Metabolomic Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

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Just saw this article posted up on the ME/CFS News twitter.

Link is here.

Abstract:
Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. The pathogenesis is not fully understood. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods

Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results

In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. To the best of our knowledge, this is the first study suggesting peroxisomal dysfunction in ME/CFS based on a comprehensive plasma metabolomic analysis. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5'-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion

Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
Emphasis above is my own. It made me think of a relatively recent (6-8 months ago..?) discussion I saw regarding plasmalogens. I made preliminary notes on them but didn't search further - perhaps this is worth exploring? @Pyrrhus @Hip ?

Here are the notes I took:

Listened to an interesting discussion between Dr Seeds (somewhat scammy peptide doctor) and Dr Goodenowe (plasmalogen expert). He theorises that many issues in aging and chronic disease are present because of a lack of plasmalogens, and that returning to a healthy plasmalogen level can return the majority of function / help regenerative capacity dramatically.

Only starting to read about this as of this moment - preliminary info. Need to flesh out.

Plasmalogens are glycerophospholipids, more specifically plasmenyls with an ester linked lipid at the sn-2 carbon on the glycerol backbone. They fall into either plasmenylcholine (PC), or plasmenylethanolamine (PE, sometimes written plasmenylethalomine) plasmalogens, depending on their head group. They are found in cell membranes in immune, cardiac, and nerve cells, and are theorised to be intimately involved in the mediation of the effects of reactive oxygen species (ROS), as well as modulating cell membrane dynamics and serving as cellular signalling molecules.

Plasmalogens are synthesised in peroxisomes, small cytoplasmic organelles that in addition to plasmalogen production, are involved in the catabolism of long-chain fatty acids, branched-chain fatty acids, D-amino acids, polyamines, bile acid intermediates in liver tissue, and serve to reduce hydrogen peroxide.

A novel, orally available plasmalogen precursor, PPI-1040, was developed recently (by Dr Goodenowe’s team? Haven’t checked). It demonstrated dramatically positive effects in a mouse model of plasmalogen deficiency. Dr Goodenowe also spoke about multiple other studies in which their precursor was able to treat and prevent degenerative diseases - in some cases even returning to normal function despite ongoing treatment with a disease-inducing drug or intervention.
There didn't seem to be very much available pharmaceutically or in the news/literature, so I didn't look into it more at the time. If it is significant to ME/CFS then it is likely worth more effort.
 

Pyrrhus

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Thanks for posting!

This metabolomics preprint was originally written by the authors with a different title, and is discussed here:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
https://forums.phoenixrising.me/thr...cle-in-me-cfs-che-et-al-2021-pre-print.84668/
This metabolomics paper found decreased levels of certain membrane phospholipids in ME patients compared to controls, notably phosphatidyl-choline, phosphatidyl-ethanolamine, and related plasmalogens. This confirms previous research findings of decreased membrane phospholipids.

Phosphatidyl-choline and phosphatidyl-ethanolamine are the two most abundant phospholipids in cells and are important components of cell membranes and mitochondrial membranes, especially in the nervous system.

The authors suggest that this finding might indicate metabolic changes to the Kennedy Pathway, also known as the CDP-choline pathway, which is one of two metabolic pathways for synthesizing phosphatidyl-choline in the body. The other pathway is the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine, and then converts it to phosphatidyl-choline with the use of a methyl donor (AdoMet/SAMe).

Whereas in the previous draft of this paper they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this draft they suggest that these findings might indicate peroxisomal dysfunction.

To me, however, these findings simply suggest downstream deficiencies related to oxidative stress:
To me, the lack of certain phospholipids could come down to a simple secondary nutrient deficiency, as is often seen in the case of oxidative stress or chronic inflammation. As an example, oxidative stress might lead to a lack of methyl donors, which would disrupt the activity of Phosphatidyl-ethanolamine methyl-transferase (PEMT) in the liver, compromising the CDP-ethanolamine pathway to the eventual synthesis of phosphatidyl-choline. In this case, the observed lack of certain phospholipids would also be seen in other conditions with oxidative stress or chronic inflammation.

