Different triggers, shared systems: a new biological view of chronic fatigue

Different triggers, shared systems: a new biological view of chronic fatigue

Research into ME/CFS, long Covid, PTSD, rheumatoid arthritis and multiple sclerosis points towards convergence within interconnected regulatory networks

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“For many years, patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long Covid and other chronic exhaustion illnesses have struggled with two connected problems: the severity of their symptoms and the difficulty of demonstrating an underlying biological mechanism using routine clinical tests.

This article in The Times describes research led by the University of East Anglia and Oxford BioDynamics which identified striking network-level similarities across five apparently different conditions: ME/CFS, long Covid, post-traumatic stress disorder (PTSD), rheumatoid arthritis and multiple sclerosis.

The initiating events are very different. ME/CFS and long Covid are commonly associated with infection; PTSD follows overwhelming trauma; rheumatoid arthritis and multiple sclerosis are established immune-mediated diseases. Yet patients may report overlapping features including profound fatigue, brain fog, unrefreshing sleep, poor concentration, autonomic disturbance and a substantial loss of everyday function.

The important proposal is not that these are all the same illness. Nor is it that one gene causes chronic fatigue. Rather, different triggers and different genetic inputs may converge upon interconnected biological networks involving immune regulation, inflammatory signalling, mitochondrial energy production, neurotransmission and the physiological stress response.

That is a subtle but extremely important distinction: different roads may lead to a similar state of regulatory dysfunction.

What did the researchers actually study?

Newspaper reports understandably simplify complex science. The researchers did not take fresh cellular samples from matched groups of patients with all five conditions and demonstrate one identical biological abnormality.

The study combined a previously characterised ME/CFS blood-based 3D genomic dataset with published genome-wide association data for ME/CFS, long Covid, PTSD, rheumatoid arthritis and multiple sclerosis. Computational methods were then used to predict three-dimensional regulatory ‘anchors’, map these signals to genes and analyse the resulting protein and pathway networks.

At the level of individual genes, direct overlap was limited. At the level of biological networks, however, the conditions showed extensive interconnection and convergence around immune, metabolic and neurological processes.

This makes the work intriguing and potentially important, but it remains largely computational and hypothesis-generating. The candidate hub genes and pathways require independent experimental and clinical validation. It does not yet provide a routine diagnostic blood test that can distinguish or diagnose all five conditions.

Why three-dimensional genomics matters

DNA is not arranged inside the cell as a straight instruction manual. It folds into a complex three-dimensional structure, bringing distant regions into contact and helping determine which genes are switched on, switched off or regulated differently.

The research examined this regulatory architecture rather than looking only for identical gene variants. This may help explain how conditions with limited gene-level overlap can nevertheless disturb similar physiological processes.

It also reinforces the distinction between genetic sequence and gene regulation. The findings do not imply that psychological trauma changes somebody’s basic DNA sequence. They suggest that genetic susceptibility, biological stress and disease processes may influence shared regulatory networks through different routes.

A striking parallel with the Seven Regulatory Systems

The findings have a remarkable conceptual overlap with my Integrated Regulatory Systems Framework™. The framework considers seven interacting systems:

• Respiratory
• Neural
• Endocrine
• Immune and inflammatory
• Metabolic
• Musculoskeletal
• Circulatory

These are not seven separate compartments. They form a continuously communicating network. Dysfunction in one system can increase demand upon the others until the individual loses physiological resilience and becomes less able to adapt to infection, exertion, psychological stress, disturbed sleep or pain.

This research similarly suggests that complex chronic illnesses may be understood as disturbances of interconnected regulatory networks rather than isolated defects within a single organ or pathway.

Immune activation and immune exhaustion

One of the most interesting findings involved LAG3, an immune-checkpoint molecule associated with T-cell exhaustion. T-cell exhaustion can develop when immune cells remain repeatedly or persistently stimulated and gradually lose aspects of their normal function.

This does not prove that every patient with ME/CFS has exhausted T cells, nor does it establish the original persistent trigger. However, it offers a plausible research direction for understanding how an illness may continue after the initiating infection has apparently resolved.

