Visual hypothesis of ME/CFS dysregulation, combining multiple patient-led hypotheses.

S

Sebastiaan

Established Member
Dear all,

I'm new to s4me but I wanted to share a visual overview/hypothesis on dysregulated metabolic feedbacks in ME/CFS and other PAIS illnesses that I've made recently in order to better understand how different disease mechanisms combine and amplify eachother. I made this out of frustration with the trial-and-error approach of current treatments, hoping to discuss more individually targeted options with my physician, but it got a bit out of hand and I think it's worth sharing here. The overview includes recent research as well as 3 different patient-led hypotheses by @TamaraRC (link), Patricia Donnellan (link) as well as Jeff Wood (the mechanical basis, as published recently by the renegade research team). So I hope it ties together some of the research discussed on this forum too. I believe it does not require a PhD in immunology to understand some of the key mechanisms at play.

The figure starts from the idea that one can get stuck in this 'maze' of physiological feedbacks, regardless of the initial trigger. So I think similar feedbacks may play a role in both ME, Long Covid or other PAIS illnesses (my initial trigger was Lyme disease). At the center of the figure is dysfunctional compression and dilation of the blood vessels, which causes insufficient blood flow and oxygenation, which in turn triggers inflammation, endothelial dysfunction and many known symptoms. All known and well-studied mechanisms, but the figure details a cascade of pathways and mechanisms that contribute to and amplify this issue. Starting with a rather central role of cortisol dysregulation, based on genetic sensitivity of the mineralocorticoid receptor. Which may indirectly affect both the (nor)adrenaline and serotonin synthesis (which are all vasoconstrictors!) as well as the nitric oxide synthesis pathway (essential for vasodilation!). A key suspect involved in triggering the runaway dysregulation is the 'itaconate shunt' hypothesis as discussed by Rob Phair and people like Ron Davis from the OMF foundation. Ron also has an ongoing research project into biopterin - or BH4 - which also takes a central role in the figure as it is an enzymatic co-factor in many of the dysregulated metabolic pathways.

I hope this helps to take some of the ongoing hyper-specialized research out of isolation and put it into contex. And I hope that by highlighting the many symptoms, it helps create more understanding between research, physicians and patients. I admit that the figure, like the illness, is overwhelming. So I've created an interactive version where you can click on the legend to switch elements on/off. Please find it here:


I'm curious about your ideas and any feedback is very welcome, but I'm still struggling, so I can't promise a quick reply.
Best! Sebastiaan Deetman

patient_led_hypothesis_on_ME_CFS.webp
 
Have you read the thread you linked on cortisol disruption? It seems the opposite of “central role”, and cortisol is largely normal. Just following some of the links in that image site some rather dodgy studies that are the basis for this image along with the large “inflammation with GLP1s this seems rather like the always sunny in Philadelphia meme with Charlie and the red string. There’s almost too much dodgy to unpack, the HBOT, GLP1, cortisol, spirolactone. Follow those links and find the discussions here for the threads
 
Hi @Sebastiaan,

I am afraid to say that none of that makes much sense to me. You have joined together a lot of fashionable buzzwords
Sebastiaan said:
At the center of the figure is dysfunctional compression and dilation of the blood vessels, which causes insufficient blood flow and oxygenation, which in turn triggers inflammation, endothelial dysfunction and many known symptoms.
Click to expand...
but rather than these being
Sebastiaan said:
All known and well-studied mechanisms,
Click to expand...
they are not something I recognise as an inflammation scientist.
Lack of oxygenation does not trigger inflammation, unless there is overt damage and in ME/CFS there is neither inflammation nor damage (nor evidence of insufficient blood flow).

As @ChronicallyOverIt says, you might like to read various threads here on ideas of this sort. Unfortunately there is an awful lot of half-baked quasi-science around ME/CFS on social media.
 
Jonathan Edwards said:
Hi @Sebastiaan,

I am afraid to say that none of that makes much sense to me. You have joined together a lot of fashionable buzzwords

but rather than these being

they are not something I recognise as an inflammation scientist.
Lack of oxygenation does not trigger inflammation, unless there is overt damage and in ME/CFS there is neither inflammation nor damage (nor evidence of insufficient blood flow).

