Deciphering Cross-Cohort Metabolic Signatures of Immune Responses and Their Implications for Disease Pathogenesis
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The intricate interplay between circulating metabolites and immune responses, though crucial to disease pathophysiology, remains poorly understood and underexplored in systematic research. Here, we performed a comprehensive analysis of the immune response and circulating metabolome in two Western European cohorts (534 and 324 healthy individuals) and one from sub-Saharan Africa (323 healthy donors). At metabolic level, our analysis uncovered sex differences in the correlation between phosphatidylcholine and cytokine responses upon ex-vivo stimulations. Notably, sphingomyelin showed a significant negative correlation with the monocyte-derived cytokine production in response to Staphylococcus aureus stimulation, a finding validated through functional experiments. Subsequently, employing Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for a modulatory effect of sphingomyelin on immune responses during human infection. Collectively, our results represent a unique resource ( https://lab-li.ciim-hannover.de/apps/imetabomap/ ) for exploring metabolic signatures associated with immune function in different populations, highlighting sphingomyelin metabolism as a potential target in treating inflammatory and infectious diseases.
