Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to long COVID. — CFSMEATLAS
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Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to long COVID.
Al Masoodi, Wasim Talib Mahdi, Radhi, Sami Waheed, Abdalsada, Habiba Khdair et al. · PloS one · 2025 · DOI
Quick Summary
This study looked at 90 people, some with Long COVID and some without, to understand why Long COVID patients develop depression, anxiety, and chronic fatigue. Researchers measured several substances in the blood related to inflammation and metabolism. They found that people with Long COVID had higher levels of inflammatory markers and abnormal insulin function, and these changes were linked to their mood and fatigue symptoms.
Why It Matters
This research identifies specific biological pathways—particularly galanin signaling and inflammatory markers—that may underlie the mood and fatigue symptoms many Long COVID patients experience. Understanding these mechanisms could help explain why ME/CFS-like symptoms persist after COVID-19 and may guide development of targeted treatments.
Observed Findings
People with Long COVID had significantly higher levels of depression, anxiety, fatigue, CRP, PGE2, galanin, GALR1, insulin resistance, PAI-1, NSE, and S100B compared to those without Long COVID.
Depression, anxiety, and fatigue scores were significantly correlated with PGE2, CRP, galanin, GALR1, insulin resistance, and PAI-1 levels.
Biomarkers explained 33.6-42.0% of the variance in fatigue and affective symptom scores, with galanin-GALR1 signaling, PGE2, and CRP being the three most important predictors.
The peak body temperature-to-oxygen saturation ratio during acute infection predicted increases in galanin-GALR1 signaling.
Including the acute-phase severity index increased predictive accuracy to 55.3-67.1%.
Inferred Conclusions
Chronic fatigue and affective symptoms in Long COVID result from metabolic dysfunction, activated immune-inflammatory pathways, and the severity of inflammation during acute SARS-CoV-2 infection.
Galanin-GALR1 signaling, prostaglandin E2, and C-reactive protein are the most important biomarkers associated with these symptoms.
The severity of acute infection (reflected in body temperature and oxygen saturation parameters) may predict the development of persistent neuropsychiatric and fatigue symptoms.
Remaining Questions
Does galanin-GALR1 signaling contribute causally to affective and fatigue symptoms, or is it an epiphenomenon of inflammation?
What This Study Does Not Prove
This study is cross-sectional and does not establish causation—elevated biomarkers correlate with symptoms but may not directly cause them. The study cannot prove whether these biomarkers are permanent features or whether they change over longer time periods, and findings at 3-6 months post-infection may not apply to earlier or later stages of Long COVID. The study also does not assess functional impairment or post-exertional malaise, key ME/CFS diagnostic features.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →