Chronic Fatigue Syndrome Study Uncovers Hidden Biological Signs

The largest ever biological study of ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) has identified consistent blood differences associated with chronic inflammation, insulin resistance and liver disease. 

Significantly, the results were mostly unaffected by patients’ activity levels, as low activity levels can sometimes hide the biological signs of illness, experts say. 

The volume and consistency of the blood differences support the long-term goal of developing a blood test to help diagnose ME/CFS, researchers say. 

Mystery condition

ME/CFS’ key feature, called post-exertional malaise, is a delayed dramatic worsening of symptoms following minor physical effort.  

Other symptoms include pain, brain fog and extreme energy limitation that does not improve with rest. Causes are unknown and there is currently no diagnostic test or cure. 

Large dataset

Scientists from the University of Edinburgh’s Institute of Genetics and Cancer worked with researchers from the Schools of Mathematics and Informatics to better understand the biology that underpins the condition. 

They used data from the UK Biobank – a health database of over half a million people – to compare 1,455 ME/CFS patients with 131,000 healthy individuals.  

They examined more than 3,000 blood-based biomarkers and used advanced models to account for differences associated with age, sex, and activity levels.  

"For so long people with ME/CFS have been told it’s all in their head. It’s not: we see people’s ME/CFS in their blood. Evidence that there is a large number of replicated and diverse blood biomarkers that differentiate between ME/CFS cases and controls should now dispel any lingering perception that ME/CFS is caused by deconditioning and exercise intolerance." – Professor Chris Ponting, Chair of Medical Bioinformatics and a Principal Investigator at the MRC Human Genetics Unit, Institute of Genetics and Cancer

Biological signs

The results, which were replicated afterwards using data from the US, showed that hundreds of biomarkers differed between ME/CFS patients and healthy people. 

Some 116 significant differences were found in both men and women, a key finding as ME/CFS can affect sexes differently. The consistent results across both groups strengthens the reliability of the biomarkers, experts say. 

The strongest biomarker differences were found in people who reported symptoms consistent with post-exertional malaise, highlighting its central role in the illness.  

Researchers believe these biomarker changes are more likely a result of ME/CFS, rather than the initial trigger of the illness.

University of Edinburgh researchers were supported by partners from the Harvard T.H. Chan School of Public Health.

"Blood differences are sometimes attributed to reduced activity levels, rather than ME/CFS directly. By applying very recent advances in the statistical and causal inference literature, our study provides strong evidence that ME/CFS affects blood traits through paths other than activity." – Dr. Sjoerd BeentjesChancellor's Fellow, School of Mathematics

"This work has been an exciting cross-disciplinary and collaborative effort to integrate mathematical statistics, machine learning and biomedical expertise from across the University to answer a challenged-led question for ME/CFS research." –Dr, Ava KhamsehLecturer in Biomedical AI, School of Informatics

Reference: Beentjes SV, Miralles Méharon A, Kaczmarczyk J, et al. Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity. EMBO Mol Med. 2025:1-24. doi: 10.1038/s44321-025-00258-8

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