Hypotheses and Research Directions for ME/CFS

D

Dude

Established Member (Voting Rights)
Since things will likely be a bit quieter over the holidays in terms of new research, I wanted to start a discussion on a topic that really interests me. I’m sure a thread like this may have existed before, but as new studies are constantly being published, opinions and perspectives tend to change over time.

My questions are:

  • Most likely hypothesis: In your personal opinion, and considering the current body of research, what is the most likely hypothesis explaining ME/CFS?
  • Supporting studies: Which studies do you consider the most convincing in supporting this hypothesis?
  • Future research: If you had unlimited funding, what research questions or areas would you most like to see investigated in greater depth?
  • Unlikely hypotheses: Which commonly accepted hypothesis do you consider unlikely or even misguided, and why?
  • Subtypes: Do you believe there are clearly distinguishable subtypes of ME/CFS?
  • PEM as common pathway: Could PEM be a common final pathway resulting from different underlying pathomechanisms?
  • PEM as key: Or, put differently: if PEM were fully understood, could that potentially unravel the disease as a whole?

I look forward to hearing your thoughts and discussing different perspectives!

Edit: These questions are just suggestions; I’m mostly interested in your hypotheses if you don’t want to answer everything :-)
 
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I’ll just say that if ME/CFS is an immune-mediated diseases like a variant of an autoimmune disease, then it should be relatively easy to treat since there are now so many new treatments, especially mab drugs—e.g. Daratumumab.

If it is a brain disease like schizophrenia/depression or a metabolic trap like Rob Phair proposes, that requires developing new small molecule drugs, that’s going to be a longer slog.
 
In my opinion, one of the most promising hypotheses for ME/CFS is that impaired oxygen delivery and energy production in the muscles are central mechanisms.

Prof. Christian Puta and colleagues have shown in recent research that in ME/CFS, the smallest blood vessels and oxygen transport may be disrupted, due in part to issues with microcirculation, limited vasodilation, and deformed red blood cells. As a result, muscle tissue does not receive enough oxygen during exertion, leading to inefficient mitochondrial energy production and an early shift to anaerobic metabolism, producing waste products like lactate and potentially explaining post-exertional malaise. These mechanisms are considered part of a systemic problem involving both circulatory and metabolic aspects.

A review that fits well with this idea is:
Wirth et al., 2024 — Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome.

As a potential trigger, I find it plausible that some studies have identified autoantibodies against vascular receptors (e.g., beta-adrenergic or muscarinic receptors), though this likely does not apply to everyone.

I would like to see more research on mitochondria. While it is not yet proven that we have an ATP deficit, I think this area has been under-investigated so far.

I consider the viral persistence hypothesis very unlikely. I know many researchers believe in it (e.g., PolyBio), but viral persistence is, in my view, the weakest theory. People develop ME/CFS following a wide range of triggers—vaccinations, fluoroquinolone antibiotics, trauma, viruses, dehydration, etc. How likely is it that different viruses all cause the same disease? It just doesn’t make sense, at least to me. This is not very scientific—I admit it’s more of a gut feeling—but current research has not provided strong evidence yet.
 
OrganicChilli said:
How does the muscle theory reconcile with sensory triggers like sound?
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My explanation would be that sound, light, cognitive load, and physical exertion all increase ATP demand.
If oxygen delivery, mitochondrial function, or microcirculation are impaired, any stressor can push cells beyond the same critical energy threshold. Muscles show this most clearly, but the brain and the autonomic nervous system are equally affected.
 
Jaybee00 said:
I’ll just say that if ME/CFS is an immune-mediated diseases like a variant of an autoimmune disease, then it should be relatively easy to treat since there are now so many new treatments, especially mab drugs—e.g. Daratumumab.
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I also believe that B-cell depletion could be an answer for a subset of patients, but the question remains why the results so far have not been clearly positive or consistent?
 
Dude said:
My explanation would be that sound, light, cognitive load, and physical exertion all increase ATP demand.
If oxygen delivery, mitochondrial function, or microcirculation are impaired, any stressor can push cells beyond the same critical energy threshold. Muscles show this most clearly, but the brain and the autonomic nervous system are equally affected.
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I think that's unlikely. We had a discussion a few months ago where people said the brain doesn't actually use all that much energy. I've experienced a very weird switch a week ago where I triggered PEM by watching TV. I was physically severe until then and since then I am physically moderate, but looking at my phone for as little as 10 minutes triggers a headache (down from 10h screen time a day). That does not require more "energy" than walking to the bathroom.
 