For more information on how oxidative stress can result in the downstream deficiencies seen in this study, see this discussion:

Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)
https://forums.phoenixrising.me/thr...-study-at-7-tesla-godlewska-et-al-2021.85779/


EDIT: Clarified that this paper is a new draft of a previously discussed draft of this paper.
 
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Thanks for posting!

This metabolomics study is a follow-up to a previous metabolomics study by the same authors:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
https://forums.phoenixrising.me/thr...cle-in-me-cfs-che-et-al-2021-pre-print.84668/



Whereas in their previous metabolomics study they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this study they suggest that these findings might indicate peroxisomal dysfunction.

To me, however, these findings simply suggest downstream deficiencies related to oxidative stress, as described in this discussion:

Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)
https://forums.phoenixrising.me/thr...-study-at-7-tesla-godlewska-et-al-2021.85779/
Very interesting, thank you
 

Pyrrhus

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This metabolomics study is a follow-up to a previous metabolomics study by the same authors:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
Oops, I just realized that this is NOT a follow-up study, rather it is the exact SAME study.

Since this is a pre-print, not a published study, the authors are free to rewrite this paper as they see fit.

They have now re-written the pre-print with a different title and a different hypothesis.

Whereas in their previous draft of this paper they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this draft they suggest that these findings might indicate peroxisomal dysfunction.
 
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I didn’t know which thread to post this in… but I’m trying to learn more about peroxisomes after reading Cort’s latest (March 3, 2022) article on the Limpkin preprint.

I thought this was interesting as I couldn’t find much about possible therapeutics:

- Therapeutic developments in peroxisome biogenesis disorders, Mcguinness, 2000 https://pubmed.ncbi.nlm.nih.gov/11060787/.
(sodium phenylbutyrate is the only therapeutic I saw mentioned when I skimmed the abstract but I can’t focus enough to read)

“Recently, our laboratory demonstrated that sodium 4-phenylbutyrate induces peroxisome proliferation and improves biochemical function (very long chain fatty acid beta-oxidation rates and very long chain fatty acid and plasmalogens levels) in fibroblast cell lines from patients with milder PBD phenotypes.”
 

mitoMAN

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I didn’t know which thread to post this in… but I’m trying to learn more about peroxisomes after reading Cort’s latest (March 3, 2022) article on the Limpkin preprint.

I thought this was interesting as I couldn’t find much about possible therapeutics:

- Therapeutic developments in peroxisome biogenesis disorders, Mcguinness, 2000 https://pubmed.ncbi.nlm.nih.gov/11060787/.
(sodium phenylbutyrate is the only therapeutic I saw mentioned when I skimmed the abstract but I can’t focus enough to read)

“Recently, our laboratory demonstrated that sodium 4-phenylbutyrate induces peroxisome proliferation and improves biochemical function (very long chain fatty acid beta-oxidation rates and very long chain fatty acid and plasmalogens levels) in fibroblast cell lines from patients with milder PBD phenotypes.”
This sounds very interesting
 

halcyon

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We might want to study the effect of The peroxisome proliferator-activated receptor (PPAR). Which is part of Saroglitazar (PPAR alpha and gamma agonist)
A quick google says activation of this receptor allows creation of new peroxisomes.
I was just looking into palmitoylethanolamide (for mast cell inhibition), which is an agonist of the PPAR-α receptor. Seeing that quickly reminded me of this study pre-print. Revisiting it now after recently reading about red blood cells, the decreased phosphatidylcholine finding in the study jumped out at me a bit more.

When red blood cells are exposed in vitro to phosphatidylcholine (PC), they will uptake this lipid, which then induces a shape change in the cell, first causing a change to an echinocyte, followed by reversion to a normal discocyte. When exposed to phosphatidylserine (PS), the cell also changes into an echinocyte, rapidly converts to a discocyte, but then transforms into a stomatocyte (the poorly deforming cup shaped cells found in increased amounts in ME) (Daleke & Huestis, 1989). Echinocytes themselves are also poorly deformable relative to normal discocytes (Geekiyanage et al., 2020). It's tempting to wonder if in vivo in ME then that RBCs exposed to a disadvantageously low PC to PS ratio might contribute to the increase in stomatocytes seen, and if PC repletion might improve things. This study doesn't mention PS at all, and the only PS abnormality in ME that I see at a quick glance is the presence of PS antibodies in 5% of patients in one study. Daleke and Huestis (1989) also mentions that sphingomyelin is found mainly in the outer membrane like PC is, so perhaps the diminished sphingomyelins found in this study might contribute to the RBC shape issues as well.
 

