Researchers have identified a shared biological network across five distinct conditions, suggesting a hidden mechanism may explain chronic fatigue. A new study published in the Journal of Translational Medicine from the University of East Anglia and Oxford BioDynamics found that chronic fatigue syndrome, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis share genomic connections despite their different causes. The research used advanced technology to examine how genes interact in three-dimensional space inside cells, revealing patterns that could help explain severe fatigue, brain fog, and exhaustion common to these illnesses.
Traditionally, these illnesses have been studied separately. However, the team found that looking beyond individual genes revealed broader connections between them. Instead of simply examining DNA sequences, the researchers used EpiSwitch Orion technology from Oxford BioDynamics to study how DNA folds and interacts in three-dimensional space inside cells. These interactions can influence how genes are regulated and may reveal biological connections that conventional genetic analysis can miss. The research combined previously available data from long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis with earlier 3D genomic data from ME/CFS. The team identified 3D genomic anchors—regions where important regulatory DNA interactions occur—and mapped them to nearby genes.
Different Conditions, Similar Network
The most important finding was that the overlap between individual genes was limited, but much stronger connections emerged when researchers examined the larger networks in which those genes interact. In other words, these conditions may look genetically different when studied gene by gene while still sharing important biological pathways at the network level. This could help explain why five apparently unrelated illnesses can produce strikingly similar symptoms of persistent exhaustion and cognitive difficulties. However, the findings do not mean that these conditions are the same disease. Rather, they suggest that some of the biological processes contributing to chronic fatigue may be shared across different illnesses.
The shared biology appears to involve several major systems in the body. According to the study report, the different illnesses affect the immune system and inflammation, energy production inside cells, metabolism and how the body uses energy, the body’s response to stress, and hormone and brain-body signaling. The researchers also found links with antiviral immune responses and other inflammatory pathways. In simple terms, the illnesses may start differently but eventually disrupt some of the same biological systems. For example, a viral infection may trigger long-lasting immune changes, while severe trauma may affect stress hormones and inflammation. Over time, these different triggers could disturb the systems that help the body manage energy, stress, and immune activity.
Diagnosing Fatigue Through a New Lens
One of the most promising possibilities from this research is the development of a simple blood test for conditions such as ME/CFS and long COVID. At present, these conditions are largely diagnosed based on symptoms, which can leave patients facing long periods of uncertainty. Earlier research using the same EpiSwitch technology had already developed a blood-based test for ME/CFS.
In an independent validation group, the test showed 92% sensitivity, 98% specificity, and 96% overall diagnostic accuracy. The new research raises the possibility that similar biological patterns could eventually help identify several fatigue-related conditions through objective blood-based markers. However, this is still an early possibility. The newly identified genetic patterns have not yet been validated as a clinical diagnostic test, and further studies in larger groups of patients are needed.
It is worth noting that this work builds on earlier observations that exercise can worsen symptoms in these conditions. A study published in npj Metabolic Health and Disease found that people with ME/CFS showed biological changes involving the immune system and energy production. The immune system appeared to respond more strongly than expected when exposed to microbial antigens, and energy production pathways were disrupted. Many of these abnormalities became more pronounced after exercise and were linked with greater symptom severity. This is particularly important because post-exertional malaise—a worsening of symptoms after physical or mental activity—is one of the defining features of ME/CFS.
Brain Inflammation and Energy Production
The shared biological patterns identified across ME/CFS, long COVID, and other chronic conditions may also help explain why patients experience persistent fatigue and brain fog. Two separate reviews provide additional clues by looking at the brain and nervous system and the body’s ability to produce energy. A review examined the neurological effects of long COVID. The authors reported that persistent symptoms can continue after SARS-CoV-2 infection, with some patients experiencing problems such as brain fog, memory difficulties, and persistent fatigue. The review suggested that inflammation may play an important role, with inflammatory signals produced elsewhere in the body potentially affecting the brain and contributing to ongoing neurological symptoms.
Another important piece of the puzzle involves the body’s ability to produce energy. A clinical resource from the Institute for Functional Medicine highlighted evidence suggesting that some people with ME/CFS may have problems with mitochondrial function. Mitochondria are the cell’s energy-producing structures. When they do not function efficiently, cells may struggle to meet the body’s energy demands. The resource cited an observational study in ME/CFS patients that found reduced mitochondrial respiration, lower capacity to produce cellular energy, and difficulty meeting increased energy demands. This could help explain why ordinary physical or mental activities can sometimes leave people with chronic fatigue conditions feeling severely exhausted.
It is easy to look at the symptoms and assume the causes must be the same, but the new data complicates that assumption. These conditions involve complex interactions between the immune system, cellular energy production, and stress responses. The overlap in symptoms suggests that the body’s regulatory systems are overwhelmed in similar ways across different diseases, even when the starting point varies. This perspective helps explain why patients with diverse conditions often describe their experience in nearly identical terms, yet their underlying biology remains distinct.
The shared biological pathways identified in this study do not yet change how these conditions are diagnosed or treated. However, they offer an important new direction for understanding why people with long COVID, ME/CFS, PTSD, rheumatoid arthritis, and multiple sclerosis can experience similar symptoms. Future research could help develop better diagnostic tests and treatments by targeting shared biological pathways. For patients, the findings also provide growing scientific evidence that persistent fatigue may reflect underlying changes in the body’s immune, energy, and stress-response systems.
Understanding the biological underpinnings of chronic fatigue can be complex. The interplay between various systems in the body is vast, and identifying a specific cause often requires a deep dive into cellular mechanisms. For instance, the impact of specific substances on health is a subject of ongoing research. Betel nut addiction impacts brain and body in ways that are still being fully mapped out by scientists. Just as the mechanisms of chronic fatigue are revealing new connections, studies into other health behaviors are uncovering their own distinct pathways to illness.
