The itaconate shunt hypothesis
- Thread starter Jaybee00
- Start date
I agree, it's a nice presentation and the idea is appealing in many ways.
Towards the end there are some hypotheses of what should be able to be found if the idea is true. Robert says that a number of the hypotheses have already been found to be correct - it would be good to have a good look at those.
I'm glad Robert's team continues to work on the idea.
Towards the end there are some hypotheses of what should be able to be found if the idea is true. Robert says that a number of the hypotheses have already been found to be correct - it would be good to have a good look at those.
I'm glad Robert's team continues to work on the idea.
Many of us can't see Twitter threads.
Can someone say whether this is just chat or has some valid scientific content?
Jonathan Edwards
Senior Member (Voting Rights)
I thought even Robert had given up the metabolic trap idea.
Mij
Senior Member (Voting Rights)
There are 24 tweets following his original. He goes on to explain the "tryptophan metabolism" theory and the "trap hypothesis".
Have the studies cited here been discussed before – and have they been validated or rejected?
If you replace the x.com in the URL with nitter.net you'll be able to read the thread.
Jonathan Edwards
Senior Member (Voting Rights)
We had quite. lengthy discussion with Robert in a thread here. The itaconate idea is intriguing and the implication of alpha interferon makes some sense. However, inasmuch as it has been tested I think the results for the interferon were negative. That does not kill the theory but I don't think we have any strong evidence in favour of it.
Were there any ideas as to what scientists could test to prove or disprove the hypothesis?
Jonathan Edwards
Senior Member (Voting Rights)
Further tests ? I think you would have to ask Robert. I forget.
wigglethemouse
Senior Member (Voting Rights)
Sjoerd Beentjes, PhD, University of Edinburgh presented "Seven replicated genomic associations of ME/CFS: A biobank study" at the Stanford ME/CFS community symposium on 11 Sept 2026. He only presented one of the 7 genes by name which turned out to be CLYBL which Robert Phair also discussed today again as a part of the Itaconate shunt hypothesis talk.
DMissa
Senior Member (Voting Rights)
which talk? it would be good to see the current version of rob's ideas
wigglethemouse
Senior Member (Voting Rights)
Last years talk is here
And a support talk also from last year about a zebra fish model here
This years talk was at the Stanford Symposium 11 Sept 2026 and should be posted to the same YouTube channel.
Link to a copy of the slides is in this post (hosted on google share drive)
This was a key slide showing separation between 10 patients and 10 controls.
DMissa
Senior Member (Voting Rights)
I am watching the talk. The pictured experiment was done using mixed PBMC by the sound of it. If so, these observations cannot be attributed directly to mitochondrial or metabolic differences because differences in the composition of those mixed PBMC will confound these measurements (different types of cells comprising mixed PBMC can have very different metabolic states and preferences to each other). The proportions of these different cell types naturally shift between individuals and even within individuals depending on many common factors. Greatly so.
This is the same confounder plaguing all of the PBMC seahorse work or that recent Long COVID PBMC omics paper that made the claim of mitochondrial problems.
The model is interesting and of course is very well thought out by Rob (especially the estrogen link) but I remain unaware of reliable evidence supporting the suspected mitochondrial issues. This needs to be tested in a homogeneous and comparable sample type. This can easily be done - this experiment is extremely cheap and easy. Put some cells into a few hundred bucks worth of biolog plates with some dye and press a button on a plate reader. You just need the cells to not have this confounding factor present. Well-sorted PBMC would be a good start since the question revolves around immune cells. With and without immune stimuli would be even better. I will write to Rob about this.
Last edited:
DMissa
Senior Member (Voting Rights)
PS I want to add separately that monocytes and NKs are probably the biggest source of any sort of mitochondrial signal from mixed PBMC. If mitochondrial gene expression, rates of oxygen consumption or production of XYZ thing are often measured to be down in pwME this would instead suggest to me that NKs and/or monocytes are less functionally active or present (for both possibilities; proportional to the entire PBMC background. This is critical. There may be relatively more of the other stuff rather than less of these ones. Or maybe a combination.).
Greetings, everyone. I’m a fan of the Itaconate Shunt Hypothesis. Hats off to those who have brought it so far. For me, it stands head and shoulders above other theories in terms of its explanatory power, and because of how closely it tracks with my experience of ME/CFS. But I have a proposal for the hypothesis based on experimentation on myself.
