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<p>The complex interplay between circulating metabolites and immune responses, which is pivotal to disease pathophysiology, remains poorly understood and understudied 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 the metabolic level, our analysis revealed sex-specific differences in the correlation between phosphatidylcholine and cytokine responses following ex vivo stimulation. Notably, sphingomyelin exhibited a significant negative correlation with monocyte-derived cytokine production in response to <i>Staphylococcus aureus</i> stimulation, a finding that was validated through functional experiments. Subsequently, using Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for its modulatory role in immune responses during human infection. Collectively, our results represent a unique resource (<a href="https://lab-li.ciim-hannover.de/apps/imetabomap/">https://lab-li.ciim-hannover.de/apps/imetabomap/</a>) for exploring metabolic signatures associated with immune function in different populations, highlighting sphingomyelin metabolism as a potential target in treating inflammatory and infectious diseases.</p>

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Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月10日

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  • Jianbo Fu,
  • Nienke van Unen,
  • Andrei Sarlea,
  • Nhan Nguyen,
  • Martin Jaeger,
  • Javier Botey Bataller,
  • Valerie A C M Koeken,
  • L Charlotte de Bree,
  • Vera P Mourits,
  • Simone J C F M Moorlag,
  • Godfrey Temba,
  • Vesla I Kullaya,
  • Quirijn de Mast,
  • Leo A B Joosten,
  • Cheng-Jian Xu,
  • Mihai G Netea,
  • Yang Li

摘要

The complex interplay between circulating metabolites and immune responses, which is pivotal to disease pathophysiology, remains poorly understood and understudied 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 the metabolic level, our analysis revealed sex-specific differences in the correlation between phosphatidylcholine and cytokine responses following ex vivo stimulation. Notably, sphingomyelin exhibited a significant negative correlation with monocyte-derived cytokine production in response to Staphylococcus aureus stimulation, a finding that was validated through functional experiments. Subsequently, using Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for its modulatory role in 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.