 (even those not supplementing) is probably due to the buildup of B6 caused by low cortisol prevelant among PWME.
Adequate cortisol is needed for alkaline phosphatase to allow B6 to eventually enter cells

.https://www.ncbi.nlm.nih.gov/pubmed/4301410

So if ALP is needed for B6 to enter cells then a low level of ALP could perhaps cause an issue with the pathway shown in the diagram from @JES and B6 supplementation wouldn't help. Maybe I'm making too many assumptions....

 

[wigglethemouse]

From wikipedia

Blood levels of alkaline phosphatase also increase two to four times during pregnancy. This is a result of additional alkaline phosphatase produced by the placenta.[7]

It has been observed that pregnancy sometimes helps women with ME improve.......

 

[nandixon]

@wigglethemouse
I don't think I found anything of interest in my 23andMe results either regarding ALPL when I looked at this several years ago. I'm waiting for full genome sequencing results so maybe something will show up there.

 

[nandixon]

This post is interesting. Perhaps those of us with low cortisol and low ALP pre-illness due to ALPL gene mutations have a double whammy that prevents utilization of B6 in cells.

I'm not sure the study being cited in that post is applicable because, just quickly glancing at the abstract, it's referring to Intestinal ALP, which is a different isoform of ALP than the Tissue-nonspecific ALP (TNSALP) that I thought was primarily responsible for affecting blood levels of B6. (TNSALP is the isoform that's measured in routine blood labs.)

That's interesting that your ALP is normal but yet you still have the elevated B6 finding.

 

[nandixon]

I'm not sure the study being cited in that post is applicable because, just quickly glancing at the abstract, it's referring to Intestinal ALP, which is a different isoform of ALP than the Tissue-nonspecific ALP (TNSALP) that I thought was primarily responsible for affecting blood levels of B6. (TNSALP is the isoform that's measured in routine blood labs.)

That's interesting that your ALP is normal but yet you still have the elevated B6 finding.

@wigglethemouse, I looked further into this and it is known that ACTH stimulates TNSALP at least in the adrenal gland and possibly elsewhere. So the idea that a suppressed HPA axis could cause lower ALP levels and/or increased B6 levels looks like a reasonable possibility. It's also consistent with Klimas's model for ME/CFS (my favorite model) and possibly with Cortene's model.

The increased B6 could possibly be more than just a downstream effect too if there's a feedback mechanism on the part of B6 with respect to glucocorticoid receptors in the HPA axis. Definitely need to look at this in more detail.

 

[aquariusgirl]

Same here... Wildly elevated serum B6,,, Alkphos runs low