Severe fatigue can appear after very different health problems, from viral infections to trauma and autoimmune disease. Yet people with long COVID, ME/CFS, PTSD, rheumatoid arthritis, and multiple sclerosis often describe a similar experience: exhaustion that does not ease with rest, trouble concentrating, poor sleep, and a sharp drop in daily functioning.
New research from the University of East Anglia (UEA) and Oxford BioDynamics suggests these conditions may share biological pathways that help explain why their symptoms can look so similar.
The study, published in the Journal of Translational Medicine, points to a possible common biological mechanism behind chronic fatigue. Researchers found connections between the five illnesses at the level of complex gene-regulation networks, even though the individual genes linked to each condition showed surprisingly little overlap.
Five Different Conditions
The illnesses examined in the research have very different triggers.
ME/CFS, also known as myalgic encephalomyelitis/chronic fatigue syndrome, can develop after an infection. Long COVID follows infection with SARS-CoV-2. PTSD can occur after severe psychological trauma. Rheumatoid arthritis is an autoimmune disease that mainly affects the joints, while multiple sclerosis involves the immune system and nervous system.
Professor Dmitry Pshezhetskiy of UEA’s Norwich Medical School led the research. He noted that these disorders had generally been treated as unrelated because their origins differ.
Still, patients often report several symptoms in common. These include:
1. Severe and persistent fatigue
2. Brain fog and difficulty concentrating
3. Disturbed sleep
4. Problems involving the autonomic nervous system
5. Reduced ability to manage normal daily activities
The similarity raised a basic question: How can such different conditions produce comparable forms of exhaustion?
Looking Beyond DNA
Researchers did not focus only on the DNA sequence. Instead, the UEA team used Oxford BioDynamics’ EpiSwitch Orion platform to study the three-dimensional structure of the genome.
DNA does not sit inside cells as a straight strand. It folds into a complex three-dimensional structure. As a result, sections that are far apart in the DNA sequence can come into contact. Those interactions can influence how genes are controlled.
Dr. Ewan Hunter, chief data officer at Oxford BioDynamics, explained that these contact points are important because they can determine how genes are regulated. Orion predicts where such interactions are likely to occur.
The research relied on published genomic data rather than collecting new patient samples. Data from genome-wide association studies involving long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis were combined with three-dimensional genomic information from an earlier ME/CFS patient study.
This approach allowed researchers to compare biological networks across all five conditions.
A Shared Biological Network
The results produced an unexpected pattern.
Researchers expected to see some of the same genes associated with the illnesses. Instead, they found little direct overlap when individual genes were compared.
The picture changed when the team examined how those genes interact.
Pshezhetskiy said the illnesses appeared deeply connected when viewed through their wider biological networks. That connection would be difficult to identify by studying the DNA sequence alone.
The analysis showed that genes associated with the five conditions fed into several common biological systems. These included immune and inflammatory signaling, mitochondrial energy production, metabolic regulation, stress responses, and neuroendocrine signaling.
That finding offers a possible explanation for a symptom shared by millions of people with chronic illnesses: profound fatigue.
How Different Triggers May Converge
A viral infection and psychological trauma may seem biologically unrelated. The research suggests that the body’s response to those events could still affect some of the same regulatory systems.
A COVID-19 infection may cause prolonged changes in immune activity. Severe psychological stress can affect stress-hormone pathways and inflammatory responses. According to the researchers, both processes may eventually interfere with biological circuits involved in energy production, immune control, and cellular resilience.
Pshezhetskiy described the finding as approaching “a biological unifying theory of fatigue.”
The idea does not mean that the five illnesses are the same disease. Their triggers, symptoms, and clinical features remain different. Instead, the study suggests that different starting points may disturb some of the same systems inside the body.
When those systems remain disrupted, fatigue may become persistent rather than temporary.
Immune System Clues
The study also identified several potential “hub genes.” These genes occupy important positions within the shared networks and are involved in areas such as immune regulation, inflammation, and mitochondrial energy production.
The researchers stressed that these genes are candidates for further investigation. Their exact role in chronic illness still needs to be confirmed through additional research.
One finding involving ME/CFS drew particular attention. The analysis identified LAG3 as a gene worth studying further. LAG3 is associated with T-cell exhaustion, a condition in which immune cells can become less effective after prolonged activation.
If future research confirms a meaningful connection, the finding could offer another clue about why some people remain unwell long after the original trigger has passed.
Pshezhetskiy said the work adds to evidence that persistent immune dysfunction may play a larger role in chronic fatigue-related illnesses than previously recognized.
Could Blood Tests Follow?
The findings may also have implications for diagnosis.
ME/CFS and long COVID are currently diagnosed mainly through symptoms and clinical assessment. There is no universally accepted laboratory test that can confirm either condition in routine clinical practice. This can make diagnosis difficult, particularly when symptoms overlap with other disorders.
Earlier research using the EpiSwitch platform produced a blood-based ME/CFS test that showed promising diagnostic accuracy. That work still requires further validation before it can be used broadly in clinical settings.
The latest study raises a wider possibility. Biological signatures may not only help distinguish one illness from another. Some signatures could potentially identify shared patterns across several chronic conditions.
Pshezhetskiy said the researchers hope their work can support objective blood tests that identify biological signatures rather than relying only on reported symptoms.
What Comes Next
The UEA and Oxford BioDynamics study offers a different way to understand chronic fatigue across long COVID, ME/CFS, PTSD, rheumatoid arthritis, and multiple sclerosis.
Although these conditions have different triggers, the research found connections involving immune activity, inflammation, metabolism, mitochondrial energy production, stress responses, and neuroendocrine signaling.
The analysis also identified potential hub genes, including LAG3 in the ME/CFS data. However, these findings still need to be confirmed through larger studies. Researchers will need to determine whether these biological pathways directly contribute to persistent symptoms and whether they can produce reliable diagnostic markers.
The findings do not suggest that the five illnesses are the same. Instead, they point to shared biological networks that may help explain why different conditions can cause similar patterns of severe fatigue and cognitive difficulties.
This could eventually guide the development of more objective diagnostic tests and treatments, but those applications remain subjects for future research.
