Preprint Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction, 2025, Heng

[Dolphin]

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5131664

Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction
Cell Reports Medicine
53 Pages Posted: 12 Feb 2025 Publication Status: Under Review

Ruiwen Benjamin Heng
Macquarie University

Bavani Gunasegaran
Macquarie University

Shivani Krishnamurthy
Macquarie University

Sonia Bustamante
University of New South Wales (UNSW)

Ananda Staats
Macquarie University

Sharron Chow
Macquarie University

Seong Beom Ahn
Macquarie University

Moumita Paul-Heng
The University of Sydney

Yolande Maciver
The Grove Health Pymble

Kirsten Smith
The Grove Health Pymble

Denise Phuong Tran
The University of Sydney

Peter P. Howley
Macquarie University

Ayse Aysin Bilgin
Macquarie University

Alexandra Sharland
The University of Sydney

Richard Schloeffel
Macquarie University

Gilles J. Guillemin
Macquarie University

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments.

Multiple areas of dysfunction have been extensively studied, but rarely examined together.

We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels.

Elevated levels of adenosine monophosphate (AMP) were detected in both plasma and immune cells.

Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio.

These findings imply decreased ATP generation and the presence of energy stress within the immune cell population.

Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and gd T cells, and proportions of CD1c+CD141-conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients.

Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS.

Together, this study provides new insights into the somatic symptoms and underlying biology of ME/CFS.

Note:
Funding Information: BG is supported by the Susie Myers Glioblastoma Scholarship (PANDIS) and Macquarie University Research Training Program Domestic Scholarship; SK is supported by International PhD scholarships from Macquarie University; MPH is supported by Sydney University Research Training Program Domestic Scholarship; SBA is supported by Cancer Council NSW funding RG23-06 and Targeted Call Research-National Health and Medical Research Council (NHMRC) funding GNT2015197; GJG was supported by the NHMRC funding APP1176660.

Declaration of Interests: The authors declare no competing interests

https://twitter.com/user/status/1890409895528104214

 

[Creekside]

Yet another study of inactive PWME vs healthy, active people. I expect they'd find similar differences between couch potatoes and Olympic athletes.

 

[SNT Gatchaman]

Published as —

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction

Spoiler: Authors

Heng; Gunasegaran; Krishnamurthy; Bustamante; Pires; Chow; Ahn; Paul-Heng; Maciver; Smith; Tran; Howley; Bilgin; Sharland; Schloeffel; Guillemin

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments.

To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multimodal analysis of energy metabolism, immune profiles, and plasma proteomics.

Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing toward less mature effector subsets of CD4+, CD8+, and γδT cells, with reduced CD1c+CD141− conventional DC type 2 and CD56lowCD16+ terminal natural killer cells.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and regression tree modeling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.

HIGHLIGHTS
• This study involves age- and sex-matched 61 healthy controls and 61 ME/CFS patients

• Abundance of AMP and ADP, with reduced ATP/ADP ratio in immune cells

• Lower proportion of terminal effector memory T cell, NK, and DC subpopulations

• Elevated plasma proteins associated with vascular and anti-inflammation activity

Web | DOI | Cell Reports Medicine | Open Access

 

[Amw66]

So ATP being chucked out of cells
AMP in abundance
Rather than low energy state could we look at it as signalling going haywire ?

 

[SNT Gatchaman]

Prior papers from this group came in for criticism, esp the 2022 one. This paper looks to be of better quality and reads pretty clearly.

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS complex puzzle? (2022)

Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS (2023)

It is also clear when it comes to the idea of psychological factors. The conclusion overplays things if anything. Obviously the ivory tower anti-dualists would argue about the framing of psychological disorders not being medical conditions, but we all know how that plays out in the real world. (And we should be long past the point where this even needs to be written.)

In conclusion, this study provides compelling evidence that ME/CFS is associated with dysfunction across multiple biological systems, challenging its dismissal as a psychological disorder. Notably, we identified variables from three distinct biological systems with strong predictive potential for ME/CFS, highlighting the crosstalk between immune, vascular, and energy production dysfunction. These findings reinforce the legitimacy of ME/CFS as a medical condition and should pave the way for promoting broader acceptance of the condition within the medical community and society at large, thus improving patient management and outcomes.

It doesn't look like the preprint had much of an analysis or commentary. I'll put some summary findings and discussion quotes up in case of interest.