Columbia University researchers uncover immune and metabolic disruptions in ME/CFS patients, offering insights into Long COVID and paving the way for targeted therapies.
New Columbia University study uncovers immune and metabolic dysfunctions that could lead to targeted treatments
For decades, patients with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS) have endured debilitating symptoms extreme fatigue, post-exertional malaise (PEM), and cognitive impairment often without clear explanations or effective treatments. Now, new research led by the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health, in collaboration with a multicenter team, is shedding light on the molecular underpinnings of ME/CFS.
The study, published in npj Metabolic Health and Disease, also strengthens the connection between ME/CFS and post-infectious syndromes such as Long COVID and post-treatment Lyme disease.
ME/CFS: More Than “All in the Mind”
Once dismissed as a psychological condition, ME/CFS is now firmly recognized as a biological disorder. According to the CDC, up to 3.3 million Americans may live with ME/CFS, contributing to an annual economic burden of $51 billion. Many patients report an influenza-like illness before onset, suggesting that infection acts as a trigger.
Researchers have long suspected that ME/CFS stems from an abnormal immune response that causes inflammation, damages tissues, and disrupts cellular energy production. The overlap with Long COVID symptoms further supports this infection-linked origin.
Inside the Study
The research team analyzed blood samples from 56 ME/CFS patients and 52 healthy controls recruited in New York and California. Using advanced molecular tools, they mapped:
- The metabolome small molecules involved in energy and metabolism
- The proteome proteins that drive biological processes
- Immune responses to simulated infections, both before and after exercise
The findings revealed multiple biological disruptions that help explain ME/CFS symptoms:
- Impaired energy production, leading to exhaustion and toxic metabolite buildup
- Lipid abnormalities, perpetuating tissue damage and inflammation
- Weakened gut barrier function, allowing bacteria to leak into the bloodstream and trigger immune responses
- Overactivation of the complement system, causing chronic inflammation
- Oxidative stress from disrupted copper-dependent antioxidant pathways
- Dysregulated tryptophan serotonin kynurenine pathways, linked to cognitive dysfunction
When researchers exposed patient blood cells to bacterial and viral mimics, they observed heightened inflammatory responses, particularly elevated IL-6, a key pro-inflammatory cytokine. Responses were strongest in women over 45, correlating with lower estrogen levels.
Toward Targeted Therapies
These molecular insights point toward new therapeutic opportunities. Potential interventions include:
- Metformin, IL-37, or rapamycin to calm overactive immune responses
- Prebiotics and probiotics to restore gut health
- 12,13-diHOME supplementation or GDF15-blocking therapies for patients with metabolic disruption
- 5-hydroxytryptophan (5-HTP) or SSRIs for those with tryptophan-related abnormalities
- Carnitine supplementation to restore cellular energy metabolism
- Estrogen therapy to modulate immune activity in older women
“Our findings indicate that people with ME/CFS have dysregulated immune responses to common infections,” said Xiaoyu Che, PhD, co-first author.
“While what gives rise to ME/CFS remains obscure, understanding the ways it disrupts the body’s biological processes on the molecular level is revealing biomarkers for specific subtypes that may lead to targeted interventions,” added senior author W. Ian Lipkin, MD.
Why It Matters
By identifying specific immune and metabolic pathways tied to ME/CFS symptoms, this study opens the door to precision medicine for millions of patients. The work also provides crucial insights into Long COVID, which shares many overlapping biological features.
For patients long told their condition was “in their head,” these findings provide validation and hope that tailored treatments could soon become reality.
