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

[forestglip]

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]

 

[SNT Gatchaman]

Now published.

 

[Jonathan Edwards]

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

 

[DMissa]

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."

 

[forestglip]

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.

 

[Jonathan Edwards]

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."

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?

 

[Utsikt]

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.

 

[DMissa]

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?

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

Is there any real evidence for ROS being 'bad' anyway?

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

 

[Jonathan Edwards]

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

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.

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

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.)

The issue is that ROS will spontaneously react with and damage a wide spectrum of molecules -

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!)

 

[DMissa]

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.

 

[Jonathan Edwards]

Have a read through some modern Parkinson’s Disease research or DNA damage and repair in cancer.

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.

 

[Dolphin]

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

 

[Mij]

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

 

[DMissa]

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.)

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!)

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 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.

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

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'?

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.

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

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.

 

[SNT Gatchaman]

In terms of a general review, this one is 8 years old but is highly cited.

Oxidative Stress (2017)
Helmut Sies; Carsten Berndt; Dean P. Jones

Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level of oxidant challenge, termed oxidative eustress, is essential for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which redox signaling integrates these converse properties.

Redox balance is maintained by prevention, interception, and repair, and concomitantly the regulatory potential of molecular thiol-driven master switches such as Nrf2/Keap1 or NF-κB/IκB is used for system-wide oxidative stress response. Nonradical species such as hydrogen peroxide (H2O2) or singlet molecular oxygen, rather than free-radical species, perform major second messenger functions. Chemokine-controlled NADPH oxidases and metabolically controlled mitochondrial sources of H2O2 as well as glutathione-and thioredoxin-related pathways, with powerful enzymatic back-up systems, are responsible for fine-tuning physiological redox signaling.

This makes for a rich research field spanning from biochemistry and cell biology into nutritional sciences, environmental medicine, and molecular knowledge-based redox medicine.

Link | SciHub (Annual Review of Biochemistry)

To Jo's point they do also comment in their "The Concept of Oxidative Stress" section —

As useful as the term oxidative stress may be in research, there has been an inflationary development (i.e., the term has been overstressed). Warrantable cautionary words were voiced regarding the translation of the concept into clinical applications and the general use of the terms oxidative stress and reactive oxygen species

 

[Jonathan Edwards]

In terms of a general review, this one is 8 years old but is highly cited.

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.

 

[Sly Saint]

Oxford Uni, Nuffield Dept, Womens and reproductive health

The release of the government's ME/CFS delivery plan is imminent, but the lack of a strategic call for these complex, chronic conditions has left patients frustrated and demanding action.

Recently published in Frontiers in Neuroscience; experts including Tiffany Lodge and Karl Morten shed light on the links between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM). These three chronic conditions share similar symptoms and currently lack reliable diagnostic tests. A key factor in these conditions appears to be oxidative stress, which can disrupt muscle energy production and lead to fatigue.

Studies have shown that patients with ME/CFS present with signs of energy production failure associated with muscle weakness, impaired cognition with evidence of increased oxidative stress liked to upregulation of antioxidant pathways.

Scientists are now using advanced research techniques like metabolic profiling and MRI to understand better why these elevated levels may lead to new treatment options for ME/CFS, GWS, and FM.

Research unlocks new insights
Interestingly, researchers have drawn comparisons between these conditions and Alzheimer's disease, which shares similar issues and energy dysfunction is also observed. In ME/CFS, patients also face challenges regarding physical activity; their bodies may not respond to exercise as effectively due to unknown mechanisms. This can lead to a worsening of symptoms known as post-exertional malaise (PEM), making it crucial for patients to manage their activities carefully.

Overall, the findings highlight the importance of understanding oxidative stress and energy dysregulation in ME/CFS, GWS, and FM. Researchers hope to develop better ways to support individuals living with these challenging conditions by exploring these connections.

Read the publication in full: "Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia"

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

 

[Hutan]

I don't think we've had much comment on the paper itself.

There are 11 authors, some of whom are very high profile. They all claim to have been involved in writing the paper.

Leah Davis1, Maisy Higgs1, Ailsa Snaith2, Tiffany A. Lodge1, James Strong1, Jose A. Espejo-Oltra3, Sławomir Kujawski4 Paweł Zalewski 4,5 Etheresia Pretorius 6,7 Michael Hoerger 8 Karl J. Morten1*

1The Nuffield Department of Women's and Reproductive Health, The Women Centre, The John Radcliffe Hospital, The University of Oxford, Oxford, United Kingdom

2Veterans and Families Institute for Military Social Research, Anglia Ruskin University, Chelmsford, United Kingdom

3Department of Pathology, Catholic University of Valencia Saint Vincent Martyr, Valencia, Spain

4Department of Exercise Physiology and Functional Anatomy, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland, Nicolaus Copernicus University in Torun, Torun, Poland

5Department of Experimental and Clinical Physiology, Warsaw Medical University, Warszawa, Poland

6Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa

7Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom

8Departments of Psychology, Psychiatry, and Medicine, Tulane Cancer Center, Tulane University, New Orleans, LA, United States

I've got as far as the Introduction. It is very repetitive. It makes the same points in several places. And there doesn't seem to be a clear structure to it.

