New Research Finds Shared Biological Pathways Behind Chronic Fatigue Across Multiple Conditions
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Why can conditions as different as ME/CFS, Long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis produce such similar experiences of debilitating fatigue?
New research from the University of East Anglia (UEA) and Oxford BioDynamics may offer an important piece of the puzzle.
A study published in the Journal of Translational Medicine has identified shared biological pathways across five conditions that have traditionally been viewed as separate diseases: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Long COVID, post-traumatic stress disorder (PTSD), rheumatoid arthritis, and multiple sclerosis (MS).
Although these illnesses can have very different triggers, researchers found that they may ultimately affect some of the same biological systems within the body.
Different Conditions, Similar Symptoms
ME/CFS often develops following a viral infection, while Long COVID occurs after infection with SARS-CoV-2. PTSD can develop following traumatic experiences, and rheumatoid arthritis and multiple sclerosis involve autoimmune processes affecting different areas of the body.
Despite those differences, patients across these conditions can experience remarkably similar symptoms, including severe fatigue, brain fog, difficulty concentrating, disrupted sleep, autonomic dysfunction, and significant reductions in their ability to carry out everyday activities.
Researchers wanted to better understand why.
Rather than looking only for individual genes shared among the five conditions, the team examined the larger biological networks in which those genes operate.
Looking Beyond Individual Genes
Researchers used Oxford BioDynamics' EpiSwitch® Orion platform, which studies the three-dimensional architecture of the genome. Instead of simply examining the DNA sequence, this approach looks at how DNA folds and interacts within living cells and how those interactions can influence gene regulation.
The analysis was computational and did not require researchers to collect new patient samples. Published genomic data from Long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis were combined with 3D genomic data from an earlier ME/CFS patient study.
Interestingly, researchers found relatively little direct overlap when they compared individual genes associated with the five conditions.
The picture changed when they looked at how those genes function within larger biological networks.
Genes associated with the different illnesses appeared to converge on several of the same major systems, including immune and inflammatory signaling, mitochondrial energy production, metabolic regulation, stress-response mechanisms, and neuroendocrine signaling.
This suggests that very different initial triggers may eventually disrupt similar biological processes.
How Different Triggers Could Lead to Similar Fatigue
The findings could help explain how experiences as different as a viral infection and psychological trauma might eventually result in overlapping symptoms.
For example, COVID-19 infection may lead to prolonged immune activation, while traumatic stress may interfere with stress-hormone pathways and inflammatory responses.
According to the researchers, both types of disruption may ultimately affect common biological circuits responsible for energy production, immune regulation, and cellular resilience.
If these systems remain dysregulated over time, the result could be the profound and persistent fatigue experienced by people across several different chronic illnesses.
The Potential Role of Immune Dysfunction
Researchers also identified several potential "hub genes" within these shared biological networks. These genes are involved in areas including immune regulation, inflammatory signaling, and mitochondrial energy production.
The researchers emphasized that these genes are candidates identified through the analysis and that additional research will be necessary to determine their precise roles.
One finding specific to ME/CFS highlighted the gene LAG3 as an area for further investigation.
LAG3 is associated with T-cell exhaustion, a state in which immune cells become less effective following prolonged activation. If future research confirms this connection, it could potentially help explain why some people remain chronically ill even after the event that originally triggered their condition has passed.
The findings add to evidence suggesting that persistent immune dysfunction may be an important part of chronic fatigue-related illnesses.
Could the Research Eventually Improve Diagnosis?
Another potential implication of the study involves diagnosis.
ME/CFS and Long COVID are currently diagnosed largely based on symptoms, and there is no universally accepted laboratory test for either condition. This can contribute to long periods of uncertainty for patients seeking answers.
Previous research using the EpiSwitch platform has already produced a blood-based ME/CFS test that showed promising levels of diagnostic accuracy and requires further validation before potential clinical use.
The new research raises the possibility that biological signatures could eventually be identified across multiple fatigue-related conditions.
Researchers hope this work could contribute to the development of objective blood tests that identify underlying biological patterns rather than relying exclusively on reported symptoms.
A Different Way of Looking at Chronic Fatigue
Perhaps one of the most interesting aspects of the research is the possibility of viewing these conditions through their shared biology rather than only through their different origins.
ME/CFS, Long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis may not simply be unrelated illnesses that happen to cause fatigue. Instead, different triggers could disturb overlapping biological networks involving immune function, metabolism, energy production, and stress responses.
This does not mean the five diseases are the same. Rather, the research provides a framework for understanding how very different conditions may converge on similar biological pathways and ultimately produce similar experiences of severe, chronic exhaustion.
The 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.
The study, 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, was published in the Journal of Translational Medicine in 2026.
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