A Metabolic Trap for ME/CFS?

boolybooly

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Thanks for the link above. Its an intriguing hypothesis, worth researching for pure science alone.

The biggest stumbling block I can see is I cannot understand why TDO2 would not correct problems with tryptophan build up due to IDO2 failure, that may be why SNPs are so common for IDO2, i.e. it is not highly conserved. Makes me cautious about the finding that TDO2 is not expressed in some cells. Feels like slim odds that the living reality follows the mathematical model but its worth checking, evolutionarily you could see how this situation might happen if conditions changed from a situation where IDO2 was less critical to one where it was more necessary.

I hope studies with more than 6 patients will be feasible and bring greater clarity but they need to be the same subtype or nothing that comes out of them will make sense. The cell model sounds like it could be instructive.
 
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The thing about stats is they tell you nothing about the absolute truth of an hypothesis. p values are a way of estimating the confidence we should have in an hypothesis.
We can never know absolute truth. All we ever have is observations (in aggregate, statistics).

I prefer a Bayesian approach. Set a prior and update as data comes to hand.

I think you and I both have a low prior on any explanation of ME/CFS - the difference is you've lifted yours slightly as new info on the tryp-trap has come to hand and I've dropped mine slightly. Either way we're haggling over a few percentage points of probability that this disease model is accurate.

And as you say, the hypothesis testing is where we will get some real information.
 

nandixon

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I believe Dr Phair is going to need to measure the amount (or relative amounts) of IDO1 protein (enzyme) in the patients’ cells versus controls. Based on the known immunomodulatory abilities of IDO2, and this includes with respect to IDO1, I think the chances are better now that the reduced consumption of tryptophan (trp) and lower production of kynurenine (kyn) he found in the small in vitro tracer experiment is due to a decreased amount of IDO1 rather than an inhibited IDO1, which the metabolic trap hypothesis requires.

(It wouldn't be sufficient to measure mRNA in this case because the IDO1 enzyme can be subject to increased degradation under conditions related to the immunomodulatory ability of IDO2. See later below.)

For example, in this recent study:

Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through the regulation of IL-6/stat3 signalling

it was found that IDO2 appears to act in a way that decreases the production of inflammatory cytokines, in particular IL-6, at least in mice exposed to LPS. Thus, in mice lacking the IDO2 gene, levels of IL-6 increased to significantly higher levels upon exposure to LPS than mice with a functional IDO2. (Human results relative to IDO1 and IDO2 have so far appeared largely consistent with mouse studies, I believe,)

And IL-6 has been found to drive regulatory proteolysis (i.e., degradation) of IDO1. See in particular the relevance of this study:

Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes

where it is stated:

IDO1 functioning is, in turn, modulated at multiple levels (i.e., transcriptional and/or posttranslational levels; refs. 11, 12, 15). In fact, the expression of IDO1 protein may not be sufficient per se for full enzymatic activity (16, 17) because IDO1 proteasomal degradation occurs in a microenvironment dominated by IL-6 (18, 19).
(My emphasis.)

The above study is very interesting because it's one of the few examples of another disease where a low intracellular (PBMCs) kyn/trp ratio has also been found, although it's also low in sera in that case as well and there are other important differences.

So, based on a (hypothetical) IL-6 related immunomodulatory scenario in which lack of a functional IDO2 results in increased local IL-6 concentrations which in turn cause an increased degradation of IDO1, it might be possible to ameliorate the effects of a non-functional IDO2 gene in some ME/CFS patients with the use of the anti-IL-6 receptor monoclonal antibody tocilizumab. (Tocilizumab has been mentioned a few times before on this forum in various threads.)

That drug only works in a subset of juvenile type 1 diabetes patients and, intriguingly, which subset it works in may be largely dependent on a single IDO1 SNP (rs7820268), and this may or may not be applicable in ME/CFS.

(I'm guessing that if tocilizumab were in fact useful in ME/CFS that it might not appear effective in Ron Davis’ nanoneedle unless the cells were first cultured with that drug for some period of time.)

Finally, it's obvious that even before measuring IDO1 protein levels the very first step must be to verify that the controls used for the kyn/trp tracer experiment are appropriately matched in terms of number of non-functional IDO2 alleles, i.e. their levels of homozygosity and heterozygosity for the inactivating SNPs.

The bad news is that the immunomodulatory scenario involving IDO2 makes it more likely that if appropriately matched controls weren't used then the results of the tracer experiment may actually be perfectly normal for individuals with an inactivation of IDO2, whether they have ME/CFS or not.

