ME/CFS Biomarkers Explained: What the Research Shows About Immune, Autonomic, and Energy Changes
Aimee Mills-Viscovich, LICSW, The Rainbow Initiative, PLLC
Last reviewed: September 26, 2026
If you live with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), you may have been told your tests are normal, your symptoms are “nonspecific,” or that you just need to push a little harder. When there’s no single test that proves what you’re living with, it’s easy for other people, and sometimes you, to start doubting it.
The research tells a more complicated and more validating story. There’s no diagnostic test yet, but scientists have found real, measurable differences in the bodies of people with ME/CFS. Here’s what the evidence shows, how strong it is, and what it means for care.
What is a biomarker, and why doesn’t ME/CFS have one yet?
A biomarker is a measurable sign in the body, such as a blood value, a scan result, or a heart-rhythm pattern, that reliably separates people who have a condition from people who don’t. ME/CFS doesn’t have a validated one yet, so it’s diagnosed from symptoms after other causes are ruled out.1 That’s a gap in our tools, not proof that the illness isn’t physical.
What did the 2023 review look at?
Researchers in Australia gathered 101 studies, published between 1994 and 2022, that compared people with ME/CFS to healthy people on possible biomarkers. The largest share looked at the immune system (about 30%), followed by genes, blood vessels and circulation, metabolism, ion channels, physical function, and the brain.1
The studies were small, averaging about 44 people with ME/CFS each, and most participants were women who had been ill for around 10 years. The review found that results often weren’t repeated from one study to the next. Even so, several studies agreed that the immune system is involved.1
What does the immune research show?
The most repeated finding involves natural killer (NK) cells, immune cells that help clear infections and damaged cells. Several studies in the 2023 review found that NK cells in people with ME/CFS were less effective at this job.1 A 2019 review of 17 studies, written by the same research group, called this the most consistent immune finding in ME/CFS.2
Not every study agrees. Two studies in the 2023 review found no difference,1 and in 2023 a large U.S. study across several clinics tested 174 people with ME/CFS and 86 healthy people and found no difference in NK cell killing ability at all. Its authors concluded the test isn’t ready for clinical use.3 One possible reason for the disagreement is that labs handle blood samples differently; that study tested blood shipped overnight. Research on cytokines, the immune system’s chemical messengers, has been even more mixed, with some higher and some lower than in healthy people. That pattern points toward an immune system that is poorly regulated rather than simply “inflamed.” (My post ME/CFS Is Not Static explains one reason cytokine findings vary: the stage of illness may matter.)
What are ion channels, and why do they come up?
Ion channels are tiny gates in cell walls that control the flow of calcium and other minerals, which cells use as signals. One research group has repeatedly found that a channel called TRPM3 works poorly in the NK cells of people with ME/CFS.1,4 It’s a promising lead, but nearly all of this work comes from that one group, which also wrote the 2023 review.
In a study published in January 2026, the group tested NK cells from 36 people with ME/CFS and 42 healthy people, with investigators at two separate lab sites, and again found reduced TRPM3 function, with no difference between sites.4 That strengthens the finding. It still needs to be confirmed by research teams outside that group before it could become a test.
What about energy, blood flow, and the brain?
Smaller sets of studies in the review looked at metabolism, blood vessels, heart-rate patterns, and brain imaging. Findings included signs of disrupted energy metabolism, reduced function in the lining of blood vessels, lower heart-rate variability, and higher lactate in the fluid spaces of the brain.1 Each is interesting, but most rest on one or a few small studies.
Heart-rate variability is the natural beat-to-beat variation in heart rhythm, and lower variability can signal strain on the autonomic nervous system, which runs automatic functions like blood pressure and heart rate. That may help explain why many people with ME/CFS feel worse standing up. One of the brain lactate studies found the same pattern in fibromyalgia, so that marker isn’t specific to ME/CFS.1
Is there newer evidence since 2023?
Yes. A 2025 study used health data from the UK Biobank, comparing about 1,455 people with ME/CFS to more than 131,000 people without it. Hundreds of blood measures differed between the groups, pointing to chronic inflammation, insulin resistance, and liver stress, and several were confirmed in a separate U.S. group.5
Two findings stand out. First, the differences could not be explained by people with ME/CFS being less active, which challenges the idea that the illness is mainly deconditioning. Second, no single measure could reliably tell people with ME/CFS from people without it.5 So the biology is real and measurable, but a one-tube blood test still isn’t here.
Why do results vary so much from person to person?
ME/CFS appears to involve several body systems interacting, and people differ in their genetics, how their illness started, their hormones, and how long they’ve been ill. One person’s most abnormal finding may be immune, another’s autonomic. Small studies and different diagnostic criteria add to the noise.1 This “network” explanation is my reading of the evidence, not a proven model.
What does this mean for therapy?
For therapists, the biology changes how some behaviors should be read. A client who cancels after a good session may be in a crash, not resisting. Unfinished homework may reflect limited mental stamina, not ambivalence. Post-exertional malaise, the delayed worsening of symptoms after effort, can look a lot like avoidance from the outside.
