The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS 2019 Kashi, Davis, Phair.

My interpretation is that the connection is the remarkable chronicity of the condition, which often occurs with a sudden switch from good to poor health.

Phair isn't the first person to think that the body's attempts to maintain good health are somehow backfiring and creating poor health.
 
Has degree been modelled - ie upstream and downstream effects of various levels of inhibition of various cell types susceptible to the "trap"; this is a systems condition - it is how this may affect other processes and mechanisms by degree that is the interesting bit.

It never ceases to amaze me how " siloed" research and medicine is ; the positive aspect of research over the past few years is the multiple threads searching for mechanisms.

The disappointing aspect at our level is the complete lack of knowledge in primary care.
 
Please pardon what is likely obvious to the scientific minds here, but how does tryptophan initially become elevated?The process almost sounds like it starts with elevated tryptophan - but that's probably not the case - maybe a chicken and egg process?

Also, some sleep MDs prescribe tryptophan - this seems like this should be contraindicated for pwME.
 
DokaGirl said:
Please pardon what is likely obvious to the scientific minds here, but how does tryptophan initially become elevated?The process almost sounds like it starts with elevated tryptophan - but that's probably not the case - maybe a chicken and egg process?
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This is a question I also have and would love to know more about. The only chemistry I studied in my undergraduate was when cognitive psych was part of my course material, so I acknowledge my limitations. But many of us trace back the initial onset of symptoms to some sort of stress to our bodies. My layperson’s assumption is the body would be burning through tryptophan like it was nobody’s business during a bout of influenza (my suspected trigger) therefore pushing the body toward a low-tryptophan state. That’s not to say I can’t imagine scenarios more complex than my initial assumption.
I’m grateful the research is coming out of this team because I feel I can trust them not to become so enchanted by their own theory at the expense of pwME. Their cautiously, cautiously approach in not prematurely making too grand a claims about this hypothesis is outstanding in my opinion.
 
Thank you @theJOYdecision, for echoing my question.

My ME started with food poisoning, followed very shortly by EBV. Thereafter much increased GI pain, fatigue both mental and physical, increased allergies,and new sensitivities,sleep problems, and a downward spiral from there.

I agree, the OMF is a super group. Their collaboration philosphy will hopefully help find some of the answers.
 
I'm not terribly convinced about the IDO Metabolic Trap Hypothesis explaining either the epidemiology, nor the specific pattern of symptoms. I think the reasoning about genetics is a classic case of confirmation bias...

The modelling is intriguing but it is fairly non-specific and could be applied to many such biochemical events that have a similar overall structure.
 
"Mutations in IDO2 are common in the human population but it is unlikely that many would get ME/CFS. This is because the triggering is unlikely. Apparently, it is difficult to increase tryptophan enough to trigger the trap. That trigger likely requires an overlay of many factors, including pathogens, stressors and the environment."


This is from Chris Armstrong's commentary.

https://www.omf.ngo/2019/07/26/the-ido-metabolic-trap/?utm_source=twitter&utm_medium=organic
 
DokaGirl said:
Please pardon what is likely obvious to the scientific minds here, but how does tryptophan initially become elevated?
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My attempt at an explanation of the theory. Tryptophan becomes elevated because IDO1, which would normally keep it in check, isn't operating properly, if at all. Normally this wouldn't be a problem because IDO2 is a back-up, but in our case IDO2 isn't operating properly either, so there is nothing slowing down/halting the natural build-up of tryptophan.

Am happy for better minds to tell me that I'm wrong, but this is how I understand it at the moment.
 
Michiel Tack said:
Yet I still don't see what the connection is between bistability and ME/CFS. The paper only says about this: "Some ME/CFS patients experience the onset of the disease as a switch being thrown." But there are also the frequent reports of relapses in ME. These were quite prominent in the descriptions of ME in the time before CFS came into play, for example in the description by Ramsay. How does that fit with the idea of a 'trap' people can't get out of? If the reports about relapses being common are correct, it seems that people are stepping in and out of the trap. Also, there seems to be fluctuation in severity: people frequently report they get a little better over time.
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To be fair, they do address the issue of fluctuating symptoms to an extent :

Another implication of the critical point is that therapeutic perturbations need only reduce cytosolic tryptophan below the critical point. Below that point a return to the normal physiological steady-state is inevitable. It must be kept in mind, however, that the trap persists, and subsequent triggers can cause relapse.

It remains to be determined whether this bistable system is also capable of limit cycle oscillations or deterministic chaos, which could explain relapsing-remitting forms of ME/CFS and the seeming impossibility of multiple metabalomics studies converging on the same plasma signature.
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Andy said:
My attempt at an explanation of the theory. Tryptophan becomes elevated because IDO1, which would normally keep it in check, isn't operating properly, if at all. Normally this wouldn't be a problem because IDO2 is a back-up, but in our case IDO2 isn't operating properly either, so there is nothing slowing down/halting the natural build-up of tryptophan.

