The itaconate shunt hypothesis

Could there be a much simpler explanation for the data outliers (apart from the outliers the data is reasonably well separated)?

Could the high interferon levels in the 2 controls be due to those two fighting a minor infection at the time of sampling?

Could the patient group with low interferon be a subgroup with different underlying pathophysiology? We still can't be sure that everybody diagnosed with ME, even with the strictest criteria, has the same thing going on underneath. We have some interesting "opposite" immune phenotypes going on: pwME who almost never catch a virus versus those who catch everything going, pwME with persistently slightly elevated WBC versus those with persistenly lowish WBC, and pwME who got some brief symptom improvement after the covid vaccine versus those who reacted very badly.

None of which proves anything one way or the other but it does suggest it's not impossible we have a situation similar to type 1 and type 2 diabetes. In diabetes both types end up with too much glucose in the blood but for different reasons. In ME we all end up with PEM but are there different paths to PEM?

Talking of the devil, I'm not sure I understand how this hypothesis accounts for PEM? I can sort of see how physical exercise could lead to translocation of gut bugs into the blood stream and the innate immune system getting upset about that. But orthostatic or cognitive exertion?

And the lowered ATP production would seem to predict a more stable misery than the fluctuating symptom load we actually get? This is a question I have for all the hypotheses centered on low ATP. Sure, a cell without enough ATP to do its job is going to be compromised but how do you get from there to PEM? Depending on the type of exertion the starting point would be different types of compromised cells but all would lead to PEM. Do the affected cells send out a common alarm signal that ultimately leads to PEM? But this particular hypothesis assumes only a small number of cells are dysfunctional so how are they affected by all manner of different types of exertion? Does it have to be a very specific type of cell in the trap. e.g. vagus nerve cells or cells near it, to be able to have such system-wide impact?

In the unlikely event anyone's still reading, you can see I'm thoroughly confusing myself here!

You'd think there must be at least a few.

If ME is maintained by a self-sustaining feedback loop that would be good news. Briefly interrupting the loop could reset the system. I doubt it would be as easy as it sounded in the video to work out how exactly to do this but it would be a very concrete target for a pharmaceutical company to get stuck into if existing drugs aren't quite up to the job.

But if ME is maintained by a persistent pathogen continuously reactivating the feedback loop then you'd also have to stop the pathogen and that would be a whole lot more difficult.

Anyway, I'm pleased to see testing of the hypothesis' predictions is taking place

 

Perhaps, if a subset of cells are impaired but are themselves able to compensate just enough to maintain degraded function, then there might be a balancing of energy needs or other functions across the system. If demands increase (eg standing, moving, thinking) maybe the usual compensation mechanism can be out-stripped. This could be detrimental to the affected cell subset, leading to more symptoms relating to functions of those cells; but might also affect the normal cells that are doing the compensating - perhaps they're driven just a little too hard and/or have to use more and less favourable emergency backup mechanisms. In so doing they may develop temporary impairments to their usual functions that takes time to return to baseline?

It could even be that "too much PEM" can lead to a deterioration in disease severity, as the previously normal compensating cells became damaged from doing too much or using unfavourable biochemical mechanisms. That might also be an itaconate shunt or some different biochemical pathway or just generic "mitochondrial damage" from say reactive oxygen species.

Signals showing favouring of eg fatty acids, or other metabolic shifts, might be occurring in the otherwise normal cells, that are contributing to the compensation. I'm thinking of ideas like the paper that described lactate as a universal fuel that allowed the balance of energy needs across the whole system.

 

It would be really interesting to compare two cohorts, one with ME and the other on interferon therapy, in a study comprising carefully-designed physical and cognitive tests. Especially as patients who're due to begin interferon therapy could presumably be tested beforehand to see what changes.

 

https://twitter.com/user/status/1624302189241069568


https://twitter.com/user/status/1624314122644111360


https://en.m.wikipedia.org/wiki/Baldomero_Olivera

 

Some very recent Robert Phair posts on PR

“Chris and I recently had a great Zoom meeting with Bob Naviaux and Bhupesh Prusty and agreed on two important points: 1) our two theories are converging on the innate immune system, and 2) ME/CFS is a cell-autonomous or mosaic-dysfunctional disease.

Questions welcome.”

Not sure what a cell autonomous or mosaic-dysfunctional disease is—would welcome any clarification if anyone has an idea.

https://forums.phoenixrising.me/thr...fa-itaconate-shunt-part-2.89388/#post-2430533

plus two posts in members only threads which s4me prohibits links to but you can find by searching PR for Htester.

 

Here’s the mosaic—


Mosaic dysfunction of mitophagy in mitochondrial muscle disease

https://www.sciencedirect.com/science/article/pii/S1550413121006367

 

So Phair is saying the metabolic trap hypothesis is dead?
“When the experimental data do not consistently corroborate a theory like the IDO metabolic trap, I'm naturally disappointed.”

 

There are probably better review articles to be found, but Google highlighted this slideshow PDF from Washington University at St Louis with a simple summary —

 

Were they looking at the JAK-pathways or did I remember that wrong?

 

Not sure, but I do know that on a different forum they brought up Filgotinib https://en.m.wikipedia.org/wiki/Filgotinib Some were saying that it might be helpful for very short-term use.

 

That’s what it sounds like. It seems these ‘trap’ hypothesis’s are falling out of favor. Hopefully the speeches coming up in May reveal some findings from the studies that have been done.

 

This basically means "cell damage."

 

Further responses from RP

https://forums.phoenixrising.me/thr...fa-itaconate-shunt-part-2.89388/#post-2431109

 

Question from Robert Phair on PhRising
An ACOD1 genomics question
https://forums.phoenixrising.me/threads/an-acod1-genomics-question.90574/

 

Merged thread

Itaconate or how I learned to stop avoiding the study of immunometabolism Coelho 2022

Short article no abstract.

https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010361&type=printable

 

Online version, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010361