Review Dysregulation of lipid metabolism, energy production, and oxidative stress in [ME/CFS], [GWS], and Fibromyalgia, 2025, Davis, Morten et al

Dysregulation of lipid metabolism, energy production, and oxidative stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Gulf War Syndrome and Fibromyalgia

Leah Davis, Maisy Higgs, Ailsa Snaith, Tiffany A Lodge, James Strong, Jose Oltra, Sławomir Kujawski, Pawel Zalewski, Etheresia Pretorius, Karl Jonathan Morten

[Line breaks added]

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the aetiology of these illnesses remains largely unknown.

Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients. The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases.

Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterisation of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unravelling the metabolic phenotypes associated with these complex diseases.

Emerging evidence suggests that ME/CFS, GWS, and FM are all characterised by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention.

Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.

Link (Frontiers in Neuroscience) [Provisionally Accepted]

 

Can anyone tell me what 'oxidative stress' actually means?
It always sounds to me about as clearly defined as 'bad vibes'.

 

the abstract explains what they are meaning "Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage."

 

I was confused since it's not in the thread's paper, but found the quote in a different paper:

Preprint - Oxidative Stress is a shared characteristic of ME/CFS and Long COVID, 2024, Shankar, Bonilla, Davis et al.

 

That is what they measured but what is 'oxidative stress'?!
Is it a state, a result of something, a tendency, a cause or what? If it is something inferred what is it? If it is something found why not just call it what is found?
Is there any real evidence for ROS being 'bad' anyway?

 

I remember reading something about how ROS allegedly induces damage during ischemia and reperfusion. E.g. this article:
https://www.sciencedirect.com/science/article/pii/S2213231714000718

I believe I read about it in the context of some hypothesis about how endothelial damage could possibly create very local ischemia og reprefusion. I might completely misremember everything, though. And I have no idea about the quality of the paper above.

 

"Oxidative stress" would generally be referring to a biological scenario that involves increased likelihood of damage to molecules usually by accumulated reactive oxygen species

yes

It is one of those phrases that is wielded often and probably too loosely (which phrase in biology isn't? alas) but the concept itself is founded on a bedrock of a lot of biochemistry & cell biology

I am also hesitant to label things good or bad, as we both know everything in biology is relative and too much or too little of just about anything causes problems. The issue is that ROS will spontaneously react with and damage a wide spectrum of molecules - intrinsically so

Have a look at parkinson's disease

Yes, it has bactericidal properties, if this kind of thing was what was being gotten at, but this also comes with side effects to the host

 

But that is handwaving, surely. I spent my life working out specific inflammatory effector mechanisms, having been trained in the experimental Path department at Bart's and with John Vane's old group at Wellcome. Reactive oxygen species were a buzz in the 1980s - when they were called free radicals. Various people including Tony Segal then pointed out that they probably have very little to do with tissue damage, except in true ischaemia perhaps, and are involved in regulating local conditions for lysosomal enzyme function. Having been steeped in chronic inflammatory disease for 45 years I never came across a credible invocation of ROS.

But is it? Around 2000 my information was that everyone had got the role wrong and that ROS really weren't inflammatory mediators as such. What I go on hearing is repetition of old memes from the last century. Sure, there are pathways, with glutathione and stuff, but is any of it of any interest? (Other than in ischaemia.)

Yes, but that is like the metalloproteinase story for joint destruction in arthritis, again from the 1980s. Collagenase will eat tissue anywhere, and so everyone assumed that joint damage was due to IL-1and TNF driving collagenase. But then Barrett showed that there was so much TIMP around it wouldn't work. What later became clear is that collagenase is only allowed to attack cartilage that has already died probably from starvation due to the absence of glucose and/or oxygen availability in inflammatory joint effusions. As far as I know ROS do not react with anything very much because of protetive mechanisms other than in situations where there is already necrosis.

The weird thing is that these old memes seem to have come to dominate science chat even more than they did forty years ago. It is as if everyone has gravitated to the lowest common denominator discussion because everything is now done by Twitter. (Actually it is the highest common factor but in common parlance people say lowest common denominator- a manifestation of the same sort of meme perhaps!)