Am happy for better minds to tell me that I'm wrong, but this is how I understand it at the moment.
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As I understand it there's nothing wrong with our IDO1. Yes, it stops working properly at high tryptophan levels but that's normal and happens in everybody.

IDO2 is the backup system to get rid of the excess tryptophan and that is what appears to be broken in our case.

Additionally, somehow we got unlucky that some unknown trigger or combination of triggers elevated our tryptophan in the first place. There are a lot of people out there with broken IDO2 backup systems - the snps are very common - who never fall ill because the conditions that require the backup system are very rare.

I don't think anybody has any firm idea why tryptophan goes too high in some people. There seem to be many ways of elevating it somewhat (infection, diet, and more I can't recall right now) but none that by themselves would elevate it to very high. So maybe an unfortunate combination of several elevating mechanisms happening at the same time?

My biggest question re any sort of trap theory is how does it explain PEM?
 
Forbin said:
Yes - "epidemic" can even be used quite loosely, such as in "we're experiencing an epidemic of diabetes." More to the point, you can have an "epidemic" of, say, cancer as a result a of geographic exposure to a toxin, radiation, parasites, etc., none of which is communicable in the way a virus or bacteria might be.

A place could experience an epidemic of malaria if the mosquito population increased, but person-to-person transmission does not occur (except through transfusion or organ transplantation).

Legionaries' Disease, which is cause by a bacteria, is not transmissible between people, yet occurs in "outbreaks" which might be loosely called "epidemics."
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In the context of ME they specifically meant it as outbreaks of infectious disease. They took it from the life cycle of polio where the virus caused infection in many people but only some developed what was thought of as "polio" with paralysis and death.

There could be many reasons there do not seem to be the outbreaks as there were before. Mass vaccination against polio must be a factor, leading to an increase in other enteroviral infections which may be less likely to lead to complications, then viruses and bacteria change their behaviour in strange ways, like the way scarlet fever almost disappeared for a generation but is now on the increase.

ME being a different disease now than it was 30 years ago is the least likely explanation since there has been a continuous overlap of cases - 30 years ago there were people who had been ill for years, now there are people who have been ill for decades and ones who have been ill for a few years.
 
DokaGirl said:
Please pardon what is likely obvious to the scientific minds here, but how does tryptophan initially become elevated?The process almost sounds like it starts with elevated tryptophan - but that's probably not the case - maybe a chicken and egg process?

Also, some sleep MDs prescribe tryptophan - this seems like this should be contraindicated for pwME.
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Assuming an infection, the brain depletes tryptophan in order create a non-specific antimicrobial environment. The difficulty is neurotropic viruses actually thrive in this environment and have created specific anti-tryptophan defense to survive, causing further depletion.
 
That is interesting beverlyhills. The behaviour of microbes is oversimplifed because that works pragmatically most of the time. It is a pity that microbiology as a research speciality was so neglected for years.

PCR has given it boost again but that has its limitations too. Epidemiology is neglected too much as well.
 
Mithriel said:
That is interesting beverlyhills. The behaviour of microbes is oversimplifed because that works pragmatically most of the time. It is a pity that microbiology as a research speciality was so neglected for years.

PCR has given it boost again but that has its limitations too. Epidemiology is neglected too much as well.
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The idea of any infection starting CFS's specific fatigue was abandoned rapidly when a few people had an atypical onset and didn't have peripheral antibodies.

This was a problem in other illnesses too, until a few researchers suspected it was impossible for that rapid of an onset to not be infectiously- mediated (or massive immunological trauma e.g. Gulf War Illness or blunt force trauma).

They then did post-mortem examinations indicating histological evidence of massively disseminated viral infections not detectable by imaging, pathogen presence positive by PCR, in patients negative by peripheral PCR.

Fringe doctors with Lyme disease patients use this phenomenon as a gambit. But for the most part, Lyme disease can make you really sick immediately as it enters your bloodstream, it does not have a convoluted immunosurveillance pattern unlike viruses.

The timing is even more prescient because no one ever gives CFS to anyone - you will see surface claims and outliers but deep investigation indicates horizontal transmission is extremely rare and these reports are confounded by the transmission actually being familial. It is because two people in equally perverse states of stress, one of whom is deeply symptomatic are not typically going to be engaged in behavior conducive to transmission.
 
beverlyhills said:
The idea of any infection starting CFS's specific fatigue was abandoned rapidly when a few people had an atypical onset and didn't have peripheral antibodies.
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At Incline Village Stephen Strauss got involved because his pet theory was chronic epstein barr virus and he saw this as a classic outbreak that would push his work. When some of the patients proved negative for EBV he was furious. He simply took the definition of chronic EBV, left out that virus and called the disease chronic fatigue syndrome instead.

Because it was an upmarket resort the town did not want it to be an outbreak of an "unknown virus" so they went along with it. The two doctors who had called in the CDC left.

Strauss refused to take any input from the ME specialists and spent the next years bad mouthing patients across the US.

It was not a scientific process at any point.
 
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