As @ChronicallyOverIt says, you might like to read various threads here on ideas of this sort. Unfortunately there is an awful lot of half-baked quasi-science around ME/CFS on social media.
Click to expand...
Hi Jonathan, thanks a lot for the feedback. I appreciate it. The figure is a first version and honestly a somewhat desperate attempt to make sense of the horrible symptoms, the latest science as well as current treatment strategies. So indeed it may well be half-baked. However, I have tried to stick to peer-reviewed literature where possible. Would you be able to provide some reflection, context or further reading with regards to the link that I used to link hypoxia to inflammation? https://doi.org/10.1073/pnas.1318345110 If not that, what would you consider the main inflammatory mechanism? Do you think the top-right boxes describing cox-2 upregulation & phosphatidylcholine deficiency are likely involved? Thanks again! Best, Sebastiaan
 
ChronicallyOverIt said:
Have you read the thread you linked on cortisol disruption? It seems the opposite of “central role”, and cortisol is largely normal. Just following some of the links in that image site some rather dodgy studies that are the basis for this image along with the large “inflammation with GLP1s this seems rather like the always sunny in Philadelphia meme with Charlie and the red string. There’s almost too much dodgy to unpack, the HBOT, GLP1, cortisol, spirolactone. Follow those links and find the discussions here for the threads
Click to expand...
Hi @ChronicallyOverIt thanks so much for your feedback. I do appreciate it. It's why I'm here. I'll try to respond to what I think are 2 separate issues, first regarding cortisol, then regarding the rest:

What I think is interesting about the cortisol part of the figure is that it's focused at the genetic predisposition to mineralocorticoid receptor (MR) sensitivity, or rather a high cortisol binding affinity for the MR, leading to MR overactivation and (supposedly) lower glucocorticoid receptor (GR) activation. Looking at the list of possible effects, that does fit surprisingly well with a certain set of ME/CFS symptoms. Most studies under the thread on cortisol seem to discuss cortisol levels. These are notoriously hard to get a meaningful reading for (my doctor refused to even test them). Even so, I wouldn't immediately dismiss normal cortisol levels, or equate them with normal functioning, if the receptor response is likely the problem. The rest of the figure details some (admittedly messy) indirect mechanisms through which 5 of the key cortisol regulators (GABA, Na+, Serotonin, Acetylcholine and noradrenaline) may be dysregulated too. This strongly involves another hypothesis on the 'itaconate shunt' from a relatively respectable research team at the OMF foundation. I'm just showing how they might be connected. Proof may be hard to come by, but a few promising case studies on spironolactone (an MR antagonist) seem to be in line with these findings. You mention that even spironolactone is a dodgy suggestion, and I'm very curious to hear why. I'm happy to learn and adjust where needed. Thanks.

Regarding the suggested medications, supplements and things like HBOT. Some of these are based on the linked peer-reviewed publications and there's even some of my own experience in there (I've tried HBOT, and while it didn't do magic, it did improve some unexpected side-symptoms notably). I've been in doubt whether to add these 'suggestions', as it isn't the main focus of the figure. Yet, I hoped that if a patient used an overview like this in discussions with a physician, they might get some ideas of a more targeted treatment to try based on a symptom profile, rather than just based on what is often still a trial-and-error approach. So I kept the suggestions in, hoping they may benefit some patients. But if you have any substantial concerns or further reading on why you consider any of these 'dodgy', I'm all ears. Sincerely.

Thanks again for the feedback! I do realize it's a bit of a risk posting this while new on this forum. I'm unaware of the sentiment towards some of the science and theories. But I do think we need to work towards an overview, tie the hypotheses together and use the best available information to start treating patients better.
 
Sebastiaan said:
The figure is a first version and honestly a somewhat desperate attempt to make sense of the horrible symptoms, the latest science as well as current treatment strategies. So indeed it may well be half-baked.
Click to expand...

None of what you mention is 'the latest science'. It is based on a muddle of poor quality studies, none of which have been adequately validated. Please be aware that in biomedical science in general something like 85% of studies prove worthless or misleading. For ME/CFS that is more like 95%. All the stuff you refer to falls below a basic standard level, which has given some legitimacy to the failure to fund by major organisations like MRC. Most of this stuff is just bad.
Sebastiaan said:
However, I have tried to stick to peer-reviewed literature
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Peer review is bust. The fact that something is peer-reviewed gives no indication whatever that it is valid.
Sebastiaan said:
Would you be able to provide some reflection, context or further reading with regards to the link that I used to link hypoxia to inflammation?
Click to expand...

If you want further reflection from myself and others familiar with ME/CFS science then spend a month or so reading through threads here that have been generated over 9 years. Pretty much all the arguments you might be interested in are argued out here until we cannot find any more to say.