The good news is that the IDO2 SNPs that yield a non-functional enzyme are quite common in the general (European ethnicity) population. Looking at the genotype data, just for the two most common ones alone, R248W (rs10109853) and Y359stop (rs4503083), true homozygotes are around 35% of the population, and when you add in likely effective homozygotes (i.e., individuals who are compound heterozygous for the two SNPs) together with all remaining SNP possibilities the total number of actual and effective homozygotes who have a non-functional IDO2 may be over 45% of the general population.(!)

These SNPs are thus so common that Phair may have used matched controls by sheer chance alone. (Note that it may be necessary to control for IDO1 as well, because one relatively common SNP, the aforementioned rs7820268, may afford a significant upregulation of that enzyme.)

One last little side note, I sure hope that when Dr Phair indicated that an average of 1.7 damaging IDO2 mutations per patient were found in the severe ME/CFS patient study that he meant 1.7 damaged alleles per patient, and not actually 1.7 different IDO2 SNPs, because the latter would only matter if the SNPs were on different alleles of course.
 
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Hopeful1976

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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.
 

Belbyr

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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.
Mine as well, so I'm right there with you. I don't know if you saw Dr Ron Davis's closing statement but he covered how it can affect 400+ functions in the body. Everything from immune, to neurological, to endocrine, to metabolism.
 

Hopeful1976

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Mine as well, so I'm right there with you. I don't know if you saw Dr Ron Davis's closing statement but he covered how it can affect 400+ functions in the body. Everything from immune, to neurological, to endocrine, to metabolism.
I did see it, I'd just really like some theoretical specifics if you know what I mean. Something to tie it all in...
 
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You are aware elite CFS patients are already so much better since Mikovits was "wrong"? The patients with money take supplements that cost upwards of $1000 a month, anti virals, antiretrovirals, oxygen chambers, have multiple doctors their own nurses at home and all of this is out of our hands without a cheap, cost effective treatment.
I take a cheap, cost effective treatment. Aconitum carmichaelii, as well as Scutellaria baicalensis. Both antiviral and antiretroviral substances.

Additionally, I just purchased 1/4 lb. of Cistus Incanus, about €34.

I understand your frustration, but all hope is not lost. ;)
 

melihtas

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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.
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.

Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome.
Stasi C1, Bellini M, Bassotti G, Blandizzi C, Milani S.
Author information

Abstract
BACKGROUND:
Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal discomfort, pain and changes in bowel habits, often associated with psychological/psychiatric disorders. It has been suggested that the development of IBS may be related to the body's response to stress, which is one of the main factors that can modulate motility and visceral perception through the interaction between brain and gut (brain-gut axis). The present review will examine and discuss the role of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes in the pathophysiology and therapy of IBS.

METHODS:
Search of the literature published in English using the PubMed database.

RESULTS:
Several lines of evidence indicate that 5-HT and its receptor subtypes are likely to have a central role in the pathophysiology of IBS. 5-HT released from enterochromaffin cells regulates sensory, motor and secretory functions of the digestive system through the interaction with different receptor subtypes. It has been suggested that pain signals originate in intrinsic primary afferent neurons and are transmitted by extrinsic primary afferent neurons. Moreover, IBS is associated with abnormal activation of central stress circuits, which results in altered perception during visceral stimulation.

CONCLUSIONS:
Altered 5-HT signaling in the central nervous system and in the gut contributes to hypersensitivity in IBS. The therapeutic effects of 5-HT agonists/antagonists in IBS are likely to be due also to the ability to modulate visceral nociception in the central stress circuits. Further studies are needed in order to develop an optimal treatment.
https://www.ncbi.nlm.nih.gov/pubmed/24425100
 

Hopeful1976

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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
Thanks! This makes sense.
 

Moof

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I hope you find ways to improve it, @Vicki Cole. I've only ever experienced two specific food intolerances, one of which now seems to have resolved anyway, but I was sooo miserable during the long period when I was trying to work out what was going on.

I unknowingly ate something containing a small amount of potato starch yesterday, which set my gut off a little bit this morning, and it reminded me how horrible it was having that going on all day, every day. It's quite bad enough having the pain, brain fog and fatigue of ME, without being unable to enjoy food without dire consequences as well! I really feel for people who have to live with this all the time, or have severe intolerances to lots of things. :(
 

Hopeful1976

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I hope you find ways to improve it, @Vicki Cole. I've only ever experienced two specific food intolerances, one of which now seems to have resolved anyway, but I was sooo miserable during the long period when I was trying to work out what was going on.

