Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise. We report evidence of an exaggerated innate immune response after exposure to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked to lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways; and dysregulation of tryptophan-serotonin-kynurenine pathways. Many abnormalities were worse following exercise and correlated with the intensity of symptoms. Our findings may inform development of targeted therapeutic interventions for ME/CFS and PEM.
Authors
- Anthony L. Komaroff (ORCID: https://orcid.org/0000-0001-7672-2518)
- Cheng Guo (ORCID: https://orcid.org/0000-0002-6602-8810)
- Nancy G. Klimas (ORCID: https://orcid.org/0000-0003-1459-3268)
- Nischay Mishra (ORCID: https://orcid.org/0000-0002-1177-9641)
- Lixin Ge (ORCID: https://orcid.org/0000-0002-8554-1054)
- Sabra L. Klein (ORCID: https://orcid.org/0000-0002-0730-5224)
- Susan Levine
- Mady Hornig (ORCID: https://orcid.org/0000-0001-7572-3092)
- José G. Montoya (ORCID: https://orcid.org/0000-0002-3378-8071)
- Amit Ranjan (ORCID: https://orcid.org/0000-0001-7325-4560)
- Kegan Moneghetti (ORCID: https://orcid.org/0000-0001-9503-6660)
- Xiaoyu Che (ORCID: https://orcid.org/0000-0003-0001-4122)
- Lucinda Bateman (ORCID: https://orcid.org/0000-0002-9546-9922)
- Oliver Fiehn (ORCID: https://orcid.org/0000-0002-6261-8928)
- Walter Ian Lipkin (ORCID: https://orcid.org/0000-0002-8768-9386)
- Keming Zhang (ORCID: https://orcid.org/0000-0002-9587-9796)
- Yali Zhai
- Daniel L. Peterson
- R. S. Goldsmith
Institutions
- Brigham and Women's Hospital (US)
- Feinstein Institute for Medical Research (US)
- NewYork–Presbyterian Hospital (US)
- Harvard University (US)
- Johns Hopkins University (US)
- The University of Melbourne (AU)
- Nova Southeastern University (US)
- Columbia University Irving Medical Center (US)
- Sierra Nevada College (US)
- Bateman Horne Center (US)
- Medical Research Foundation (GB)
- Columbia University (US)
- University of California, Davis (US)
Publication Details
- Journal
- npj Metabolic Health and Disease
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1038/s44324-025-00079-w
- Citations
- 8
- Primary Topic
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Type
- article
- Field-Weighted Citation Impact
- 11.77
Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases