A shared biological secret that helps explain chronic exhaustion in conditions including long Covid and PTSD has been discovered by researchers at the University of East Anglia and Oxford BioDynamics.
A new paper published today in the Journal of Translational Medicine reveals striking biological similarities between five major illnesses which until now have largely been viewed as separate disorders.
The findings suggest that chronic fatigue syndrome (also known as ME), long Covid, post-traumatic stress disorder (PTSD), rheumatoid arthritis and multiple sclerosis (MS) may be driven by common underlying mechanisms.
This is despite the conditions being triggered by different events – ranging from viral infections to psychological trauma or autoimmune responses.
Lead researcher Prof Dmitry Pshezhetskiy, from UEA’s Norwich Medical School, said: “Until now, illnesses including long Covid, PTSD, ME/CFS, multiple sclerosis and rheumatoid arthritis were viewed as seemingly unrelated and triggered by completely different events.
“ME/CFS often follows viral infection. Long Covid develops after SARS-CoV-2 infection. PTSD emerges after traumatic experiences. Rheumatoid arthritis is an autoimmune disease attacking the joints, while multiple sclerosis attacks the nervous system.
“But one thing that links them all is that patients frequently report remarkably similar symptoms – overwhelming fatigue, brain fog, poor concentration, disturbed sleep, autonomic dysfunction and a dramatic reduction in everyday functioning.
“We wanted to find out why this is.
“What we discovered is something approaching a biological unifying theory of fatigue.”
How the research happened
Rather than conventionally analyzing DNA sequences, researchers from UEA used Oxford BioDynamics’ innovative EpiSwitch® Orion platform, which examines the three-dimensional architecture of the genome, essentially studying how DNA folds and interacts inside living cells.
The analysis was computational. Published genomic data for long Covid, PTSD, rheumatoid arthritis and multiple sclerosis, drawn from existing genome-wide association studies, were combined with 3D genomic data from an earlier ME/CFS patient study, without needing to collect new patient samples.
“DNA is folded in our cells, so regions far apart in the linear sequence can touch, and those contact points are where genes get controlled. Orion predicts where these contact points are likely to be,” said Dr Ewan Hunter, Chief Data Officer at Oxford BioDynamics.
Applied to the five conditions, Orion found that genetic changes, that appeared to have little in common, connected into the same regulatory circuitry.
Prof Pshezhetskiy said: “We expected to find at least some overlap in genes across the conditions. But we actually found the opposite.
“At an individual gene level, there was surprisingly little direct overlap between ong Covid, ME/CFS, PTSD, multiple sclerosis and rheumatoid arthritis.
“But when we analyzed how those genes interact in complex biological networks, a completely different picture emerged. Suddenly, the diseases appeared deeply connected.
“This is not something you can see by reading the genetic sequence alone, which is why these conditions may have looked unrelated for so long.
“Although these conditions are triggered by completely different events, they may ultimately disrupt the same fundamental biological systems and produce the similarly devastating exhaustion experienced by millions worldwide.”
The study found that genes linked to each illness were feeding into the same major biological systems – including immune and inflammatory signalling, mitochondrial energy production, metabolic regulation, stress-response mechanisms and neuroendocrine signalling.
Why trauma and viruses can produce the same symptoms
The team say the study could help explain why people who have experienced a viral infection or psychological trauma can go on to develop similar symptoms.
“We now think the answer may lie in shared regulatory networks embedded within the body’s immune and metabolic systems,” said Prof Pshezhetskiy.
“A Covid infection may trigger prolonged immune activation. Traumatic stress may disrupt stress-hormone pathways and inflammatory responses.
“But both disturbances appear capable of converging on common biological circuits controlling energy production, immune regulation and cellular resilience.
“When those systems become persistently dysregulated, the result may be the profound and disabling fatigue seen across multiple disorders.”
A new role for the immune system
The study also highlighted several ‘hub genes’ that sit at the busiest points within these shared networks.
Among them were genes involved in immune regulation, inflammatory signalling and mitochondrial energy production. The authors stress that these are candidates identified by the analysis, and more work is needed to confirm what role they play.
One part of the analysis, looking specifically at ME/CFS, flagged LAG3 as a gene to investigate. This is a molecule associated with ‘T-cell exhaustion’, a state in which immune cells become worn out after prolonged activation.
The team say that if this can be confirmed in further studies, it could help explain why many patients appear stuck in a state of chronic illness long after the original trigger has disappeared.
“This work adds to a growing body of evidence suggesting that persistent immune dysfunction may play a far larger role in chronic fatigue-related illnesses than previously recognized,” said Prof Pshezhetskiy.
Paving the way for blood tests and treatments
“Perhaps the most significant implication is what this could mean for diagnosis.
“ME/CFS and long Covid are currently diagnosed largely through symptoms, with no universally accepted laboratory test available.
“That has left many patients facing years of uncertainty.”
Separate earlier work using the EpiSwitch platform had already produced a blood-based ME/CFS test promising high levels of diagnostic accuracy, ready to be taken through further validation needed for clinical use.
The new findings raise the prospect of signatures shared across several conditions, beyond only ME/CFS.
“We hope our work could pave the way for objective blood tests capable of identifying underlying biological signatures rather than relying solely on patient-reported symptoms,” said Prof Pshezhetskiy.
Now, the team hope the newly identified shared biological pathways could eventually lead to broader diagnostic tools and even treatments that work across several chronic conditions.
“Rather than viewing long Covid, ME/CFS, PTSD, rheumatoid arthritis and multiple sclerosis as entirely separate disorders, we now think they may be different manifestations of disturbed biological networks operating throughout the body.
“In that scenario, chronic exhaustion is not simply a symptom. It is the visible consequence of a deeper systems failure affecting immune function, metabolism and stress-response pathways.
“This study offers a framework for understanding how different triggers can converge to cause the exact same profound clinical exhaustion.”
This research was led by the University of East Anglia in collaboration with Oxford BioDynamics, the London School of Hygiene and Tropical Medicine, and Cornwall Partnership NHS Foundation Trust.
‘Beyond Genes: EpiSwitch® and Orion Platform-powered 3D Genome Architecture Biomarkers Reveal Shared Biology Across ME/CFS, Long COVID, PTSD, Rheumatoid Arthritis, and Multiple Sclerosis’ is published in the Journal of Translational Medicine.
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