In a groundbreaking new study published in npj Metabolic Health and Disease, researchers from Columbia University’s Center for Infection and Immunity (CII) in collaboration with a multi-institutional team have unveiled critical insights into the elusive pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This debilitating condition, characterized by profound fatigue, cognitive dysfunction, and post-exertional malaise, has long puzzled the scientific community due to its complex and multifactorial nature. The study provides compelling molecular-level evidence demonstrating how heightened innate immune responses may drive chronic inflammation and contribute to the persistent symptoms experienced by ME/CFS patients, potentially paving the way for novel therapeutic avenues.
ME/CFS affects millions globally, with the United States alone facing an estimated 3.3 million cases and a staggering economic burden surpassing $50 billion annually. Traditionally misclassified as psychosomatic, the syndrome is increasingly recognized as a biological disorder with immune dysregulation at its core. Most patients report a viral-like illness preceding symptom onset, implicating infectious triggers in the disease’s pathogenesis. This new research substantiates these observations by elucidating how abnormal immune activation following microbial exposure leads to systemic metabolic disturbances and chronic inflammation, central drivers in ME/CFS morbidity.
The investigative team conducted a comprehensive analysis of blood samples from 56 ME/CFS patients alongside 52 matched healthy controls, recruited from diverse geographic regions including New York and California. Employing state-of-the-art molecular profiling techniques, the study mapped both the metabolome—reflecting the collection of small-molecule metabolites involved in cellular metabolism—and the proteome, encompassing the protein expression landscape. Crucially, they simulated infection via microbial stimuli and monitored immune cell responses, enabling an unprecedented view into the functional dysregulation within immune pathways associated with ME/CFS.
Results revealed profound disruptions in interconnected biological processes commonly implicated in chronic inflammatory conditions. ME/CFS patients exhibited impaired mitochondrial function, leading to deficient cellular energy production—a mechanistic explanation for the pervasive fatigue and cognitive impairment observed clinically. Alongside these energy deficits, researchers identified lipid metabolism abnormalities that exacerbate tissue injury and sustain inflammatory signaling cascades, further perpetuating disease pathology.
Structural components of the extracellular matrix, which typically maintain tissue integrity and modulate immune cell behavior, were also found to be dysregulated in ME/CFS. This deregulation facilitates aberrant release of pro-inflammatory mediators, thereby intensifying systemic inflammation. A notable disruption of epithelial barriers, particularly within the gastrointestinal tract, was also documented. This barrier dysfunction fosters gut dysbiosis, allowing microbial products to translocate into the bloodstream and provoke widespread immune activation.
At the immunological level, heightened activation of the complement system—a key component of innate immunity—was observed. While essential for pathogen defense, overactivation of complement proteins can induce collateral tissue damage and drive the chronic inflammatory milieu characteristic of ME/CFS. Furthermore, antioxidant defenses dependent on copper exhibited functional impairments, leading to increased oxidative stress and further tissue injury.
The study delved deep into the metabolic underpinnings affecting neurotransmitter pathways as well. Dysregulation of the tryptophan-serotonin-kynurenine axis was implicated in cognitive deficits associated with ME/CFS, illuminating potential biochemical targets for ameliorating brain fog and other neuropsychiatric symptoms. Peripheral blood mononuclear cells (PBMCs) from patients demonstrated hyper-reactivity to microbial mimics such as lipopolysaccharide (LPS) and viral RNA analogs, producing elevated levels of interleukin-6 (IL-6), a prominent pro-inflammatory cytokine. These hyperinflammatory responses were amplified notably in women over 45 years of age with diminished estradiol levels, suggesting a sex hormone link to immune dysregulation.
Leveraging their findings, the investigators proposed several promising targets for therapeutic intervention tailored to distinct ME/CFS subtypes. Immunomodulatory agents such as metformin and rapamycin, the latter an mTOR inhibitor with immunosuppressive properties, emerged as candidates for patients exhibiting exaggerated innate immune activation. Additionally, gut-targeted therapies including prebiotics like inulin and probiotics featuring Faecalibacterium prausnitzii were recommended to restore mucosal barrier function and recalibrate immune responses in those with microbiome imbalances.
From a metabolic standpoint, supplementation strategies were highlighted based on specific biomarker profiles. Individuals exhibiting low baseline levels of the lipid 12,13-diHOME might benefit from dietary restoration of this molecule, while those with elevated post-exercise levels of growth differentiation factor 15 (GDF15)—a stress-responsive hormone regulating energy expenditure—could respond to GDF15 neutralization therapies. Moreover, abnormalities in tryptophan metabolism could potentially be corrected with 5-hydroxytryptophan or selective serotonin reuptake inhibitors (SSRIs), addressing neurocognitive symptoms.
Another compelling avenue involves carnitine supplementation to rescue defective fatty acid transport and oxidation in patients with documented carnitine deficiencies, restoring cellular energy homeostasis. Given the elevated inflammatory response measured in postmenopausal women, estrogen replacement therapies may also modulate immune activation and improve symptomatology in this demographic subset.
The study’s co-first authors, Xiaoyu Che, PhD, and Amit Ranjan, PhD, emphasize that their work not only delineates biological pathways correlating with ME/CFS symptom clusters but also identifies biomarkers capable of stratifying patients into clinically relevant subgroups. Such stratification is vital for designing precision medicine trials to evaluate targeted treatments and improve outcomes in this heterogeneous patient population.
Senior author W. Ian Lipkin, MD, underscores that although the initial cause of ME/CFS remains enigmatic, these molecular insights into immune-metabolic dysregulation provide a roadmap for future research. The identification of intracellular signaling abnormalities linked to clinical symptoms bridges a critical gap between bench science and patient care, heralding a new era of biomarker-informed, mechanism-based therapies.
This research was supported by generous funding from the Hutchins Family Foundation’s Chronic Fatigue Initiative and the National Institute of Allergy and Infectious Diseases (NIAID) under grant 4U54AI138370. The authors report no conflicts of interest, reinforcing the integrity and translational potential of their findings.
As the ME/CFS community continues to seek effective treatments, this comprehensive study represents a milestone, unraveling the pathological interplay between immune activation, metabolic dysfunction, and systemic inflammation. It also highlights the overlapping biological themes shared with other post-infectious syndromes such as Long COVID and post-treatment Lyme disease, emphasizing the broader relevance of these findings to chronic illness research. With mechanistic clarity and therapeutic prospects now clearer, patients and clinicians alike may look forward to advancements in personalized care grounded in robust molecular science.
Subject of Research: People
Article Title: Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS
News Publication Date: 1-Sep-2025
Web References: 10.1038/s44324-025-00079-w
References:
Che X, Ranjan A, et al. Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. npj Metabolic Health and Disease. 2025; DOI:10.1038/s44324-025-00079-w.
Keywords: Chronic fatigue syndrome, ME/CFS, innate immunity, inflammation, metabolomics, proteomics, immune dysregulation, post-exertional malaise, gut dysbiosis, mitochondrial dysfunction, cytokines, IL-6, metabolic disruption, personalized therapy
