Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?(2019) - G.Morris,Maes,Berk,Puri

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Abstract

A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals.

The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation.

The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
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https://link.springer.com/article/10.1007/s11011-019-0388-6
 
The paper is open access if anyone wants to have a read.

I don't think they are trying to be funny or ironic with this bit but hard to be sure. ;)
Many patients complain of ‘brain fog’, which is often described as slow thinking, difficulty focusing, slow thinking, lack of concentration..
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To those of you, like me, wondering what endotoxin tolerance might be this bit starts to explain. (Edited to add line breaks only)
Upon detecting danger signals, IIS cells trigger a robust inflammatory response. However, this reaction must be closely regulated because uncontrolled inflammation leads to clinical complications (for example, septic shock, cancer, and autoimmune diseases). In the event of bacterial colonization, a number of mechanisms regulate the inflammation and protect against shock. One of the most important mechanisms for protecting the host is endotoxin tolerance (ET).

Under ET, cells and organisms exhibit a transient state in which they are unable to respond to endotoxin challenges [5]. The phenomenon has been described as a type of tolerance in which exposure to low concentrations of endotoxins reprograms IIS cells. In other words, the innate response to further endotoxin challenges is compromised. However, this does not constitute an ‘immunoparalysis’ but rather an alternative activation that triggers other mechanisms that have yet to be described.

The presence of ET has been studied and reported in several pathologies such as sepsis [6] cystic fibrosis (CF) [7], acute coronary syndrome (ACS) [8], and trauma and pancreatitis [9,10] (Figure 1). In the past few years, a growing number of studies have focused on the main characteristics of ET, revealing much about its mechanisms. This review discusses the main characteristics of ET, ET models, and the molecules involved in this process and its clinical significance.
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ETA: Smiley at the end of my comment showing they had repeated "slow thinking".
 
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It's a great paper, if a little convoluted, but very up to date. They place emphasis on pem as a necessary part of study inclusion, which is great.

The two strong points imho are the correlation of miRNA to immune dysregulation, and the conexion of tgf, il10 and cxcl8 with a hypoinmune state.

They tie it all with a Lps-tolerance homeostatic state, where the body becomes "tolerant" to inflammatory stimuli, and enters a hypoinmune and hypometabolic state, shifting from oxphos to aerobic glycolisis and finally to b-oxidation as the source of ATP. However they write that in this state carnitine palmitoyltrasnferase I is upregulated, which I don't think matches the latest metabolome study.

Finally they state that this hypo state is sustained by a high IDO activity and high kynurenine production. Kinda the opposite of the metabolic trap.
 
Interesting to look at the author's affiliations, shows not all in the psych world are beholden to the BPS crowd.
  • Gerwyn Morris, 1
  • Michael Maes, 1,2
  • Michael Berk 1,3,4,5
  • Basant K. Puri 6

  1. IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia
  2. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  3. Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
  4. Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia
  5. Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Australia
  6. Department of Medicine, Imperial College, London, Hammersmith Hospital, London, UK
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Thanks for the summary @S-VV. Very helpful because this article is waaay over my head but it does sound interesting - or is it just the technical lingo fooling me?

I did note - and appreciate - the number of times the authors commented on the impact of patient selection criteria on study results. But they did seem to equate Fukuda with international consensus criteria (in lower case, as opposed to International Consensus Criteria as in ICC)?

Anyway, is there anyone here with the necessary knowledge and energy to provide a more detailed summary, in plain English?

ETA: Also, it's not clear from the paper if the authors understand the difference between common-garden exercise intolerance and PEM. They seem to think their model of ME can explain exercise intolerance, which is good, but as far as I can see they don't explain PEM - though that's very possibly due to me not understanding much of the paper.
 
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Snow Leopard said:
It's an interesting hypothesis, but unfortunately, it's also almost certainly wrong.
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Why? Why wouldn't it be correct for a subset? Or for a subset of symptoms? Could the direction be interesting? Why not?

I agree though that nitrosative stress maybe is not the answer alone. (Is there any evidence of nitrosative stress/hypernitrosylation in ME or elsewhere?)

They are not speaking of endoplasmic reticulum (ER) stress explicitly, but about elevated NO and ROS (amongst others), which leads to ER stress. ER stress is found in several diseases. There are indications in Alzheimer's, Parkinson's, ALS, inflammation etc. (though, up til now, these are only animal experiments, so...). Exercise, heat, fasting, infections etc are triggers of ER stress. They also mention LPS (Lipopolysaccharide), which is an ER stress trigger, too, and may interrupt with signaling pathways. Yet, there are so many ways that can lead to ER stress. And I think it's complex.