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Dude said:
In my opinion, one of the most promising hypotheses for ME/CFS is that impaired oxygen delivery and energy production in the muscles are central mechanisms.
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The basic problem here is that muscle function and microstructure were the first thing researchers looked at in ME/CFS and found nothing wrong. A very competent clinical service histologist I knew well found no microstructural changes. Functional testing with power measurements and more recently cardiopulmonary exercise testing gives normal results at least on first test. If there was oxygen lack that should have shown up on MRI or infra-red spectroscopy. (The same applies to brain if that is supposed to suffer similarly.) And the symptoms don't actually fit for muscle ischaemia - which clinically is reported differently. People with ME/CFS are disabled for a different reason - they feel too unwell to do things.

Negative findings are often the most important in biomedical research and for muscle oxygen lack I think we have very robust negative data on all sides.
 
I'm not at all confident enough to make any strong claims, but these are basically the vague ideas that float around in my head:

Dude said:
Most likely hypothesis
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Dude said:
Supporting studies
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Symptoms related to sickness response (similar to flu symptom mechanism) - Genetic studies pointing to brain (DecodeME, Zhang preprint on HEAL2 model), aligns with symptoms, similarly associated with infection.

Antibodies - Daratumumab and previous Fluge/Mella studies/evidence (cyclophosphamide), IGHV3-30 studies, association with infection. (Though mindful of discussions pointing out that these things don't necessarily implicate antibodies specifically.)

Dude said:
Future research
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Large study characterizing B cell receptors, B cell subsets, T cell receptors, and antibodies - compared with controls, and before/during/after PEM, before/during/after having ME/CFS

Large scale brain imaging/CSF testing - compared with controls, and before/during/after PEM, before/during/after having ME/CFS

Autopsy brain tissue/immune system studies

SequenceME

Long term actimetry

Environmental associations with having ME/CFS or symptom severity (toxic chemicals in air, water, etc)

Investigate whether EBV is doing anything special in ME/CFS (I don't know how to study it specifically)

Dude said:
PEM as common pathway
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Seems likely to me.
 
OrganicChilli said:
I think that's unlikely. We had a discussion a few months ago where people said the brain doesn't actually use all that much energy. I've experienced a very weird switch a week ago where I triggered PEM by watching TV.
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I'm not a neuro expert—there are smarter people on the forum :-)
But for a expl. the study (Beata R. Godlewska et al., Mol Psychiatry, Nov 2025) used MRS, a type of imaging that measures chemical markers in the brain. The result: ME/CFS patients had elevated lactate levels in the anterior cingulate cortex indicating impaired energy metabolism in the brain. In healthy people, these levels were low.
There is evidence that in ME/CFS, not only physical energy production may be impaired, but also factors like cerebral blood flow, brain energy metabolism. This could explain why even “small” cognitive or sensory stressors can trigger severe symptoms, even when the energetic load in the classical sense (calorie expenditure) is relatively low. At least this is my attempt at an explanation.
 
Jonathan Edwards said:
The basic problem here is that muscle function and microstructure were the first thing researchers looked at in ME/CFS and found nothing wrong
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I remember a talk by Wirth where he talked exactly about this. Back then he said, “Many patients show abnormal responses on repeated exercise tests (2-day CPET), consistent with Post-Exertional Malaise.”
Off the top of my head, this study might fit: Betsy Keller et al., J Transl Med, 2024. But there are a few like this, what really matters is the pattern. A quick test might look normal, but in cfs, performance drops a lot the next day even if the effort is the same or full something you don’t see in healthy people or individuals,
 
Dude said:
I remember a talk by Wirth where he talked exactly about this. Back then he said, “Many patients show abnormal responses on repeated exercise tests (2-day CPET), consistent with Post-Exertional Malaise.”
Off the top of my head, this study might fit: Betsy Keller et al., J Transl Med, 2024. But there are a few like this, what really matters is the pattern. A quick test might look normal, but in cfs, performance drops a lot the next day even if the effort is the same or full something you don’t see in healthy people or individuals,
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Everyone here is very aware of these findings but, as I indicated before, they don't add up.

Firstly, differences are only found on a second CPET. If there was shortage of oxygen in muscles that would show up on all studies. Maybe CPET isn't such a good one to look for this (I think it probably isn't), in which case the results don't support lack of tissue oxygen anyway.

Secondly, a difference on a second CPET is not 'consistent with PEM' in any sense I can follow. PEM is something people feel before they try to exercise. It is not a symptom of failing on an exercise test. Anyone with significant PEM is no way going to even try an exercise test as I understand it.

The problem I see here is researchers not having a clear enough idea of what they are looking for and why. As a result they look for things that don't really add up - like a drop off on a second CPET as a 'measure of PEM' which it isn't going to be. And researchers tnd to find what they are looking for. You will always find a few papers that seem, sort of, to confirm a superficially likely hypothesis. But if you take a wider angled view it becomes clear that the findings won't explain anything much anyway.

