Potential biomarkers for chronic fatigue syndrome (ME/CFS) include changes in immune-system signals, energy-related chemicals in the blood, gene activity, and proteins linked to blood-vessel function. Researchers have reported differences in these areas, but results are not consistent enough to create a reliable diagnostic test. At present, clinicians diagnose ME/CFS from a person's history and symptoms and use routine tests to look for other possible causes of fatigue.
What does a biomarker mean in ME/CFS research?
A biomarker is a measurable feature of the body that may provide information about a disease, a biological process, or a person's response to treatment. Biomarkers can include substances in blood or urine, patterns of gene activity, immune-cell characteristics, or measurements of how the body functions.
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), researchers are looking for biomarkers that could help identify the illness more objectively, distinguish it from other conditions, or reveal biologically different groups of people with the same diagnosis. A potential biomarker is a research finding, however, not necessarily a reliable clinical test.
A systematic review published in Frontiers in Medicine examined 101 studies of potential ME/CFS biomarkers. The researchers identified candidates involving immune function, genetics, metabolism, mitochondria, the gut microbiome, circulation, and neurological or physical function. The findings varied across studies, and no candidate had been validated sufficiently for routine diagnosis.
Which potential biomarkers are researchers investigating?
1. Immune-system signals and inflammatory markers
The immune system is one of the major areas of ME/CFS biomarker research. Scientists investigate cytokines, which are proteins that help cells communicate and regulate immune responses. Other areas of interest include the numbers and activity of different immune cells, antibodies, and changes in the genes that control immune-cell behavior.
Some studies have reported differences in cytokines or immune-cell activity between people with ME/CFS and healthy comparison groups. However, studies have not consistently found the same changes. Cytokine levels can also be influenced by other illnesses and biological circumstances, making it difficult to identify a pattern that is specific to ME/CFS.
Researchers are also examining how immune cells respond to substances from microbes. These experiments may reveal differences that are not obvious from a routine blood test, but the findings need independent confirmation before they can guide individual diagnosis.
2. Metabolic markers and cellular energy production
Metabolism describes how the body processes nutrients and uses them to produce energy. Researchers studying ME/CFS have investigated metabolites, which are substances produced or used during these processes, as well as the function of mitochondria, structures inside cells that help generate usable energy.
Potential markers include changes in certain fats, amino acids, and other metabolic compounds. Scientists are also studying adenosine triphosphate (ATP), a molecule cells use for energy, and related compounds that may provide clues about energy production. These measurements could help explain aspects of the illness, but no specific metabolic pattern is currently accepted as a diagnostic signature.
In September 2025, the National Institutes of Health (NIH) described research involving blood samples from 56 people with ME/CFS and 52 healthy controls. Researchers reported differences in inflammatory responses, proteins, and energy-related processes, including changes in fat metabolism. Some findings were more apparent following an exercise challenge. These results provide possible research leads rather than a validated test for clinical use.
3. Blood-vessel and circulation-related markers
Another research area involves the endothelium, the thin layer of cells lining blood vessels, and proteins associated with vascular function. Scientists are investigating whether measurable changes in these systems help explain some of the biological differences observed in ME/CFS.
A study published in Cell Reports Medicine in December 2025 combined measurements of metabolism, immune cells, and proteins in blood from 61 people with ME/CFS and 61 healthy controls. The researchers reported differences in cellular energy-related measurements, immune-cell populations, and plasma proteins associated with vascular function.
The study identified variables with potential predictive value within its research sample. Such findings still require validation in other populations and clinical settings. They do not establish that any individual vascular protein or blood test can confirm ME/CFS.
4. Genetic and gene-expression markers
Genes contain instructions that help cells carry out their functions. Gene-expression tests examine which genes are active and how strongly they are expressed under particular conditions. Epigenetic research examines changes in how genes are regulated without changing the underlying DNA sequence.
Researchers are investigating whether particular gene-expression or epigenetic patterns are associated with ME/CFS. Some studies have reported differences in immune-related gene activity, but findings have not established a reproducible signature that can reliably distinguish ME/CFS from other illnesses.