In my clinical experience, depression and anxiety in people with ME/CFS are often reactions to loss, disbelief from others, and difficult medical experiences, rather than the cause of the illness. Many people I work with describe feeling relief simply from hearing that their body, not their character, is struggling. Therapy can then become a place for pacing, grief, rebuilding identity, and self-advocacy rather than pushing for performance.
Evidence-Based Treatment Recommendations
“Guideline-based” means it comes from a formal clinical guideline. “Research-based” means the cited studies directly support it. “Extrapolated” means it’s my reading of where the research points, not something a study tested. “Clinical perspective” is my own practice.
For you
Stay within your energy limits rather than pushing through symptoms (pacing). (Guideline-based.6)
Be cautious with any program that increases activity on a fixed schedule, such as graded exercise therapy. (Guideline-based.6)
Normal routine labs don’t rule out ME/CFS. If your symptoms fit, ask for an evaluation from a provider familiar with it. (Research-based: there is no validated diagnostic biomarker, and diagnosis is symptom-based.1)
Be skeptical of private tests or products marketed as diagnosing or fixing ME/CFS. Any supplement or medication aimed at your immune system or energy is something to talk through with your prescriber. (Research-based: no biomarker has been validated for diagnosis.1,5)
For clinicians
Before interpreting cancellations or unfinished homework as avoidance, ask about crashes in the days after effort. (Extrapolated.)
Adjust the work to energy limits: shorter sessions, lower cognitive load, and remote options where possible. (Extrapolated from the guideline’s emphasis on staying within energy limits.6)
Pace intensive work, including trauma processing, so a session doesn’t trigger a crash. (Extrapolated.)
Offer cognitive behavioral therapy as support for living with the illness, not as a cure. (Guideline-based.6)
When writing accommodation letters, stay within your scope: document the mental health effects you assess and treat, and leave documentation of ME/CFS itself to medical providers. (Clinical perspective.)
Honest caveats
The studies in the 2023 review were small and used several different diagnostic definitions, some older and broader than others. Their quality varied, and many findings weren’t repeated.
Much of the NK cell and TRPM3 evidence comes from one research group, which also wrote the review, and a large independent U.S. study did not find the NK cell difference.
The 2025 UK Biobank study relied on people reporting their own diagnosis, and it only included adults aged 40 to 69.
All of these findings are group averages. None of them can currently be used to test one person for ME/CFS.
The 2023 review only covered studies published through 2022, and the field is moving quickly.
If you’d like support
Many people I work with are autistic, and some describe living with both ME/CFS and autistic burnout, two different conditions that can be hard to tell apart from the inside. If that sounds familiar, you can learn more about our burnout group, a space to make sense of that exhaustion alongside others who understand it.
Notes
Maksoud, R., Magawa, C., Eaton-Fitch, N., Thapaliya, K., & Marshall-Gradisnik, S. (2023). Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A systematic review. BMC Medicine, 21, 189. https://doi.org/10.1186/s12916-023-02893-9
Eaton-Fitch, N., du Preez, S., Cabanas, H., Staines, D., & Marshall-Gradisnik, S. (2019). A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome. Systematic Reviews, 8, 279. https://doi.org/10.1186/s13643-019-1202-6
Querec, T. D., Lin, J.-M. S., Chen, Y., Helton, B., Kogelnik, A. M., Klimas, N. G., Peterson, D. L., Bateman, L., Lapp, C., Podell, R. N., Natelson, B. H., Unger, E. R., & the MCAM Study Group. (2023). Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A multi-site clinical assessment of ME/CFS (MCAM) sub-study. Journal of Translational Medicine, 21. https://doi.org/10.1186/s12967-023-03958-2
Martini Sasso, E., Er, T. S., Eaton-Fitch, N., Hool, L., Muraki, K., & Marshall-Gradisnik, S. (2026). Large-scale investigation confirms TRPM3 ion channel dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Medicine, 12, 1703924. https://doi.org/10.3389/fmed.2025.1703924
Beentjes, S. V., Miralles Méharon, A., Kaczmarczyk, J., Cassar, A., Samms, G. L., Hejazi, N. S., Khamseh, A., & Ponting, C. P. (2025). Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-025-00258-8
National Institute for Health and Care Excellence. (2021). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: Diagnosis and management (NICE Guideline NG206). https://www.nice.org.uk/guidance/ng206
🤖 AI DISCLOSURE: I used AI tools to help analyze and summarize the peer-reviewed research in this post. Every citation has been checked against the original source. Please refer to the original articles for complete findings.
📋 FOR INFORMATIONAL PURPOSES ONLY: This content is intended for general educational purposes. It does not constitute clinical advice, diagnosis, or treatment for any specific individual.
🩺 CONSULT A MEDICAL PROFESSIONAL: Any information related to health conditions, medications, or medical decisions should be discussed with a licensed physician or qualified healthcare provider.
🧠 CONSULT A MENTAL HEALTH PROFESSIONAL: Please consult a licensed mental health professional (LICSW, psychologist, psychiatrist, or LMFT) regarding concerns specific to your situation.