Betsy Keller was invited to talk about these studies at an IiME research conference. I was looking forward to hearing some science. Strangely, she decided instead to teach the audience how to do exercises and did not give her presentation.

You are entitled to your view, but I suggest going through the old threads here and seeing the great detail in which these ideas have been analysed by members - many of whom have a deep understanding of the problems involved.
 
Jonathan Edwards said:
You are entitled to your view, but I suggest going through the old threads here and seeing the great detail in which these ideas have been analysed by members - many of whom have a deep understanding of the problems involved.
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I’m not a scientist, so I can’t really argue against your points, it would be presumptuous of me. My hypothesis is based purely on findings from recent years. Of course, I’ve looked into it a bit myself. I’m not claiming it’s the absolute truth; this thread is mainly about sharing personal hypotheses, and it’s clear that there’s often an information bias. Still, I get the sense that hypotheses here are quickly dismissed if they’re disproven once or don’t fit someone’s preconceptions.
The fact is, many well-known researchers like Rob Wüst, Scheibenbogen, Chris Puta, and Julia Newton don’t rule out microcirculation disturbances, either as a cause or a consequence.
Here’s an interesting article on the topic that English readers might miss since it was only published in German:
www-wissenschaft-de.translate.goog

»Den Muskeln fehlt der Sauerstoff«

Das Leitsymptom von Patienten mit schwerem Long Covid und ME/CFS ist die post-exertionelle Malaise, kurz PEM. Sportmediziner Christian Puta erforscht die Mechan
www-wissenschaft-de.translate.goog www-wissenschaft-de.translate.goog
 
In terms of hypothesis I'm pretty convinced by the idea of an immune signalling loop perpetuating ME/CFS. In terms of specifics I'm not really qualified to judge but I find the idea of JE et al's T cell and IFNg mediated hypothesis, jnmaciuch's interferon/mtDNA hypothesis, and the idea of some sort of non traditional antibody story in the vain of what Fluge and Mella propose to be my top 3 candidates.

I personally think ME/CFS is likely to be mostly one or two conditions, and I'm not very convinved the idea it is many different things.

If I had unlimited research funds I would give Fluge and Mella all the funding they need, fully fund SequenceME, give jnmacuich the resources she needs to thoroughly test her hypothesis, make sure the Australian researcher members here had enough to pursue their hypotheses. I would fund more basic research into CD38 and CD24 in ME/CFS. Then I would start an organisation that funded good quality research and appoint people trusted by this forum to the advisory board.

I would also look into the feasibility of CD38 PET tracers and tracers of other molecules of interest and perhaps set up some studies of them.

[Edit: Oh and I'd fund some more T Cell studies, perhaps the Elispot (or was it Flurospot?)ones that got interesting results in Long Covid last year]
 
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Dude said:
Still, I get the sense that hypotheses here are quickly dismissed if they’re disproven once or don’t fit someone’s preconceptions.
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Look at the threads in detail. This is not the case. We often revisit and revisit hypotheses. One piece of evidence does not kill a hypothesis most of the time. But when you have a whole raft of negatives it is probably time to call it a day. And generally speaking peole here don't have preconceptions. They are prepared to try anything that might turn to be right. Most of us have no vested interest in terms of grant money or reputation. We just want to know what is real. The case against muscle hypoxia has nothing to do with anyone's preconceptions, just the evidence.
Dude said:
The fact is, many well-known researchers like Rob Wüst, Scheibenbogen, Chris Puta, and Julia Newton don’t rule out microcirculation disturbances, either as a cause or a consequence.
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OK, but I am a well known researcher in musculoskeletal disease and I don't expect anyone to take that as a reason for believing what I say. Well known researchers often push theories that sound plausible on the surface but don't have any sound evidence base. Biomedical science is full of second rate stuff I am afraid. I am very familiar with the work of Wust, Scheibenbogen and Newton and I don't see any good evidence for hypoxia yet.
 
In terms of the Puta interview, it starts with this paragraph from Puta:

Because the muscles no longer receive enough oxygen. There is increasing evidence of microclots disrupting blood flow. Even more significant, however, could be damaged red blood cells. In healthy individuals, they are smooth and resemble gummy candies. In patients after a SARS-CoV-2 infection, they are quite frayed. While these blood cells still transport oxygen, the deformation prevents them from reaching all parts of the body. Furthermore, they bind oxygen more readily to themselves and release it to the muscles only minimally, if at all.

This is all make believe as far as I am aware. There is not a shred of evidence for any abnormal access of red cells to muscle in vivo. I have not heard anything about a shift in oxygen binding. The microclots idea never materialised.
 
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