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

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

 

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?

 

@mariovitali

 

This a Network Analysis graph generated in 2017. Choline deficiency, Oxidation and Peroxisomes have been identified as important concepts

 

Cort has blogged about this study. "For all the interesting findings, the authors were unable to use machine-learning techniques to differentiate the ME/CFS patients from the controls."

I would like to know if the nano-needle could differentiate between the groups.

https://www.healthrising.org/blog/2...TizDUrJNBlR3AR6TcebebpeZV1PLWsOBWX07S9Q8CDPEc

 

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

 

Lipkin is the main author...

 

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.

 

Oliver Fiehn's work.

 

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.

 

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.

 

Che is the main author. Lipkin is the senior author.

(Che did the math)

 

Acetyl-CoA is an enzyme. Acetylcholine is neurotransmitter.

 

Yup. Sleep time.