Understanding the Puzzle: What is the root cause of chronic fatigue syndrome?

September 22, 2025 •

3 min read

Affecting millions of people worldwide, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disorder with no single known cause. In fact, what is the root cause of chronic fatigue syndrome is one of medicine's most challenging questions, and researchers believe it stems from a combination of biological factors.

Quick Summary

The root cause of Chronic Fatigue Syndrome (ME/CFS) is not yet fully understood, but it is considered a complex biological illness likely triggered by multiple interacting factors, including viral infections, genetic predispositions, immune system dysfunction, and abnormalities in cellular energy metabolism.

Key Points

No Single Cause: Scientists have not found one single root cause for chronic fatigue syndrome (ME/CFS); instead, it is a complex, multi-system biological illness.
Viral Triggers: For many, the illness is triggered by a viral infection, such as Epstein-Barr virus or SARS-CoV-2 (leading to Long COVID).
Immune System Dysfunction: Chronic immune system activation and inflammation are consistent findings in ME/CFS patients.
Energy Metabolism Problems: The illness involves abnormalities in how the body's cells produce energy, explaining the severe fatigue and post-exertional malaise (PEM).
Multi-Factorial Onset: A combination of factors, including genetics, infections, and stress, likely work together to initiate and sustain the condition in different people.
Diagnosis by Exclusion: Diagnosis relies on clinical criteria, like PEM and unrefreshing sleep, after ruling out other medical conditions, as there is no specific test.

A Multi-System Biological Illness, Not a Psychological Condition

For decades, ME/CFS was misunderstood and often dismissed as a psychological issue. However, extensive research confirms it is a genuine, multi-system biological illness with a physical basis. The World Health Organization even classifies it as a neurological disorder. The key symptom is post-exertional malaise (PEM), a severe worsening of symptoms after even minimal physical or mental exertion, which is not alleviated by rest.

Potential Triggers and Contributing Factors

Since no single root cause has been identified, researchers are investigating a variety of potential contributing factors. It is believed that these factors may interact with each other to trigger the onset and persistence of the illness.

Viral or Bacterial Infections

Many individuals with ME/CFS report that their illness began after a severe, flu-like infection. Several infectious agents are under investigation as potential triggers:

Epstein-Barr Virus (EBV): Commonly known as the cause of infectious mononucleosis, EBV is one of the most studied viral triggers.
Q Fever and Ross River Virus: These infections have also been linked to a higher risk of developing ME/CFS-like symptoms.
SARS-CoV-2 (COVID-19): A growing body of evidence shows a significant increase in ME/CFS cases following COVID-19 infection, with many Long COVID patients meeting the diagnostic criteria for ME/CFS.

Immune System Dysfunction

Abnormalities in the immune system are a consistent finding in ME/CFS research. These issues suggest the body's immune response is perpetually active, but not effectively fighting off a pathogen, leading to chronic inflammation. Key findings include:

Natural Killer (NK) Cell Activity: Studies have shown reduced function in NK cells, which are critical for fighting infections.
Cytokine Levels: Altered levels of cytokines, proteins that regulate inflammation, have been observed.
Autoimmunity: The immune system in ME/CFS patients shares some characteristics with autoimmune diseases, potentially attacking the body's own tissues, though direct tissue damage is not typically seen.

Genetic and Familial Links

While no specific ME/CFS gene has been discovered, the illness sometimes runs in families, and studies suggest a genetic component. This indicates that some people may have a genetic predisposition that makes them more susceptible to developing ME/CFS after an environmental or infectious trigger.

Energy Metabolism and Mitochondrial Dysfunction

Patients with ME/CFS often exhibit differences in how their cells produce and use energy, potentially leading to a lack of available fuel for brain and muscle activity. This theory is consistent with the hallmark symptom of PEM, where the body's energy reserves are quickly depleted by even minor activity. This cellular-level energy problem means the body's 'batteries' are never fully charged and drain rapidly.

Neurological and Hormonal Abnormalities

Research has uncovered several neurological and hormonal irregularities in ME/CFS patients:

Brain Function: Studies have shown altered function in specific brain regions involved in fatigue perception, making exertion feel much more difficult.
Spinal Fluid: Different levels of neurotransmitters and markers of inflammation have been found in the spinal fluid of ME/CFS patients compared to healthy individuals.
Hormonal Imbalance: Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the body's stress response, are frequently observed. Some patients have lower levels of cortisol, the stress hormone, which may contribute to chronic inflammation.

Comparison of Proposed Contributing Factors


Factor	Proposed Role	Evidence Level	Key Findings in Research
Viral Infections	Triggering agent, especially in cases with sudden onset.	Strong	Links to EBV, Q fever, and Long COVID demonstrated through patient reports and cohort studies.
Immune System	Perpetually activated state, leading to chronic inflammation.	Strong	Abnormal NK cell function, altered cytokine profiles, and features similar to autoimmune conditions.
Energy Metabolism	Cellular inability to produce sufficient energy.	Moderate	Differences found in how cells produce energy, correlating with post-exertional malaise.
Genetics	Predisposing individual susceptibility to triggers.	Moderate	Familial clustering of cases and twin studies suggest a genetic component.
Neurological Changes	Abnormal brain function affecting fatigue perception.	Moderate	Altered activity in certain brain regions and differences in spinal fluid composition.

Conclusion: Looking to a Future of Targeted Treatment

While there is no single, definitively identified root cause of chronic fatigue syndrome, scientific consensus points towards a complex interplay of biological factors. Ongoing research continues to shed light on these mechanisms, offering hope for future diagnostic tools and effective, targeted treatments. For now, understanding that ME/CFS is a genuine biological illness—and not a psychological one—is a crucial first step toward providing proper patient care. For more information, the Centers for Disease Control and Prevention provides valuable resources.

Frequently Asked Questions

There is no single primary cause identified for chronic fatigue syndrome (ME/CFS). It is widely accepted as a complex biological illness caused by a combination of factors, including viral infections, immune system abnormalities, and genetics.

Yes, many people report their ME/CFS symptoms beginning after a viral illness. The Epstein-Barr virus, for instance, has been linked to the onset of the condition, and more recently, COVID-19 has been recognized as a trigger for ME/CFS-like symptoms in Long COVID patients.

No, extensive research has confirmed that ME/CFS is a biological illness with measurable physiological abnormalities. It is not a mental or psychological disorder, although dealing with a chronic illness can certainly affect mental health.

Some research suggests a potential genetic link, as ME/CFS can sometimes affect members of the same family. This indicates that a genetic predisposition might make certain individuals more susceptible to developing the illness.

Diagnosis of ME/CFS is clinical, based on a specific set of symptoms, including post-exertional malaise (PEM), unrefreshing sleep, and cognitive difficulties, which must be present for at least six months. Doctors must also rule out other medical conditions that could cause similar symptoms.

Currently, there is no single diagnostic biomarker for ME/CFS. However, research has identified several biological abnormalities in patients, such as immune system dysfunction and altered energy metabolism, which help shed light on the underlying mechanisms.

For a significant number of people, Long COVID manifests with symptoms strikingly similar or identical to ME/CFS, including severe fatigue and post-exertional malaise. This connection has provided new urgency and funding for research into the post-viral origins of ME/CFS.