I don't think it's the one and only cause, but maybe it plays a role? Personally, I think there might be something like a disruption in a signaling pathway (which may be different in different persons with ME, leading to a similar problem - for instance, it seems hypernitrosylation may impact similar pathways as, e.g., the IP3 pathway), which may contribute to ER stress, amongst others, which may lead to activity, heat, cold etc. intolerance, while cleavage of the misfolded proteins takes longer as usual or is otherwise disrupted, which may lead, amongst others, to a decrease of calcium transport to the mitochondrion, which leads to decreased ATP production etc. etc. (together, could this be PEM? and why not?).

They mention calcium delivery to mitochondria (which is crucial for them to function properly), although I don't see why L-type calcium channels play the major role here. These are positioned on the plasma membrane. Does the mitochondrion move there for calcium transport? However, the ER and mitochondrion are in close proximity to each other, in the nanometer range (or the mitochondrion can move there), and it's the calcium from the ER that's "puffed" into the mitochondrion.

Oh, I see a part of the authors already published in 2017 about the topic:
https://link.springer.com/article/10.1007/s12035-016-9975-2
There they also explain "hypernitrosylation".

Edit: I need to correct: mitochondria can also move to the plasma membrane.
 
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I found this interesting:

This is pertinent given that HSP production appears to be deficient in CFS patients, and the HSPs produced appear to be dysfunctional,
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Is this correct, does anyone know?
 
Andy said:
Interesting to look at the author's affiliations, shows not all in the psych world are beholden to the BPS crowd.
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Interesting list of authors...

Anybody know more about Gerwyn Morris or Michael Maes?

On some of the quoted papers Morris is listed as a resident of Llanelli....(@JohnTheJack a near neighbour to you)
 
Like most of you I have struggled with terminology & language used.

However I did find this via Self Hacked (admittedly not always the most reliable source, however you may find the explanations on leaky gut, endotoxins, LPS etc a useful starting point.)

Lipopolysaccharides are bacterial toxins that can cause inflammation and health issues.

Normally housed safely in the gut, lipopolysaccharides become toxic by entering the blood through infection, a leaky gut, or with high-fat meals. Once in the blood, they exert many damaging effects on the brain and body.
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https://selfhacked.com/blog/lipopolysaccharides
 
Estherbot said:
Anybody know more about Gerwyn Morris or Michael Maes?
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Michael Maes is a psychiatrist from Belgium. I think he was one of the pioneers of the inflammation theory in depression. In the years 2000, he started studying CFS with pretty much the same idea in mind: that researchers focus too much on behavioral aspects and too little on biological elements such as inflammation. His theory is that ME/CFS could be another example of a runaway inflammatory process. One mechanism that is central to his theory is "leaky gut", the idea that (elements of) gut bacteria "leak out" to other parts of the body and cause immune activation.

Maes has been very critical of GET/CBT and the biopsychosocial model at a time when this was not common in academia. He has published about this together with Frank Twisk. See:
 
lansbergen said:
Maes always was interested in the biology

Gerwyn is a patient. Maybe there are still some posts of him om phoenixrising.
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Much of the history of that period was lost in the great purge of entire threads, massive after the fact editing and revision on forums leading to an exodus and the formation of new forums (themselves with great content now lost as they went into the bit void). Like the termination of the CFSAC and removing its online record into the memory hole, it can be pretended things either never happened, or happened other than they did.
 
I'm afraid some of my memories from that time are not very fond.
I remember one time on the forum that no longer exists, somebody doxxed me giving my name (and not just my first name) alongside my username. This was at a time when I was a regular poster on the forum.
I reported the message. Rather than edit the message, the moderator contacted person and asked them about it. They didn't want to change it. So the moderator said to me they were going to leave it.
It was changed a day later, after the user (not moderator) changed their mind, but still my name and username has been out there at all that time.

I didn't feel able to highlight this in the meantime elsewhere as it would draw attention to my name.

The same moderator once told me that moderating wasn't much work on that forum. I wasn't surprised, given they weren't willing to properly act on a message like that.

(I know one isn't supposed to discuss order fora but it no longer exists now so hopefully not a problem)
 
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