Researchers based largely in Australia recruited 61 individuals with ME/CFS (meeting Canadian Consensus Criteria) and age- and sex-matched healthy controls to investigate the biological basis of the disease.
They carried out multimodal analysis, which allows multiple biological systems to be studied simultaneously and makes it possible to identify interactions between them. The authors noted that this approach is particularly important for ME/CFS, due to its heterogeneous nature in which “different aspects of biological dysfunction are rarely studied within the same subjects”. In this study, the focus was on concurrent dysfunction across these three systems – energy metabolism, immune function, and vascular (blood vessel-related) biology.
Key findings
Impaired cellular energy metabolism
Immune cells from people with ME/CFS showed signs of cellular energy stress, a state in which energy supply is insufficient to maintain normal cellular function. Key molecules discussed include ATP (adenosine triphosphate), the energy currency of cells, alongside other molecules crucial in energy metabolism: ADP (adenosine diphosphate), AMP (adenosine monophosphate) and NAD+ (nicotinamide adenine dinucleotide).
Specifically, researchers observed:
- Reduced levels of ATP and ATP/ADP ratios in peripheral blood mononuclear cells (PBMCs).
- Increased levels of ADP, AMP, and NAD⁺ in blood and immune cells.
The study also identified disruptions in the kynurenine pathway, which plays a role in both energy metabolism and immune regulation. The authors suggested that these findings imply that energy constraints in ME/CFS may extend beyond mitochondrial dysfunction, potentially involving alterations in the kynurenine pathway. They suggested that these combined abnormalities could contribute to fatigue in ME/CFS, although further studies are needed to confirm this mechanism.
Altered immune cell profiles
Immune profiling revealed several notable changes:
- A shift toward less mature T cell subsets, rather than fully differentiated T cells capable of strong immune responses
- A reduced proportion of natural killer (NK) cell subset with potent anti-viral activity, suggesting increased vulnerability to viral infection.
Interestingly, the researchers did not observe elevated pro-inflammatory cytokines (signalling molecules that stimulate inflammation) in ME/CFS blood. They noted that this finding is consistent with some studies but differs from others, reflecting “inconsistent detection of cytokines” in the blood of individuals with ME/CFS. The researchers state that the lack of elevated pro-inflammatory cytokines may be explained by the reduced frequency of mature immune cells or by the activity of other proteins in blood that were increased in the disease cohort.
Vascular abnormalities
The study also found elevated levels of proteins involved in blood clotting and vascular reactivity. The authors proposed that these changes may contribute to endothelial dysfunction, a feature often reported in ME/CFS and can lead to impaired blood flow and oxygen delivery.
Conclusion
The researchers concluded that the study provides “compelling evidence” that ME/CFS is associated with concurrent dysfunction across multiple biological systems, “challenging its dismissal as a psychological disorder”. Importantly, they identified variables from energy metabolism, immune function, and vascular biology “with strong predictive potential for ME/CFS”, highlighting “crosstalk” between these systems.
Study limitations
The authors acknowledged several limitations:
- Patients were not stratified by disease severity, preventing analysis of how biological dysfunction relates to symptom severity
- The cohort was predominantly female, reflecting ME/CFS demographics but limiting robust analysis in males due to small sample size
- Participants were sampled at varying stages of disease, rather than at disease onset
- Nearly 20% of participants with ME/CFS were classified as disabled, raising the possibility of confounding from comorbid conditions that may affect ME/CFS
The authors noted that longitudinal studies, following patients over time, could help clarify whether these biological changes are stable or fluctuate with disease course.