I unknowingly ate something containing a small amount of potato starch yesterday, which set my gut off a little bit this morning, and it reminded me how horrible it was having that going on all day, every day. It's quite bad enough having the pain, brain fog and fatigue of ME, without being unable to enjoy food without dire consequences as well! I really feel for people who have to live with this all the time, or have severe intolerances to lots of things. :(
Thanks.
It's truly awful. Constant nausea. Bloating. The worst is there is most definitely a correlation between the gut symptoms appearing and a worsening of all other m.e symptoms. Ive tried everything to help - I get occasional respite depending on menstrual cycle too. Nothing solves it - diet/probiotics/prebiotics ect. The only time I had relief was when I was pregnant.
 

Moof

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I get occasional respite depending on menstrual cycle too...The only time I had relief was when I was pregnant.
I must admit, my gut has been better since the menopause – I did get a bit of nausea and bloating at times during my cycle (I'm guessing not nearly as bad as yours), but it completely disappeared once my periods stopped. So maybe the hot flushes might actually be something to look forward to?! :lol:. My menopause arrived quite early at 45, and I've since discovered this seems to be quite common in ME.
 

ljimbo423

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Thanks.
It's truly awful. Constant nausea. Bloating. The worst is there is most definitely a correlation between the gut symptoms appearing and a worsening of all other m.e symptoms. Ive tried everything to help - I get occasional respite depending on menstrual cycle too. Nothing solves it - diet/probiotics/prebiotics ect. The only time I had relief was when I was pregnant.
I think the switch the body makes from a pro-inflammatory TH1 dominant immunity to an anti-inflammatory, TH2 dominant immunity during pregnancy, so the fetus doesn't get rejected by the body. Might be why some women with CFS feel better when pregnant.

Both curcumin and resveratrol cause an increase in TH2 anti-inflammatory immunity, like pregnancy does.

Effect of resveratrol and curcumin on the production of IL-1, IL-6, TNF-α and IL-10 by macrophages

The role of proinflammatory cytokines (IL-1, IL-6 and TNF-α) is crucial in controlling inflammation. Therefore, we also measured the secretion of IL-1, IL-6 and TNF-α by LPS-activated macrophages, the major source of these cytokines.

Both resveratrol and curcumin significantly (P < 0·05) inhibited production of IL-1, IL-6 and TNF-α (Fig. 5a–c). We also monitored the release of IL-10. We noted that there was a significant (P < 0·05) enhancement in secretion by both resveratrol and curcumin (Fig. 5d).

Comparatively, it was also observed that resveratrol induced more secretion of IL-10 than curcumin. Modulation in the secretion of cytokines was observed in a dose-dependent manner.
Link to paper
 

Hopeful1976

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I think the switch the body makes from a pro-inflammatory TH1 dominant immunity to an anti-inflammatory, TH2 dominant immunity during pregnancy, so the fetus doesn't get rejected by the body. Might be why some women with CFS feel better when pregnant.

Both curcumin and resveratrol cause an increase in TH2 anti-inflammatory immunity, like pregnancy does.



Link to paper
Thanks! Not heard of resveratrol before. I'll try curcumin again I think and also look out for resveratrol
 

Wishful

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Both turmeric and resveratol make my symptoms worse, but I think that's due to their antioxidant (or peroxynitrite scavenging) properties, rather than their effects on the immune system.
 

alex3619

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We can never know absolute truth.
We can know absolute truth ... we just cannot be sure we know absolute truth. There is no perfect truth test. That is why critical rationalism is important, and why science that does not use this is a problem ... hypotheses need to be robustly tested, only after we do that can we have much confidence, but never certainty.
 

Research 1st

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Thought this paper abstract below regarding Serotonin/Kynurenine was interesting as people were wondering what might happen, at least to CFS subsets, with knackered serotonin receptors who end up depressed and it's relation to inflammation and yet the claim of conversely high serotonin?

Notice the familiar culprits mentioned in the abstract below:

1) Cytokines mentioned.
2) CNS inflammatory effect.
3) Innate immune activation.
4) Hyper HPA axis.
5) Infection/Vaccine/Stress exposure.

''Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1β, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system''.

