Chronic Fatigue Is A Complex A Multi-System Condition

Myalgic encephalomyelitis, also called chronic fatigue syndrome or ME/CFS, is a long-lasting and disabling condition marked by extreme fatigue, worsening of symptoms after physical or mental activity, and problems with memory and concentration that many patients describe as brain fog. For ME/CFS patients, even small amounts of physical or mental effort can trigger a significant symptom flare that may last days. Many people with ME/CFS report that their illness began after a viral or other infection, but the underlying biology has remained unclear to scientists.

In a 2025 study published in npj Metabolic Health and Disease (a division of Nature), researchers compared 56 people with ME/CFS to 52 healthy individuals. They analyzed blood samples taken at rest and again 24 hours after an exercise challenge. The team used an approach that entailed measuring large numbers of molecules at once, including metabolites, which are small chemicals involved in energy production and metabolism, and proteins that help regulate immune and cellular functions.

Systemic Inflammation in Immune System

The researchers found that immune cells from people with ME/CFS produced higher levels of inflammatory molecules called cytokines when exposed to microbial triggers in the laboratory. Cytokines are chemical messengers that help coordinate immune responses. This heightened response suggests the immune system may be overly sensitive in people with ME/CFS, as if it is primed to overreact. After exercise, additional signs of immune activation appeared, including activation of the complement system, a group of proteins that amplify inflammation.

Mitochondrial Dysfunction

The study also found evidence of mitochondrial dysfunction. Mitochondria are structures inside cells that generate most of the body’s energy in the form of ATP. In ME/CFS, key energy pathways appeared disrupted, especially after exercise. Levels of carnitine, a molecule needed to transport fats into mitochondria for energy production, were also reduced. Additionally, a stress-related protein linked to mitochondrial disease increased after exercise and was associated with more severe fatigue.

Gut Imbalance

Researchers also observed elevated triglycerides (suggesting altered fat metabolism), and changes in markers related to gut barrier integrity, consistent with “leaky gut” markers as well as dysbiosis—an imbalance of gut microbiota.

Neurochemical Dysregulation

Finally, the study found disruptions in tryptophan metabolism. Tryptophan is an amino acid used to make serotonin, the “happy chemical” neurotransmitter that affects mood and cognition. After exercise, more tryptophan was diverted into inflammatory pathways instead of being used in serotonin production. Because of this, the body may lack the necessary ingredients to make enough serotonin, which may help explain cognitive symptoms and mood changes.

Overall, the findings show measurable immune, metabolic, and inflammatory abnormalities in ME/CFS patients that often worsen after exercise and correlate with symptom severity. These results support the view that ME/CFS involves real biological dysfunction and is intertwined with several bodily systems and processes.