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

https://www.mdpi.com/2075-4418/9/3/82

 

Our existing discussion thread on the metabolic trap theory is here, https://www.s4me.info/threads/stanf...8-phair-metabolic-traps-tryptophan-trap.6033/

 

The Open Medicine Foundation has sent out an email on the paper.
It links to an article on their website.

https://www.omf.ngo/2019/07/26/the-...s&utm_medium=email&utm_campaign=research news

 

The thing that sticks with me about this theory is something Ron Davis alluded too in a video from #MillionsMissing 2018. I don't see why the trap theory is specific to ME/CFS - it would likely encompass many other diseases IF correct, and could be a game changer in so many fields IF it is validated. Could be a nobel prize kind of thing.

However, we still need that first validation test of the trap being detectable in cells that express IDO as a starting point..............

 

I'm just starting to read through the full text but one observation that concerns me immediately is the weight given in the hypothesis to 'its long history epidemics, outbreaks or clusters' (sic) and how this informs the notion that any genetic predisposition must be common.

I am yet to be convinced that any of the supposed outbreaks of whatever are in any way related to much the more commonly diagnosed 'ME/CFS' (which in many cases meet the so called rigorous criteria established by the CCC etc).

 

It's Friday, I have little brain left this week and I am confused as to how there's a "long history of epidemics" yet the first sentence of the abstract says it's noncommunicable. Aren't epidemics infectious, hence communicable?

 

Thank you!

 

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."

 

Thanks to Robert Phair for providing us with an interesting and testable hypothesis.

Just not sure about some of the assumptions. It begins for example with the idea that outbreaks "raise the possibility that genetic predisposition to ME/CFS is very common in the population." Yet we haven't seen much of these outbreaks or epidemics in the last 30 years. I'm no expert in this but I think there's some uncertainty whether the outbreaks in the past were instances of the same thing and if it was wether that has much relevance to ME/CFS as we know it today (as Marco noted).

The second assumption, the idea of bistability in relation to ME/CFS, doesn't really convince me either. I suppose this would result in a clinical situation where there's a clear delineation, where you either have the illness or not. Yet what we see in ME/CFS is not only heterogeneity in symptom presentation, but also in severity. There seems to be a whole spectrum of severity from barely alive to being able to work full time. Patients often report improvements, deterioration, and relapses after years of being well. Some make the progression from mild ME/CFS to the severest form. And patients who say they have recovered probably still have more symptoms than controls, as Bells prognosis study indicated. That all doesn't sound like a trap where you're in it or not.

I find the idea about IDO mutations and the kynurenine pathway fascinating. But given the above, I fail to see why it would relate to ME/CFS more than to any other unexplained illness.

 

From the paper:

Which of course raises the question, "What are these triggers?"

I don't think the paper addresses this, but rather sets out to show what hypothetically could happen if 'cytosolic tryptophan concentration' got too high.

The paper does mention stochastic (i.e. random) variations in cellular tryptophan as a factor (though maybe only after some other trigger has put the system at a tipping point).

 

From the paper:

Bolding mine.

 

@Michiel Tack I think the trap explanation for differences in severity and symptomatology is the number and type of cells trapped. ME only effects cognition would be cell type X, severe would be tons of cells, mild a few, etc.

 

As @sb4 states it could depend on the number of cells of a specific type that are in the trap. Take dendritic cells for example, the ones they are testing with. If 10% of cells are in the trap then maybe you would be mild. But if 90% were in the trap then you might be severe.

What I don't understand is that DC's are relatively short lived (days/weeks) so how is that taken into account. Does that cause possible fluctuations in symptoms? I get lost trying to read about DC's lifespan and regeneration in this paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668851/

 

Thanks.

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.

As I understand it, the only connection between the potential pathology involving IDO mutations and the kynurenine pathway and ME/CFS is (1) ME/CFS has a history of epidemics and IDO has a common mutation and (2) some people think ME/CFS has something to do with bistability. I don't see how the concept of bistability relates to ME/CFS. It shouldn't merely be compatible, it should connect the default in the kynurenine pathway to ME/CFS. Otherwise, there seems to be very little reason to think the theory about IDO mutations and the kynurenine pathway has anything to do with ME/CFS IMHO.

 

The relapses are not from a state of normal health into a state of ill health. They are from a state of ill health into an even worse state, with slow recovery back to the previous state (at times the recovery is incomplete and the new normal is worse than before).

At least that's how they are generally described.

PS: my onset was like a switch, but there was also a prodromal phase with occasionally appearing symptoms that made no sense.

 

This particular point could have the explanation that people become better at managing their condition over time, so subjectively are better i.e. once I stopped working I was far more able to limit the number of times that I went over my sustainable exertion limit, so I did feel better but not because my ME had improved.

 

I don't think fluctuations contradict the idea of a metabolic trap. As others have said, it's not all cells that are trapped, just some. The body is extremely complex. When some parts are malfunctioning, all sorts of weird things could happen. I don't think one could say that fluctuations are inconsistent.

 

Ok, but the idea of bistability and a trap is presented as one of only two reasons why the described pathological mechanisms would have anything to do with ME/CFS.

So perhaps the relapses, fluctuations, spontaneous improvements and heterogeneity in severity in ME/CFS all are compatible with the trap theory. The aim, however, should be much higher than merely being compatible. It should form a clear connection between the described mechanism and ME/CFS and why the two would be related. Otherwise, there's only the observation about the epidemics and IDO mutations being common that connects them. Or did I miss something?