TLDR:
I believe there’s another loop in the system causing the chronic nature of the condition that’s larger than the one described in Dr. Rob Phair’s Itaconate Shunt Hypothesis, and my guess (based on what I have repeatedly felt in my body, the data from my recovery journal, and my understanding of Rob Phair’s process diagrams) is that there is a stage where the Itaconate Shunt stops, but exercise causes something to emerge in the body that then causes the innate immune system to activate and the Shunt gets switched back on. This would suggest there’s a bigger feedback loop, on top of the cycle described by Rob Phair. If correct, this would also suggest chasing interferon-alpha as the cause of the chronic aspect of the condition might be the wrong avenue of investigation in the search for a cure.
Firstly, to clarify my perspective and experience:
My ME/CFS was caused by COVID in 2022 (I’m male, now 43, and still struggling with it) although I’ve had ME/CFS before when I had EBV when I was 14, which affected me badly for several years, so I’ve had several rounds of pondering this health disaster in my life. I now also have a diagnosis of POTS.
My ME/CFS symptoms are pretty classic: my chief symptoms are brain fog and PEM. A quirk of my case that is perhaps less common is I went from moderate ME (that was undergoing slow but clear improvement) to severe ME in early 2025 after getting the Moderna booster (I cannot know, of course, if there was a causal relationship, but a review of my diary indicates I didn’t do well from the Pfizer vaccines that I received regularly before that, and I experienced similar — if much shallower — declines post-Pfizer boosters from 2022-2024). My delayed onset PEM (according to my latest measurement) is also longer than most: approximately 4 days to kick in fully.
I’ve been improving slowly since that descent into severe ME/CFS last year and in May 2026 I was finally well enough to experiment with short and slow cardio on a recumbent exercise bike to see if I could confirm a larger “energy envelope” that would allow me a routine of regular light cardio (I was also desperate for the benefits of exercise), combined with taking various experimental supplements alongside. This did not go well at all, and I’ve had several set backs in the last 4 months of experimentation. I found that I couldn’t sustain even 1 or 2 rounds of 20 minute recumbent bike exercise per week, although they didn’t trigger full blown PEM. After a month off any attempts at exercise, I went back to the gym and, feeling better, I foolishly did a 30 minute session on the recumbent bike. 4 days later a very bad case of PEM struck that lasted almost 6 weeks and it felt like I had gone back to where I was a year ago. I was quite shocked by this. However, I have learnt a lot more about my disease in the process.
The Itaconate Shunt Hypothesis Connection:
As you can tell from this story, I haven’t been getting great advice on managing my ME/CFS from my doctors hitherto. The failures of the summer led me to start doing a lot more searching for information on my own, particularly focusing on ME/CFS patients’ own experiences on places like Reddit, where I found a bunch of ideas that do, in fact, help me a little bit. That’s how I eventually found my way here. I’d already found on my own that a strict DASH diet helps. Food and supplements linked to antioxidant attributes consistently help.
So I only discovered the Itaconate Shunt Hypothesis very recently. For me, it’s head and shoulders above any other theory of my case. It tracks remarkably closely to what I’ve experienced, both in the body and in terms of cognitive problems. I’ve also found it helpful to evaluate the potential of experimental treatments that I’m considering but yet to try (as we all know, cost and exertion mean any new treatment experiment is a potential ordeal with big downsides, so anything that helps us be judicious is welcome).
But I think there are a couple of things missing from Rob Phair’s version of the Itaconate Shunt Hypothesis:
1. as far as I can tell, I seem to have a problem with tipping into anaerobic energy production far too easily, judging by my heart rate monitor and seeing how it spikes from even very minor exertions that should be firmly aerobic (like taking a short and slow walk). My heart rate is not the only indicator of anaerobic energy production kicking in: I get v out of breath doing simple things alongside my peers doing the same thing, who do not (and who notice and start asking if I’m ok).
2. when I’ve done radical rest for a really really long time, I can start to feel remarkably normal. Both in terms of what I feel I could do physically and in terms of what I can do cognitively. Like I’m almost totally fine. Also, in my recumbent exercise experiments over the summer I felt huge benefits from cardio on the day I did the exercise and the days after (I mentioned my delayed onset PEM). My body was crying out to say “thank you, please do more!”. I’m a humanities scholar and those small bouts of exercise got my mind working again and I started drafting a new book (which was remarkable: it’s been years since I’ve been able to do this). This felt like a massive improvement. But the delayed onset PEM then struck.
