Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2022, Levine,Hornig,Lipkin et al

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Threads for the preprint and final paper have ben merged. Abstract for the final paper here.

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


Xiaoyu Che, Christopher R Brydges, Yuanzhi Yu, Adam Price, Sheryas Joshi, Ayan Roy, Bohyun Lee, Dinesh K Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L Peterson, Suzanne D Vernon, Lucinda Bateman, View ORCID ProfileMady Hornig, Jose G Montoya, Anthony L Komaroff, Oliver Fiehn, View ORCID ProfileWalter Ian Lipkin

Preprint

Abstract
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.

https://www.medrxiv.org/content/10.1101/2021.06.14.21258895v2
 
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What a fascinating study. It seems the metabolomics work is finally getting fairly consistent and replicable results. There is a lot to digest here.

The authors also mention a possible effect on cell signaling which has been a popular idea on this discussion board (if phospolipids are disrupted, it could affect receptors on the surface of cells).

Do we know if ME/CFS is associated with abnormal accumulation of certain lipids?
 
strategist said:
Do we know if ME/CFS is associated with abnormal accumulation of certain lipids?
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A recurring problem is that the different metabolomics studies look at different lipids, so it is difficult to say. Beyond phospholipids, there are also the sphingolipids that can influence cell membranes and cell signalling (of these there are a few ceramides that have garnered some attention as they keep coming up in regards to metabolic syndrome, cardiovascular disease and diabetes. Then again, the reason they keep coming up is also because they are actively included in studies based on previous studies, while other ceramides or lipids are not included).

Also, lipids are easily influenced by diet, which these studies rarely control for adequately.
 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.

https://www.mdpi.com/1422-0067/23/14/7906
 
Peroxisomal dysfunction ? If correct this would seem to have major implications for how we see ME/CFS:

Handbook of Clinical Neurology Chapter 163 - Peroxisomal disorders

Abstract
The peroxisomal disorders represent a group of genetic diseases in man in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are subdivided into three subgroups comprising: (1) the peroxisome biogenesis disorders (PBDs); (2) the single peroxisomal (enzyme-) protein deficiencies; and (3) the single peroxisomal substrate transport deficiencies. The PBD group comprises four different disorders that include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe, and IRD the less severe disorder, with sometimes onset in adulthood. The single peroxisomal enzyme deficiency group comprises seven different disorders, of which D-bifunctional protein and phytanoyl-CoA hydroxylase (adult Refsum disease) deficiencies are the most frequent. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy. It is the purpose of this chapter to describe the current state of knowledge about the clinical, biochemical, cellular, and molecular aspects of peroxisomal diseases, and to provide guidelines for their post- and prenatal diagnosis. Therapeutic interventions are mostly limited to X-linked adrenoleukodystrophy.

Peroxisomal Dysfunction in Age-Related Diseases

Abstract
Peroxisomes carry out many key functions related to lipid and reactive oxygen species (ROS) metabolism. The fundamental importance of peroxisomes for health in humans is underscored by the existence of devastating genetic disorders caused by impaired peroxisomal function or lack of peroxisomes. Emerging studies suggest that peroxisomal function may also be altered with aging and contribute to the pathogenesis of a variety of diseases, including diabetes and its related complications, neurodegenerative disorders, and cancer. With increasing evidence connecting peroxisomal dysfunction to the pathogenesis of these acquired diseases, the possibility of targeting peroxisomal function in disease prevention or treatment becomes intriguing. Here, we review recent developments in understanding the pathophysiological implications of peroxisomal dysfunctions outside the context of inherited peroxisomal disorders.

full article at link.


 
Some background:
https://med-life.ca/plasmalogens
Peroxisomes are organelles in the cell (the pink blobs). They make plasmalogens and acetyl-CoA and other things, and break down excess long chain fatty acids, uric acids and other things that might be a problem if they aren't broken down (reactive oxygen species).

Screen Shot 2022-07-18 at 11.02.47 pm.png

Cell membranes are made up of various phospholipids. One sort of phospholipid is the plasmalogen. It's different to a standard phosphoiipid in that it has that vinyl ether bond (in the red box), instead of a second acyl bond (in the black box). Different cell types have different compositions of phospholipids - in neurons, up to 50% can be plasmalogens.

Screen Shot 2022-07-18 at 11.08.45 pm.png

The vinyl ether bond makes for a more tightly packed, more rigid cell membrane. The more plasmalogen, the more vesicular fusion - where a vesicle fuses to the cell membrane and the contents of the vesicle get released. I think the vesicle can dock onto a cell and release its contents into the cell, or the vesicle can be formed in the cell, and release its contents out of the cell.

Neurotransmission depends on vesicular fusion, with the neuron releasing the contents of a vesicle containing neurotransmitters into the space (cleft) between it and the next neuron.

 
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strategist said:
Is the peroxysomal dysfunction sufficient to cause accumulation of certain fatty acids?

If yes, that would make reduction of fat intake or some kinds of fats a potentially useful treatment.
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I've no idea but given the range of diseases associated with peroxysomal dysfunction it seems unlikely that dietary modification would have a general application. The authors acknowledge the possibility of sub groups which suggest that a one fix fits all is going to be unlikely even if this is a promising route for research.
 
https://bscb.org/learning-resources/softcell-e-learning/peroxisome/
The decomposition of fatty acids by peroxisomes to the chemical acetyl CoA produces a great deal of metabolic energy and supplements that produced by mitochondria.
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Acetyl-CoA is of course a neurotransmitter and is important in the TCA cycle. It possibly makes sense that if the cell goes into low energy mode, reducing energy production in the TCA cycle so that pathogens can't use the energy to replicate before the adaptive immune system comes to the rescue, then it might also reduce production of Acetyl-CoA and of energy in the peroxisomes.

It certainly feels as though my neurons stop firing properly and fill up with toxic compounds when I think too much or use my muscles too much. :)

But, I guess first we need to see if the peroxisomes really aren't working right. And if lower levels of plasmalogens in the plasma (if that finding holds) equates to lower levels of plasmalogens where they are actually needed - e.g. in neurons.
 
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elevations in the levels of dicarboxylic acids, particularly the TCA cycle intermediates alpha-ketoglutarate and succinate, consistent with an impairment in the TCA cycle that may contribute to physical and cognitive fatigue.
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The build up of those two compounds is consistent with the itaconate shunt hypothesis, because the itaconate stops the breakdown of succinate (and I think alpha-ketoglutarate is upstream of succinate).
Itaconate shunt hypothesis video—Robert Phair
 
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This is for the whole ME/CFS sample versus all the controls.


To compare the levels of each metabolite between ME/CFS cases and controls, we employed a variety of regression models with the metabolite level as the dependent variable and the binary case/control status as the independent variable, adjusting for all the matching variables (age, sex, race/ethnicity, geographic/clinical site, and season of sampling), BMI and sr-IBS.
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This sort of sounds good, but it's quite a bit of fiddling with the data. For example, I wonder how much race/ethnicity or even geography actually influenced metabolite levels, and if the adjustment process might have happened to reduce variability and make results more significant?

The ME/CFS cohort had more acetominophen (paracetamol) than the controls; the ME/CFS women had more acyclovir (anti-viral medication) and alprazolam (Xanax - a sedative used to treat anxiety and panic disorders :() than the control women. That's a bit of a worry on two counts - the different drug profiles could be having all sorts of effects, and it's a damn shame some of the women either feel the need for the Xanax or get put on it. I can't see how many people were on the drugs - the log transformation makes it hard to know how important the difference between ME/CFS and controls actually is (the data might be in supplementary tables).
 
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