 

I initially began my reply by responding point by point but it became pretty clear that there’s a central issue here that it would be more efficient to address directly: what you are discussing is in the context of inflammation research and based on knowledge largely pre-2000. I was not talking about inflammation and there is 25 years’ worth of intervening research - in other fields - going unacknowledged.

The burden cannot fall on one person in a forum reply to deliver several decade’s worth of scientific consensus from several fields. All I can reasonably do is point you in relevant directions. Have a read through some modern Parkinson’s Disease research or DNA damage and repair in cancer. The relevance and consequences of excessive or inadequately handled ROS are inarguable in these and other settings.

If the issue here is directed towards the paper in this thread specifically then I don’t know, I haven’t read it yet.

 

I have not read the paper either but the suggestion is that oxidative stress may contribute to symptoms in ME/CFS, GWI or fibromyalgia. I have no idea what specific mechanisms would mediate that and I am suspicious nor do they. I am happy to be told there are plausible mechanisms for these illnesses - especially for ME/CFS but so far nobody seems to have suggested one

I am not very familiar with Parkinson's research but is there actually evidence of 'oxidative stress' leading to the damage to cells in substantial nigra etc? What would give rise to that 'stress'? I am not suggesting that the burden of delivering decades of research falls on anyone but usually when there is a relevant answer to this sort of question a sentence or two and an author's name are enough. I am very familiar with theories of DNA damage (my brother is a breast cancer biologist and we often exchange ideas) being mediated by oxidation, as in the context of alcohol and more traditional things like radiation but I don't really see the value of the 'oxidative stress' concept even there. I am really just arguing for being specific about pathways in specific contexts because so much of the field consists of people applying blurred ideas in inappropriate contexts.

 

ME Research UK:

A review paper from Dr Karl Morten’s team has highlighted that “complex chronic illnesses” ME/CFS, fibromyalgia, and Gulf War Syndrome (GWS) not only have common symptoms such as fatigue and pain but also display “significant overlap in the molecular and cellular disruptions”, but are these disruptions “primary drivers of disease or secondary effects resulting in chronic illness"?

The authors conclude that “addressing these complex challenges [in research] requires coordinated international efforts and substantial financial support”.

Read more: https://bit.ly/4ihgWxP

 

I had 'high' oxidative stress biomarkers during sampling. I also had poor plasma values for all antioxidants.

 

These bits led me to believe (I think fairly) that you were referring to ROS in disease in general, as well as human disease research in general.

I agree with this, it just didn't come across that way with the broader things being said so I made broader replies.

It depends on which form of PD we are referring to. For sporadic PD arising from exposure to mitochondrial poisons in agriculture, yes, it is clear and demonstrated. Many of the causal mutations in the genetic forms incur loss of function of proteins involved in ROS mop-up, so it's a model but with at least a clear, rational basis and a lot of evidence supporting it.

Indeed, but it is also easy to google a lit review as a starting point which I trust (in good faith) that anybody curious about a topic will have already attempted. google "PD rotenone pubmed" and one will have plenty of useful findings to read.

 

Yes, this is the sort of thing I am sceptical of. It is very reminiscent of the idea of 'TH1/TH2 cytokine balance' in immunology, which never had any coherent meaning and has never led to any progress in research - just wasted billions of public money.

I used to have slide of 'Cytokine Balance' with a pair of scales with Noddy in one pan and Big Ears in the other. It made the point. My nephew, who is a translational biochemist, still uses the slide for student lectures he told a couple of weeks ago.

People believe this stuff is meaningful. It isn't. What is meaningful is description of specific pathways that are shifted in specific ways in specific contexts to produce very specific pathomechanisms.

 

Oxford Uni, Nuffield Dept, Womens and reproductive health

https://www.wrh.ox.ac.uk/news/dysre...ients,to upregulation of antioxidant pathways.

 

Generally yes but lit reviews are a little different as they are often an entry point for new readers. Since they are discussing other illnesses too, this is context that may explain the choice to describe ME/CFS as well.