Metabolomics and Cytokine Signatures in COVID-19: Uncovering Immunometabolism in Pathogenesis

Background: This study aimed to analyze metabolic changes in blood samples from patients with confirmed COVID-19 to explore the correlation between metabolomics and cytokines in survivors and non-survivors of SARS-CoV-2 infection. Understanding the complex biochemical and immunometabolic mechanisms underlying SARS-CoV-2 infection is essential for elucidating the pathophysiology and virulence of COVID-19. Methods: This study included 40 hospitalized COVID-19 patients and 40 healthy controls. Serum metabolic profiles were analyzed using ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS), and cytokine levels were measured using ELISA. Results: Our study defined three clear metabolic phenotypes among survivors and non-survivors of COVID-19 compared with healthy controls, which might be related to mortality, severity, and disease burden. A strong relationship was observed between certain inflammatory markers, including IL-1β, IL-2, IFN-β, IFN-γ, IL-17, and GM-CSF, as well as several metabolites, particularly in COVID-19 non-survivors, such as LysoPCs, 3-hydroxykynurenine, and serotonin. Different metabolite-cytokine correlation patterns were observed according to patient outcomes, indicating unique correlations between metabolic and immune responses in survivors and non-survivors. Metabolic phenotypes were associated with clinical outcomes, comorbidities, and sex-related differences. Kynurenine and related metabolites of tryptophan metabolism were closely correlated with COVID-19 severity, age, and mortality. Compared with survivors and healthy controls, non-survivors displayed higher IL-6, together with distinct metabolic changes. These included increased kynurenine through the IDO1 pathway, elevated glucose and lactate reflecting hyperglycolysis and energy stress, and higher xanthosine from purine turnover. Stronger cytokine–metabolite correlations in this group point to tightly linked immunometabolic activation. Conclusions: Metabolomic profiling revealed distinct metabolic phenotypes that could be associated with the severity and inflammation levels of COVID-19. Correlation analysis between metabolites and cytokines demonstrated strong intercorrelations between specific metabolites and cytokines, indicating a strong interrelationship between inflammatory markers and metabolic alterations. Specific metabolic pathways associated with cytokines and their clinical relevance may serve as potential therapeutic targets.