Here are the introductory sentences, telling us way too much about "chronic illnesses" in general:

Approximately one in three adults worldwide is estimated to suffer from one or more chronic illnesses, imposing a substantial burden on both the patients and healthcare systems globally. These complex chronic conditions are associated with a marked reduction in the quality of life for affected individuals and lead to increased healthcare costs due to the need for ongoing management and intervention (Hajat and Stein, 2018). Chronic illnesses are typically defined as long-term health conditions that are persistent and require continuous management, often through a combination of pharmacological and non-pharmacological therapies. Fatigue is a common symptom in many chronic illnesses and can be debilitating; some patients become so severely affected to the point of being bedbound (Goërtz et al., 2021). Conditions such as Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fibromyalgia (FM), and Gulf War Syndrome (GWS) are examples of these chronic illnesses that are triggered by different factors but share overlapping clinical symptoms, in particular profound fatigue (see Figure 1).

And to illustrate the repetition, here are references to fatigue in the Introduction:

Fatigue is a common symptom in many chronic illnesses and can be debilitating; some patients become so severely affected to the point of being bedbound (Goërtz et al., 2021). Conditions such as Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fibromyalgia (FM), and Gulf War Syndrome (GWS) are examples of these chronic illnesses that are triggered by different factors but share overlapping clinical symptoms, in particular profound fatigue
...
To be diagnosed with GWS, the Centers for Disease Control and Prevention (CDC) criteria for Chronic Multisymptomatic Illness (CMI) require symptoms from at least two of the three symptom clusters: general fatigue, mood and cognitive abnormalities, and myalgia/athralgia pain (Fukuda et al., 1998).
...
COPIND is associated with long term symptoms resulting from prolonged or repeated exposure organophosphates which are chemicals found in pesticides, nerve agents and some industrial products. The routes of potential exposure to these chemicals are clearly not solely the preserve of the military environment, thus associated symptoms such as fatigue are prevalent across parts of society. For an excellent review of diagnostic issues in fatigue-associated conditions and brain effects, see Baraniuk (2022).
...
FM is associated with chronic musculoskeletal pain with patients also suffering from fatigue, sleep, and cognitive disturbances.
...
Despite differing aetiological factors, the clinical presentation of ME/CFS, FM, and GWS demonstrates many overlapping characteristics suggesting the possibility of common biological pathways. Fatigue is a central feature of all these disorders, often exacerbated by exertion and non-restorative sleep. Fatigue can be categorized as chronic when it persists for more than 6 months and is unrelieved by rest, often without a clear underlying medical cause. Secondary fatigue tends to be linked to identifiable medical conditions and typically lasts <6 months, whereas physiological fatigue results from imbalances in sleep, nutrition, and physical activity and is relieved by rest. Fatigue is a common symptom in both ME/CFS and Fibromyalgia, with post-exertional malaise (PEM) being a hallmark of ME/CFS.
...
While ME/CFS and FM often co-occur, and GWS has distinct initial triggers, these conditions share numerous overlapping symptoms.

Here are quotes from the introduction about EBV as a trigger:

In contrast with the circumscribed triggers of GWS, ME/CFS is associated with a number of potential infectious triggers, while Epstein-Barr virus (EBV) has been hypothesized as a contributor to FM.
...
GWS is specifically linked with exposure to neurotoxic agents, including organophosphates, carbamates, sarin/cyclosarin nerve agents, and pyridostigmine bromide, used as prophylactic measures against chemical warfare, whereas ME/CFS has been associated with viral infection triggers. Similarly, a potential trigger for FM has been suggested to be the Epstein-Barr virus (Cohen et al., 2022).

And here are quotes from the introduction about reactivation of EBV:

Long COVID, studied widely in recent years, also shares common features with these conditions, and this further complicates the landscape, as studies indicate that 20–31% of Long COVID patients also meet FM diagnostic criteria 6 months post-infection (Fernández-de-Las-Peñas et al., 2022; Ursini et al., 2021). Furthermore, there may also be a contribution made by reactivation of latent viruses. In particular, EBV reactivation is observed in ME/CFS (Koelle et al., 2002; Ruiz-Pablos et al., 2021), FM (Duffy et al., 2022), and Long COVID (Shafiee et al., 2023), suggesting a possible shared pathological pathway.
...
Reactivation of latent viruses, particularly the Epstein-Barr virus, has been observed in conditions such as ME/CFS (Koelle et al., 2002; Ruiz-Pablos et al., 2021), FM (Duffy et al., 2022) and Long COVID (Shafiee et al., 2023; Peluso et al., 2023).

Figure 2 in the Introduction is completely irrelevant to the topic:

It's about the prevalence of Long Covid relative to the number of Covid-19 infections in the US, Canada and the UK. It's worth having a look at Figure 2 and then scrolling up to remind yourself of the title of this paper. It's very strange.

I'm sorry to say this given the conversation we have been having elsewhere about being critical:
But this looks to be another student review where the other authors, in this case including quite a number who are seen by many as world-leading experts in ME/CFS research, and everyone else involved such as the peer reviewers and the editors have not paid enough attention during the process of turning the student's work into a paper.

Perhaps the paper will get better further on, but I think this is clearly very disappointing so far.

We need researchers to understand that they don't need to tell their readers all about the disease in question (in this case ME/CFS, GWS and fibromyalgia, with COPIND, POTS and Long Covid thrown in for good measure) in the introduction of a paper about something specific (in this case the biochemistry of the conditions). I'm reminded about @Ravn's comments about introductions. Keep all the background stuff about ME/CFS or whatever to a minimum - that way there is less to get wrong and there is more room to talk about the work that you actually did.

 

[DMissa]

Keep all the background stuff about ME/CFS or whatever to a minimum - that way there is less to get wrong and there is more room to talk about the work that you actually did.

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.