These approaches may eventually help researchers understand biological subgroups or identify pathways involved in the condition. At present, specialized genetic or gene-expression testing is not an established way to diagnose ME/CFS.
5. Gut microbiome and microbial metabolites
The gut microbiome consists of the microorganisms living in the digestive tract. Researchers are examining differences in these microbial communities and in metabolites produced when microbes process nutrients and other substances. Other investigations focus on indicators of the intestinal barrier and the body's immune response to material originating from the gut.
Some studies have identified differences in microbial metabolites or related immune and metabolic responses in people with ME/CFS. However, results do not yet establish a specific gut microbiome pattern that can diagnose the illness. A microbiome test marketed as an ME/CFS diagnostic test should therefore not be regarded as a proven substitute for clinical evaluation.
6. Hormones such as cortisol
Cortisol is a hormone involved in several body functions, including the response to stress. The Centers for Disease Control and Prevention (CDC) notes that some people with ME/CFS have lower cortisol levels than healthy people, but those levels may remain within the usual laboratory range. Cortisol results cannot be used to diagnose or guide treatment of ME/CFS on their own.
Other hormone-related changes have also been investigated. At present, no single hormone measurement has been shown to provide a reliable diagnosis of ME/CFS. Hormone tests may still be appropriate when a clinician is investigating another possible explanation for persistent fatigue.
Why have researchers not established a reliable ME/CFS biomarker?
Several challenges make biomarker development difficult. ME/CFS involves multiple body systems, and the biological findings reported in research do not always match from one study to another. Researchers may use different diagnostic criteria, laboratory methods, sample sizes, or study populations, which can affect the results.
The timing of a sample may also matter. Some studies examine people at rest, while others investigate responses to exercise or laboratory challenges. A difference observed under one set of conditions may not appear under another. Researchers must determine whether a proposed marker is reproducible, specific to ME/CFS, and sufficiently accurate for its intended purpose.
A useful diagnostic biomarker would need to distinguish ME/CFS from other conditions that can cause similar symptoms, not merely identify a difference between an ME/CFS group and healthy volunteers. It would also need to perform reliably across different populations and clinical settings.
What tests are used while a biomarker is being sought?
There is currently no single laboratory test that confirms ME/CFS. According to the CDC's clinical evaluation guidance, healthcare professionals assess a person's symptoms, medical history, examination findings, and laboratory results. Testing is selected according to the clinical situation, with particular attention to identifying other illnesses that may explain fatigue or occur alongside ME/CFS.
Depending on the person's history and examination, initial investigations may include:
- A complete blood count to investigate anemia and other blood-related abnormalities.
- Thyroid-function tests to assess whether thyroid problems could contribute to fatigue.
- Iron studies, including ferritin and transferrin saturation, when an iron-related problem is being considered.
- Electrolytes, glucose, kidney-function tests, and liver-function tests to assess other potential contributors.
- Inflammation markers, urinalysis, or tests for other conditions when the clinical findings indicate a reason to investigate them.
These tests are generally used to investigate other possible causes of fatigue or identify coexisting conditions. An abnormal result may provide useful information about a separate health problem, while results within the usual ranges do not rule out ME/CFS. Additional investigations may be appropriate when symptoms or examination findings suggest a specific condition.
Could potential biomarkers improve diagnosis in the future?
Research may eventually identify a combination of markers that performs better than any individual measurement. Combining immune, metabolic, genetic, and vascular information could also help researchers investigate whether different biological subgroups exist within ME/CFS.
Before such an approach becomes a routine clinical test, researchers need to confirm its accuracy in independent studies and establish how it performs in people with other causes of fatigue. They must also determine whether the test provides information that improves clinical decisions beyond the assessment already available.
For now, promising biomarker findings should be viewed as advances in research rather than proof that a diagnostic blood test is ready for widespread use. People experiencing persistent or disruptive fatigue can discuss an appropriate evaluation with a healthcare professional, including whether tests for other possible causes are needed.