Hypoxia does not produce inflammation unless it produces ischaemic damage, which has never been recorded in relation to ME/CFS. This is just basic pathology teaching. In recent years high profile second rate researchers (what I call the Twitterati) have tended to make statements about this sort of thing that reflect their lack of basic pathology training. The whole situation is a mess. Unless you have personal experience in the validity of this stuff, in terms of having examined cases or viewed microscope slides there is no way you going to be in a position to assess what is garbage and what is real I am afraid.

Sebastiaan said:
If not that, what would you consider the main inflammatory mechanism?
Click to expand...

There isn't one. What made you think there was inflammation in ME/CFS? The Twitterati again?
 
Sebastiaan said:
What I think is interesting about the cortisol part of the figure is that it's focused at the genetic predisposition to mineralocorticoid receptor (MR) sensitivity
Click to expand...
I see a part of your hypothesis and visual is based on the rs5522 variant possibly being implicated in ME/CFS.

I believe that Patrician Donnellan is one of the only people seriously proposing this connection. She is an author on the paper linked from your visual on "rs5522". She has posted on the forum, and her posts indicate that she misunderstood her own genotype and that her hypothesis is based on that misunderstanding.

Please see the thread where she posted here: https://s4me.info/threads/spironola...report-2026-donnellan-et-al.48959/post-690834
 
Sebastiaan said:
https://doi.org/10.1073/pnas.1318345110
Click to expand...

This is typical Twitterati nonsense written by people who want to have a big publication list and have no real idea of pathology. It is all buzzwords, instead of context-specific detailed biology.

I understand that it may come as a shock to realise how bad the literature is. But if you hang around here you will come to see why a large number of intelligent people with ME/CFS have seen through this stuff and out the other side. It isn't that difficult to see how threadbare the arguments are if you cast a critical eye.

Hypoxia and inflammation are not two sides of the same coin. That is a b*****ks.
 
Hi, Sebastian I’ll have to get back to you (possibly Monday) but it would be a great first pass to Google “S4me + the study you have referenced in the poster”. Essentially that is what I would do to start. Most of the studies and research you are posting has been discussed at great length here.


I always find it interesting, you have obviously spent a lot of time+ work looking into this and trying to understand it. Why not start at ground zero, DecodeME, there you’d find the spiro gene is not elevated in the GWAS. Further more @forestglip said it’s completely irrelevant.

Why all small studies (HBOT in particular that actually have had negative outcomes) how did you come across this research? It befuddles me that you can spend this much time researching and not end up here, or realize most of these small studies are of very poor quality. I’m just kind of amazed this keeps happening over and over. I would hope that someone so invested in this space would have come across S4me. It would save you a lot of time.
 
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Sebastiaan said:
Thanks again for the feedback! I do realize it's a bit of a risk posting this while new on this forum. I'm unaware of the sentiment towards some of the science and theories. But I do think we need to work towards an overview, tie the hypotheses together and use the best available information to start treating patients better.
Click to expand...
It hasn’t really got much to do about sentiments as in feelings, as with spending a lot of time going through the actual data and methodology, usually ignoring the authors’s own interpretations.

People here are trying to pull together the evidence every day. But there’s no use in building with bad data, so the first step is to discard all of that. There’s very little left then.

As it stands, there are no treatments. All you can do is to try to manage as best as you can, and give the patients the practical help they need.

Perhaps a useful starting point is to read the factsheets that have been produced recently. Much effort has been made to make sure they give an accurate and neutral account of the current evidence.
ChronicallyOverIt said:
It befuddles me that you can spend this much time researching and not end up here, or realize most of these small studies are of very poor quality. I’m just kind of amazed this keeps happening over and over. I would hope that someone so invested in this space would have come across S4me. It would save you a lot of time.
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That’s a bit harsh. I did the same for a couple of years before I found S4ME. This process takes time, and we can’t fault anyone for not having gotten here sooner. If you’re not used to scientific methodology you’ll resort to listening to the experts, and the experts that are vocal in this field are not keen on rigour. It was a truly world-shattering experience being here the first months, I had to unlearn so much.

I consider myself a skeptic by nature, but I’m not confident I would have realised how bad things truly are without the people here helping me. I know I moan at the researchers and the advocates, but it’s their job to know better so they had it comming.
 
