Exercise Triggers Immune and Energy Strain in ME/CFS

A new study shows that people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience unusually strong immune reactions and energy strain after exercise, helping to explain post-exertional malaise (PEM).

Study participants with ME/CFS were compared to healthy controls before and after exercise. The researchers found that the immune system became unusually reactive, with stronger signals of inflammation and complement activity. At the same time, the body’s energy systems exhibited stress, including difficulty utilizing fats for fuel, signs of blocked energy pathways, and markers of mitochondrial strain. Participants also had higher levels of fats in their blood that can drive inflammation, as well as shifts in gut-related molecules, suggesting a weakened barrier and changes in the microbiome.

Pathways tied to tryptophan metabolism, which affects brain function, were altered after exercise and may help explain symptoms such as “brain fog.”

Many of these biological changes were associated with increased fatigue and reduced daily activity. The authors suggest that future treatments might focus on calming the overactive immune response, supporting energy production, or enhancing gut health.

Citation

Che, X., Ranjan, A., Guo, C., Zhang, K., Goldsmith, R., Levine, S., Moneghetti, K. J., Zhai, Y., Ge, L., Mishra, N., Hornig, M., Bateman, L., Klimas, N. G., Montoya, J. G., Peterson, D. L., Klein, S. L., Fiehn, O., Komaroff, A. L., & Lipkin, W. I. (2025). Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. npj metabolic health and disease, 3(1), 34. https://doi.org/10.1038/s44324-025-00079-w