The immune system may no longer be responding in a simple ‘high’ or ‘low’ fashion. Different components may be activated, suppressed, exhausted or poorly coordinated at the same time. This is one reason why a single inflammatory marker can fail to capture a complex immune state.

Mitochondria, metabolism and the experience of fatigue

Fatigue is not simply tiredness and it should not be equated with a lack of motivation. Mitochondrial energy production, glucose and fatty-acid metabolism, oxidative stress, immune signalling and autonomic regulation all influence how efficiently cells generate and use energy.

In ME/CFS particularly, post-exertional malaise is a defining clinical feature. Symptoms can deteriorate after physical, cognitive or emotional exertion, sometimes with a delayed onset. Advice to push through symptoms or follow an inflexible programme of graded exercise may therefore be inappropriate and potentially harmful.

Activity has to be matched to the person’s current physiological capacity. Pacing is not giving up; it is an attempt to remain within the available energy envelope while avoiding repeated cycles of overexertion and relapse.

Autonomic, respiratory and circulatory regulation

Autonomic dysfunction is specifically recognised among the overlapping clinical features. It may present through orthostatic intolerance, postural tachycardia, altered temperature regulation, gastrointestinal disturbance, palpitations, poor sleep and impaired recovery following exertion.

Respiratory and circulatory regulation may also influence symptom burden. Chronic overbreathing can reduce carbon-dioxide levels, contributing to cerebral vasoconstriction and altered oxygen release from haemoglobin through the Bohr effect. This may amplify light-headedness, brain fog, anxiety, fatigue and exercise intolerance in susceptible individuals.

This does not mean dysfunctional breathing causes ME/CFS, long Covid, PTSD, rheumatoid arthritis or multiple sclerosis. However, when disordered breathing is objectively present, it can become an additional regulatory load and a potentially modifiable contributor.

Stress biology is not the same as ‘all in the mind’

The inclusion of PTSD is especially important. Psychological trauma can produce genuine and persistent changes in autonomic, endocrine, immune, metabolic and sleep regulation. Recognising this biology does not diminish the psychological experience of trauma, nor does it imply that ME/CFS or long Covid are psychological disorders.

It demonstrates instead that the separation between mind and body is biologically artificial. Different initiating events may act through overlapping stress-response networks while retaining important disease-specific mechanisms.

What might an integrated clinical approach consider?

No intervention can be recommended simply from this study. Nevertheless, a careful assessment of chronic fatigue should consider both the primary diagnosis and potentially modifiable contributors to regulatory load.

Depending upon the individual presentation, this may include:

• Appropriate investigation for anaemia, iron deficiency, vitamin B12 or folate deficiency, thyroid dysfunction, glucose dysregulation and other metabolic contributors
• Assessment of sleep quality and possible sleep apnoea
• Review of medication effects and relevant cardiac or respiratory disease
• Recognition of orthostatic intolerance and autonomic symptoms
• Adequate protein, micronutrients, hydration and appropriately balanced meals
• An anti-inflammatory dietary pattern where clinically appropriate
• Pacing and carefully individualised activity, particularly where post-exertional malaise is present
• Breathing assessment and gentle retraining when dysfunctional breathing has been demonstrated
• Psychological or trauma-informed support when relevant, without using it to dismiss physical symptoms
• Gentle osteopathic treatment directed towards pain, breathing mechanics and autonomic load when tolerated, rather than aggressive treatment during periods of instability

Supplementation should be based upon the clinical history, diet, medication and relevant investigations. Nutrients such as vitamin D, vitamin B12, folate, iron, magnesium, omega-3 fatty acids or coenzyme Q10 may be relevant in selected patients, but they are not universal treatments for complex fatigue syndromes and should not be prescribed indiscriminately.

Promising science, but not yet a finished diagnostic test

A previously reported EpiSwitch ME/CFS classifier produced encouraging sensitivity and specificity in a held-out validation cohort. However, that earlier diagnostic result and the newly reported cross-disease network analysis are related but distinct findings.

