Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis
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.
Authors
- Nhan Nguyen (ORCID: https://orcid.org/0000-0001-8720-1195)
- Jianbo Fu (ORCID: https://orcid.org/0000-0003-3358-8106)
- Vera P. Mourits (ORCID: https://orcid.org/0000-0003-3322-5145)
- Valerie A. C. M. Koeken (ORCID: https://orcid.org/0000-0002-5783-9013)
- Godfrey S. Temba (ORCID: https://orcid.org/0000-0002-1093-3037)
- Simone J.C.F.M. Moorlag (ORCID: https://orcid.org/0000-0001-8884-8417)
- Quirijn de Mast (ORCID: https://orcid.org/0000-0001-6056-157X)
- Leo A. B. Joosten (ORCID: https://orcid.org/0000-0001-6166-9830)
- Andrei Sarlea (ORCID: https://orcid.org/0000-0002-7008-1307)
- L. Charlotte de Bree
- Cheng‐Jian Xu (ORCID: https://orcid.org/0000-0003-1586-4672)
- Vesla I. Kullaya (ORCID: https://orcid.org/0000-0001-6120-3985)
- Martin Jaeger (ORCID: https://orcid.org/0000-0001-6994-493X)
- Nienke van Unen (ORCID: https://orcid.org/0009-0007-8432-8597)
- Yang Li (ORCID: https://orcid.org/0000-0003-4022-7341)
- Javier Botey Bataller
Institutions
- University of Bonn (DE)
- Radboud University Nijmegen (NL)
- Iuliu Hațieganu University of Medicine and Pharmacy (RO)
- Radboud University Medical Center (NL)
- Medizinische Hochschule Hannover (DE)
- Radboud Institute for Molecular Life Sciences (NL)
- Helmholtz Centre for Infection Research (DE)
- Kilimanjaro Christian Medical Centre (TZ)
- Centre for Individualised Infection Medicine (DE)
- Center for Experimental and Clinical Infection Research (DE)
- Life & Brain (Germany) (DE)
Publication Details
- Journal
- Molecular Systems Biology
- Published
- 2025-09-10
- DOI
- https://doi.org/10.1038/s44320-025-00146-w
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80