Science Daily

by University of East Anglia

    Researchers at the University of East Anglia and Oxford BioDynamics have identified a possible biological connection that could help explain why profound exhaustion appears across conditions as different as long Covid and PTSD.

    The new study, published in the Journal of Translational Medicine, points to striking similarities in the biology associated with five major illnesses that have traditionally been treated as largely 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 disrupt some of the same underlying biological systems.

    That possibility is notable because the conditions can begin in very different ways, including viral infection, psychological trauma and autoimmune activity.

    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."

Looking Beyond the DNA Sequence

    Instead of examining DNA only as a linear genetic sequence, the UEA researchers used Oxford BioDynamics' EpiSwitch® Orion platform to study the genome's three-dimensional organization. The technology is designed to investigate how DNA folds inside cells and how distant sections of the genome can come into contact and influence gene activity.

    The work was computational rather than based on newly collected patient samples. Researchers combined previously published genomic information for long Covid, PTSD, rheumatoid arthritis and multiple sclerosis from existing genome-wide association studies with 3D genomic data from an earlier study of people with ME/CFS.

    "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.

    When the researchers applied Orion to all five conditions, they found that genetic changes that initially looked largely unrelated could connect to the same regulatory networks.

    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 long 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 analysis showed that genes associated with the different illnesses were feeding into many of the same major biological systems. These included immune and inflammatory signaling, mitochondrial energy production, metabolic regulation, stress-response mechanisms, and neuroendocrine signaling.

How Different Triggers Could Lead to Similar Symptoms

    The findings may help explain why something as different as a viral infection or psychological trauma can eventually produce overlapping 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."

    In other words, the initial trigger may differ from one condition to another, while the biological disruption that follows could begin to affect some of the same systems involved in energy, immunity and the body's response to stress.

Immune Dysfunction Emerges as a Key Target

    The researchers also identified several 'hub genes' positioned at especially active points within the shared biological networks.

    These included genes connected to immune regulation, inflammatory signaling and mitochondrial energy production. However, the researchers emphasize that these genes are candidates identified through the analysis, and further research will be needed to establish exactly what roles they play.

    A portion of the study focused specifically on ME/CFS and highlighted LAG3 as one gene worthy of further investigation. This molecule has been linked to 'T-cell exhaustion', a condition in which immune cells become less effective after remaining activated for an extended period.

    If future studies confirm the connection, the researchers say it could offer clues about why some patients remain chronically ill even after the initial infection, stressor, or other trigger is no longer present.

    "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.

Toward Objective Blood Tests

    The researchers say one of the most important long-term implications could involve diagnosis.

    "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."

    Previous research using the EpiSwitch platform had already produced a blood-based ME/CFS test that showed promising levels of diagnostic accuracy. That test still requires further validation before it could be used clinically.

    The latest findings now raise the possibility that shared biological signatures could also be identified across several conditions rather than ME/CFS alone.

    "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.

Shared Pathways Could Point Toward New Treatments

    The team now hopes that the biological pathways identified in the study could eventually contribute to broader diagnostic tools and potentially treatments that could be relevant to more than one chronic condition.

    "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."

    '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.

    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.