The present study does not independently validate the proposed hub genes, establish a universal fatigue signature or show that one treatment will work across all five conditions. The technology was also developed by Oxford BioDynamics, which funded the study, and several authors are connected with the company. This does not invalidate the findings, but it makes independent replication particularly important.

The prospect of objective testing is genuinely encouraging, especially for patients who have spent years feeling disbelieved. The responsible conclusion, however, is that the research provides a promising systems-level model and a route towards future biomarkers – not a definitive test currently available for routine diagnosis.

The wider lesson

The most valuable message is not that five illnesses have suddenly become one. It is that very different conditions may converge upon shared regulatory systems while retaining different triggers, genetic influences and clinical features.

This is precisely why complex patients cannot always be understood by examining one symptom, one organ or one laboratory marker at a time.

Fatigue may represent the final common expression of an organism struggling to regulate immunity, energy production, circulation, autonomic control, stress responses, sleep and recovery. Understanding the network may eventually allow us to identify meaningful subgroups, select more appropriate treatments and replace therapeutic guesswork with genuinely personalised care.”

Clinical Disclaimer

This article is intended for educational and informational purposes only. It does not constitute medical advice and should not replace individual consultation with a qualified healthcare professional.

Main article

‘Deep connection’ found across ME and other exhaustion illnesses

Scientists ‘approaching unifying theory of fatigue’ from DNA structure in cells of people with ME, long Covid, PTSD, rheumatoid arthritis and multiple sclerosis

The Times | 3 September 2026 | Eleanor Hayward

Scientists have unlocked a “biological secret” which may explain why people with five major illnesses suffer from chronic exhaustion, paving the way for new treatments.

They found “striking biological similarities” between myalgic encephalomyelitis (ME), long Covid, post-traumatic stress disorder (PTSD), rheumatoid arthritis and multiple sclerosis (MS).

All the conditions cause similar symptoms, including profound fatigue and brain fog, but are triggered by different events – ranging from viral infections to psychological trauma. They had previously been considered separate and unrelated disorders.

However, by examining the DNA structure inside the cells of people living with all five diseases, scientists found that the diseases “appear deeply connected”, with all five showing signs of a similar “systems failure” involving the body’s immune response.

The study, led by the University of East Anglia and Oxford Biodynamics, suggests there is “a biological unifying theory of fatigue.”

Researchers said their findings could be particularly consequential for patients with ME, also known as chronic fatigue syndrome (CFS), which does not currently have any diagnostic test – meaning patients often struggle for years to get a diagnosis.

Professor Dmitry Pshezhetskiy, the lead researcher, said: “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.

“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.”

The five illnesses are triggered by different events or processes: ME is usually triggered by a viral infection; PTSD by traumatic experiences; long Covid by infection with Covid; rheumatoid arthritis is an autoimmune disease that attacks the joints; and multiple sclerosis attacks the nervous system.

Pshezhetskiy said that “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”.

He added: “We wanted to find out what that is. What we discovered is something approaching a biological unifying theory of fatigue.”

Rather than simply looking at genes, the study looked at the “3D architecture” of how DNA is structured within cells. This revealed the illnesses all have genetic changes which influence the same major biological systems, including the immune system, inflammatory signals, mitochondrial energy production and stress-response mechanisms.

Pshezhetskiy said: “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 analysed how those genes interact in complex biological networks, a completely different picture emerged. Suddenly, the diseases appeared deeply connected.

“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, published in the Journal of Translational Medicine, also suggested that people with ME may have “worn out” immune cells, which could explain why patients are stuck in a state of chronic illness after the original trigger – such as a viral infection – 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 recognised,” said Pshezhetskiy.

Source note

Original article: “‘Deep connection’ found across ME and other exhaustion illnesses”, The Times, 3 September 2026. Read the original Times article

Research paper: Hunter E, Alshaker H, Bundock O, et al. 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. Journal of Translational Medicine. 2026. doi:10.1186/s12967-026-08874-9. Read the open-access research paper

The Times article is reproduced here from the text supplied for educational commentary. Copyright in the original newspaper article remains with The Times and its author. The research paper is available under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 licence.