Furthermore, one thing Ron Davis at Stanford stays is that this disease leaves the body remarkably unharmed in the patients who’ve recovered from it. I feel this in my own body deeply. Like, if someone could just switch off this disease I would be not far off normal immediately, despite years in its grip.
What I’m getting at:
What I’m getting at is the Itaconate Shunt Hypothesis describes a problem that (IMO) we all knew well before we got ME/CFS: when you’ve had a virus there’s a short period where you feel like you have a dead battery and if you try and do anything it just makes you feel ill, even though you’re over the virus itself. That sounds like the Itaconate Shunt state (and what we’re going through when we’re in PEM).
But what I’m seeing now (from my summer of experimentation) is that we can get into states when we feel better (as long as we haven’t tried to exert ourselves yet), and then exertion causes something to happen in the body that, a few hours or days later, then causes your body to switch the Itaconate Shunt back on. So, rather than a permanent state of Itaconate Shunt dynamics with a feedback loop driven by the creation of interferon-alpha, there’s a state where the Itaconate shunt lets go, you feel normal, and then a threshold of exercise makes the innate immune system switch the Itaconate shunt back on (hence many of us with moderate-to-mild ME/CFS use pacing quite successfully to prevent breaching that threshold).
I know this is a perspective based on my particular symptoms and my particular stage of slow recovery with (what is now) probably moderate (or upper end of moderate) ME/CFS. But I’ve seen many others describe similar dynamics on ME/CFS and Long Covid forums. And this dynamic isn’t quite captured by the Itaconate Shunt hypothesis.
I believe there’s a higher loop in the system, and my guess (based on what I have repeatedly felt in my body, the data from my recovery journal, and my understanding of Rob Phair’s process diagrams) is that there is a stage where the Itaconate Shunt cycle stops, but exercise causes something to emerge in the body that then causes the innate immune system to activate and the Shunt gets switched back on. This would suggest there’s a bigger feedback loop, on top of the feedback loop described by Rob Phair. If correct, this would also suggest chasing interferon-alpha as the cause of the chronic nature of the condition would be the wrong avenue of investigation in the search for a cure.
Thank you for reading all of this if you got this far. I expect a real hiding from those who have been puzzling over these things in serious and scholarly ways for years. Forgive my ignorance.
TLDR:
I believe there’s another loop in the system causing the chronic nature of the condition that’s larger than the one described in Dr. Rob Phair’s Itaconate Shunt Hypothesis, and my guess (based on what I have repeatedly felt in my body, the data from my recovery journal, and my understanding of Rob Phair’s process diagrams) is that there is a stage where the Itaconate Shunt stops, but exercise causes something to emerge in the body that then causes the innate immune system to activate and the Shunt gets switched back on. This would suggest there’s a bigger feedback loop, on top of the cycle described by Rob Phair. If correct, this would also suggest chasing interferon-alpha as the cause of the chronic aspect of the condition might be the wrong avenue of investigation in the search for a cure.
Firstly, to clarify my perspective and experience:
My ME/CFS was caused by COVID in 2022 (I’m male, now 43, and still struggling with it) although I’ve had ME/CFS before when I had EBV when I was 14, which affected me badly for several years, so I’ve had several rounds of pondering this health disaster in my life. I now also have a diagnosis of POTS.
My ME/CFS symptoms are pretty classic: my chief symptoms are brain fog and PEM. A quirk of my case that is perhaps less common is I went from moderate ME (that was undergoing slow but clear improvement) to severe ME in early 2025 after getting the Moderna booster (I cannot know, of course, if there was a causal relationship, but a review of my diary indicates I didn’t do well from the Pfizer vaccines that I received regularly before that, and I experienced similar — if much shallower — declines post-Pfizer boosters from 2022-2024). My delayed onset PEM (according to my latest measurement) is also longer than most: approximately 4 days to kick in fully.
I’ve been improving slowly since that descent into severe ME/CFS last year and in May 2026 I was finally well enough to experiment with short and slow cardio on a recumbent exercise bike to see if I could confirm a larger “energy envelope” that would allow me a routine of regular light cardio (I was also desperate for the benefits of exercise), combined with taking various experimental supplements alongside. This did not go well at all, and I’ve had several set backs in the last 4 months of experimentation. I found that I couldn’t sustain even 1 or 2 rounds of 20 minute recumbent bike exercise per week, although they didn’t trigger full blown PEM. After a month off any attempts at exercise, I went back to the gym and, feeling better, I foolishly did a 30 minute session on the recumbent bike. 4 days later a very bad case of PEM struck that lasted almost 6 weeks and it felt like I had gone back to where I was a year ago. I was quite shocked by this. However, I have learnt a lot more about my disease in the process.