Source:
A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary- adrenal axis
Biomedica. 2018 Sep 1;38(3):437-450. doi: 10.7705/biomedica.v38i3.3688.
Ramirez et al
https://www.ncbi.nlm.nih.gov/pubmed/30335249
 

Wishful

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Resveratol may have that specific primary action, but it also has others, such as being an antioxidant and peroxynitrite scavenger. I get similar effects on my symptoms from turmeric, cinnamon, and a few other spices I can't bring to mind at the moment. Since they're probably not all PDE4 inhibitors, I think it's more likely the peroxynitrite scavenging that they have in common.
 

pattismith

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@Vicki Cole
we are all different, but Nimodipine improved my gut issues.
This drug is also used against uterus cramps.
I think of this because you said you were better while pregnant,
and :
-progesterone (pregnancy hormon) can inhibit L voltage gated calcium channels,
-Nimodipine is a L voltage gated calcium channel blocker!

@nandixon

very interesting! I had a Il6 dosage done years ago, and it was low.
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.

My feeling is that this polymorphisms in the IDO2 may be linked to severe outcomes in CFS/ME just like IDO1 polymorphism is related to worse clinical outcome in CROHN disease

Heme-binding-mediated negative regulation of the tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) by IDO2


Abstract
Indoleamine 2,3-dioxygenases (IDOs) are tryptophan-catabolizing enzymes with immunomodulatory functions. However, the biological role of IDO2 and its relationship with IDO1 are unknown. To assess the relationship between IDO2 and IDO1, we investigated the effects of co-expression of human (h) IDO2 on hIDO1 activity. Cells co-expressing hIDO1 and hIDO2 showed reduced tryptophan metabolic activity compared with those expressing hIDO1 only. In a proteomic analysis, hIDO1-expressing cells exhibited enhanced expression of proteins related to the cell cycle and amino acid metabolism, and decreased expression of proteins related to cell survival. However, cells co-expressing hIDO1 and hIDO2 showed enhanced expression of negative regulators of cell apoptosis compared with those expressing hIDO1 only. Co-expression of hIDO1 and hIDO2 rescued the cell death induced by tryptophan-depletion through hIDO1 activity. Cells expressing only hIDO2 exhibited no marked differences in proteome profiles or cell growth compared with mock-transfectants. Cellular tryptophan metabolic activity and cell death were restored by co-expressing the hIDO2 mutant substituting the histidine 360 residue for alanine.

These results demonstrate that hIDO2 plays a novel role as a negative regulator of hIDO1 by competing for heme-binding with hIDO1, and provide information useful for development of therapeutic strategies to control cancer and immunological disorders that target IDO molecules

https://www.researchgate.net/public...yme_indoleamine_23-dioxygenase_1_IDO1_by_IDO2


IDO1 and IDO2 non-synonymous gene variants: correlation with crohn's disease risk and clinical phenotype.

Abstract
BACKGROUND:
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Genetic polymorphisms can confer CD risk and influence disease phenotype. Indoleamine 2,3 dioxygenase-1 (IDO1) is one of the most over-expressed genes in CD and mediates potent anti-inflammatory effects via tryptophan metabolism along the kynurenine pathway. We aimed to determine whether non-synonymous polymorphisms in IDO1 or IDO2 (a gene paralog) are important either as CD risk alleles or as modifiers of CD phenotype.

METHODS:
Utilizing a prospectively collected database, clinically phenotyped CD patients (n = 734) and non-IBD controls (n = 354) were genotyped for established IDO1 and IDO2 non-synonymous single nucleotide polymorphisms (SNPs) and novel genetic variants elucidated in the literature. Allelic frequencies between CD and non-IBD controls were compared. Genotype-phenotype analysis was conducted. IDO1 enzyme activity was assessed by calculating the serum kynurenine to tryptophan ratio (K/T).

RESULTS:
IDO1 SNPs were rare (1.7% non-IBD vs 1.1% CD; p = NS) and not linked to Crohn's disease diagnosis in this population. IDO1 SNPs did however associate with a severe clinical course, presence of perianal disease, extraintestinal manifestations and a reduced serum K/T ratio during active disease suggesting lower IDO1 function. IDO2 minor allele variants were common and one of them, rs45003083, associated with reduced risk of Crohn's disease (p = 0.025). No IDO2 SNPs associated with a particular Crohn's disease clinical phenotype.

CONCLUSIONS:
This work highlights the functional importance of IDO enzymes in human Crohn's disease and establishes relative rates of IDO genetic variants in a US population.

https://www.ncbi.nlm.nih.gov/pubmed/25541686
 
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