Pyrrhus

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When red blood cells are exposed in vitro to phosphatidylcholine (PC), they will uptake this lipid, which then induces a shape change in the cell, first causing a change to an echinocyte, followed by reversion to a normal discocyte. When exposed to phosphatidylserine (PS), the cell also changes into an echinocyte, rapidly converts to a discocyte, but then transforms into a stomatocyte (the poorly deforming cup shaped cells found in increased amounts in ME) (Daleke & Huestis, 1989).
Very interesting, thanks for sharing.

I tried to look into this line of questioning a while back, but got stymied when I couldn't find a simple relationship between membrane fluidity (the ability of phospholipids to move laterally in the cell membrane) and cell deformability (the ability of the cell to bend when needed)...
 

Pyrrhus

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Consul

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I wonder if its possible to link these findings on peroxisomal dysfunction to the findings from Maureen Hansons metabolomics study from 2022 where they found glutamate metabolism to be the common denominator in disrupted pathways.
 
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This is the first theoretical evidence of what I believe has the potential to illustrate the root cause of our issues.

The lingering effects of long covid are clearly devastating, but I must thank God; for the reason that long covid finally shines the light of some real research into our long neglected illness.

I don't believe that those of us who have had this condition for many years could have it due to a lingering germ or infection, a missing or low hormone level, vitamin, mineral, or supplement, or even an overactive basic immune process. I say that with surety because with all the years I have had under my personal belt, I have had the time to thoroughly explore and experiment in each of these routes, with all coming up a dead end.

Somewhere in us sits a broken recovery process, which we are pre-disposed to genetically. Discovering just what that process will take considerable time. Then, how to fix or adjust that process will likely take longer.

If I am fortunate, they will discover an answer within my son's lifetime. I don't hold out much hope for my own.
 

Oliver3

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Not sure whether to laugh, or cry at this 😂

It's been such a long battle Oliver... I feel fortunate though to have this group and good people like you along for the ride.

Keep up the hope.
I understand your pain..quite literally!!!!

Without being blindly optimistic, I'm hoping we will get some treatment s that at least give us day release from this jail we live in.
And who knows, maybe Ron Davies is close.

Thanks for the message of solidarity
 

Consul

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Quote from the discussion section
Maintenance of peroxisomal structure with functional enzymes is imperative for both plasmalogen biosynthesis and β-oxidation of very long-chain fatty acids [31]. Peroxisomal β-oxidation of very long-chain fatty acids leads to their breakdown into short-chain products that serve as substrates for mitochondrial β-oxidation [34]. We posit that this crosstalk between mitochondria and peroxisomes plays an important role in maintaining energy homeostasis, and that dysregulation contributes to the fatigue and cognitive dysfunction that are hallmarks of ME/CFS [35,36].
The cross-talk between peroxysomes and mitochondria mentioned here, is that irrelevant for neurons in the brain? My understanding is that the brain/neurons dont utilize fats/lipids for energy like other cells do. So if the proposed cross-talk dysregulation is the cause of mecfs, but isnt present or relevant in the brain/neurons then its maybe a bit odd that pwme get fatigued from mental excertion.
 

Pyrrhus

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The cross-talk between peroxysomes and mitochondria mentioned here, is that irrelevant for neurons in the brain?
I would think that it is indeed relevant for neurons in the brain. Yes, neurons don't utilize lipids for energy as much as other cells do. But neurons do engage in a lot of lipid metabolism for non-energy reasons, especially in order to maintain their dynamic membrane components, which are essential for the specific functions of neurons.