The Itaconate Shunt Hypothesis Connection:
As you can tell from this story, I haven’t been getting great advice on managing my ME/CFS from my doctors hitherto. The failures of the summer led me to start doing a lot more searching for information on my own, particularly focusing on ME/CFS patients’ own experiences on places like Reddit, where I found a bunch of ideas that do, in fact, help me a little bit. That’s how I eventually found my way here. I’d already found on my own that a strict DASH diet helps. Food and supplements linked to antioxidant attributes consistently help.
So I only discovered the Itaconate Shunt Hypothesis very recently. For me, it’s head and shoulders above any other theory of my case. It tracks remarkably closely to what I’ve experienced, both in the body and in terms of cognitive problems. I’ve also found it helpful to evaluate the potential of experimental treatments that I’m considering but yet to try (as we all know, cost and exertion mean any new treatment experiment is a potential ordeal with big downsides, so anything that helps us be judicious is welcome).
But I think there are a couple of things missing from Rob Phair’s version of the Itaconate Shunt Hypothesis:
1. as far as I can tell, I seem to have a problem with tipping into anaerobic energy production far too easily, judging by my heart rate monitor and seeing how it spikes from even very minor exertions that should be firmly aerobic (like taking a short and slow walk). My heart rate is not the only indicator of anaerobic energy production kicking in: I get v out of breath doing simple things alongside my peers doing the same thing, who do not (and who notice and start asking if I’m ok).
2. when I’ve done radical rest for a really really long time, I can start to feel remarkably normal. Both in terms of what I feel I could do physically and in terms of what I can do cognitively. Like I’m almost totally fine. Also, in my recumbent exercise experiments over the summer I felt huge benefits from cardio on the day I did the exercise and the days after (I mentioned my delayed onset PEM). My body was crying out to say “thank you, please do more!”. I’m a humanities scholar and those small bouts of exercise got my mind working again and I started drafting a new book (which was remarkable: it’s been years since I’ve been able to do this). This felt like a massive improvement. But the delayed onset PEM then struck.
Furthermore, one thing Ron Davis at Stanford stays is that this disease leaves the body remarkably unharmed in the patients who’ve recovered from it. I feel this in my own body deeply. Like, if someone could just switch off this disease I would be not far off normal immediately, despite years in its grip.
What I’m getting at:
What I’m getting at is the Itaconate Shunt Hypothesis describes a problem that (IMO) we all knew well before we got ME/CFS: when you’ve had a virus there’s a short period where you feel like you have a dead battery and if you try and do anything it just makes you feel ill, even though you’re over the virus itself. That sounds like the Itaconate Shunt state (and what we’re going through when we’re in PEM).
But what I’m seeing now (from my summer of experimentation) is that we can get into states when we feel better (as long as we haven’t tried to exert ourselves yet), and then exertion causes something to happen in the body that, a few hours or days later, then causes your body to switch the Itaconate Shunt back on. So, rather than a permanent state of Itaconate Shunt dynamics with a feedback loop driven by the creation of interferon-alpha, there’s a state where the Itaconate shunt lets go, you feel normal, and then a threshold of exercise makes the innate immune system switch the Itaconate shunt back on (hence many of us with moderate-to-mild ME/CFS use pacing quite successfully to prevent breaching that threshold).
I know this is a perspective based on my particular symptoms and my particular stage of slow recovery with (what is now) probably moderate (or upper end of moderate) ME/CFS. But I’ve seen many others describe similar dynamics on ME/CFS and Long Covid forums. And this dynamic isn’t quite captured by the Itaconate Shunt hypothesis.
I believe there’s a higher loop in the system, and my guess (based on what I have repeatedly felt in my body, the data from my recovery journal, and my understanding of Rob Phair’s process diagrams) is that there is a stage where the Itaconate Shunt cycle stops, but exercise causes something to emerge in the body that then causes the innate immune system to activate and the Shunt gets switched back on. This would suggest there’s a bigger feedback loop, on top of the feedback loop described by Rob Phair. If correct, this would also suggest chasing interferon-alpha as the cause of the chronic nature of the condition would be the wrong avenue of investigation in the search for a cure.
Thank you for reading all of this if you got this far. I expect a real hiding from those who have been puzzling over these things in serious and scholarly ways for years. Forgive my ignorance.