Utsikt said:
That’s a bit harsh. I did the same for a couple of years before I found S4ME. This process takes time, and we can’t fault anyone for not having gotten here sooner. If you’re not used to scientific methodology you’ll resort to listening to the experts, and the experts that are vocal in this field are not keen on rigour. It was a truly world-shattering experience being here the first months, I had to unlearn so much.
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Sorry it’s no dig @Sebastiaan, I’m sorry if I came off that way. It’s my assumption that SEO for S4me is much larger than it is, as I have seen it linked frequently on Reddit, cfs discords now and other places. To me it seems as if people should be getting here faster but I’m probably biased.
 
ChronicallyOverIt said:
Sorry it’s no dig @Sebastiaan, I’m sorry if I came off that way. It’s my assumption that SEO for S4me is much larger than it is, as I have seen it linked frequently on Reddit, cfs discords now and other places. To me it seems as if people should be getting here faster but I’m probably biased.
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It showed up for me early and I even referenced it in other groups at least a year and a half before joining. I just didn’t realise what S4ME truly was, or how much help I needed with interpreting the research. I just used it as a quick source of arguments against the bad treatment trials for LC and didn’t think much about all of the other types of research.
 
Hi @Sebastiaan, welcome. I can see you are very motivated and have worked hard on your hypothesis. Like you, i used to take peer reviewed research at face value, and thought ME/CFS research published was a good basis for explaining our symptoms and would lead to treatments.

It has been both a fascinating learning process and very disillusioning being part of this forum community for the last 9 years. There is so much weak research published.

I suggest you set your model aside, and build your knowledge from the foundations, using forum discussions of research papers that interest you as starting points, as well as articles and videos explaining some of the biology, depending on how much background you already have as foundations . Forget trying to build hypotheses, and focus on learning.

The more i learn, the more i realise the depth of knowledge needed before we start building hypotheses.
 
Utsikt said:
I just didn’t realise what S4ME truly was
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Same experience here. It's not enough just to find the forum. Its knowledge and value are spread over thousands of messages. I continue to discover new interesting, shocking, important topics discussed at length in threads started years before I fell ill. Scientific results, but also historic context. The PACE trial, Cochrane reviews, concrete cases of neglect and maltreatment, the Science Media Centre, common issues with methodology, common arguments and counterarguments, threads about my own doctors...

Those new to the forum would benefit from some framing, an accessible primer, guide or overview that sketches the landscape. I'm not sure if something like that currently exists.
 
wallfish said:
Same experience here. It's not enough just to find the forum. Its knowledge and value are spread over thousands of messages. I continue to discover new interesting, shocking, important topics discussed at length in threads started years before I fell ill.
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I was too foggy today to put my thoughts into words so appreciate everyone here for putting it so well. I very much agree it would be really cool if the depth of interesting discussion on S4ME was easy to explore for newcomers.

Two threads discussing some related ideas are here:
An Introduction to Common Misunderstandings and Controversies for Newcomers
The FAQ Project - a collaborative FAQ of ME/CFS science
 
About inflammation
D

Thread 'The Problem(s) with "Inflammation"'

I hope that I have placed this question in an appropriate space and apologise in advance if, as seems likely, this has already been addressed and I have simply been unable to locate the relevant thread.

It seems that a recurrent objection expressed on S4ME to a great deal of ME research concerns "inflammation", with the S4ME consensus being that there has never been any documented "inflammation" associated with ME, while researcher after researcher and clinic after clinic bluntly assert that they have documented "inflammation" and that this "inflammation" is key to understanding ME. For...
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Welcome @Sebastiaan.

Sorry I do not have the cognitive capacity to assess your model, my ME leaves brain fog makes it hard for me to hold enough information in my awareness at once to take in such an overview. Interestingly I was just thinking minutes before coming across this thread that we do need an overview of all the disparate research themes in ME/CFS and Long Covid that tries to come to some overarching conclusion.

Progress in science sometimes seems to come from the tensions between synthesis of broad swathes of evidence and detailed analysis of the component evidence. Unfortunately with the poor quality of evidence we have so far it may be that any synthesis is currently doomed to fail, however I do think you should be commended for trying.

I think there are some areas of discussion here at S4ME that may be amenable to beginning some form of synthesis, primarily around genetics arising from the Decode ME study and less clearly around potential control systems and feed back loops, which I hope you will find interesting. Also I hope that you do not feel too frustrated that in so much of current science in this field all that we can meaningfully do is pull things apart.

However that is not to say we can not learn a lot from attempts at broad synthesis even at our current knowledge level.
 
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