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Publications

Journal Article Preprint Epublish

PubMed: 40778181 DOI: 10.1101/2025.07.23.25332049

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS.

medRxiv

Authors: Xiaoyu Che, Amit Ranjan, Cheng Guo, Keming Zhang, Rochelle Goldsmith, Susan Levine, Kegan J Moneghetti, Yali Zhai, Liner Ge, Nischay Mishra, Mady Hornig, Lucinda Bateman, Nancy G Klimas, Jose G Montoya, Daniel L Peterson, Sabra L Klein, Oliver Fiehn, Anthony L Komaroff, W Ian Lipkin

Affiliations

  • Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Medicine, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY, USA.
  • Levine Clinic; New York NY, USA.
  • Baker Department of Cardiometabolic Health, University of Melbourne, Australia.
  • Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • The Feinstein Institutes for Medical Research, Northwell Health, New York, USA.
  • The Bateman Horne Center, Salt Lake City, UT, USA.
  • Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA.
  • Palo Alto Medical Foundation, Jack S. Remington Laboratory for Specialty Diagnostics of Toxoplasmosis, Palo Alto, CA, USA.
  • Sierra Internal Medicine at Incline Village, Incline Village, NV, USA.
  • Johns Hopkins Center for Women's Health, Sex, and Gender Research, Baltimore, MD, USA.
  • UC Davis Genome Center-Metabolomics, University of California, Davis, CA, USA.
  • Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Abstract

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 exposures 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 with 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 the tryptophan-serotonin-kynurenine pathways. Many of these underlying abnormalities worsened following exercise in ME/CFS patients, but not in healthy subjects; many abnormalities reinforced each other and several were correlated with the intensity of symptoms. Our findings may inform targeted therapeutic interventions for ME/CFS and PEM.

MeSH

Exercise, Cells, Fatigue Syndrome, Chronic, Fatigue, Immunity, Immunity, Innate