Untargeted Plasma Metabolomics and Gut Microbiome Profiling Provide Novel Insights into the Regulation of Platelet Reactivity in Healthy Individuals

Nadira Vadaq; Melanie Schirmer; Rahajeng N. Tunjungputri; Hera Vlamakis; Cecilia Chiriac; Edwin Ardiansyah; M. Hussein Gasem; Leo A. B. Joosten; Philip G. de Groot; Ramnik J. Xavier; Mihai G. Netea; Andre J. van der Ven; Quirijn de Mast

doi:10.1055/a-1541-3706

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2022; 122(04): 529-539
DOI: 10.1055/a-1541-3706

Cellular Haemostasis and Platelets

Untargeted Plasma Metabolomics and Gut Microbiome Profiling Provide Novel Insights into the Regulation of Platelet Reactivity in Healthy Individuals

Nadira Vadaq

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

³Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia

,

Melanie Schirmer

⁴Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States

,

Rahajeng N. Tunjungputri

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

³Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia

,

Hera Vlamakis

⁴Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States

⁵Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, United States

,

Cecilia Chiriac

⁶National Institute of Research and Development for Biological Sciences, Institute of Biological Research, Cluj-Napoca, Romania

⁷Department of Aquatic Microbial Ecology, Institute of Hydrobiology, Biology Centre of the Academy of Sciences of the Czech Republic, České Budějovice, Czech Republic

,

Edwin Ardiansyah

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

M. Hussein Gasem

³Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia

⁸Department of Internal Medicine, Faculty of Medicine Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia

,

Leo A. B. Joosten

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

Philip G. de Groot

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

Ramnik J. Xavier

⁴Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States

⁵Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, United States

,

Mihai G. Netea

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

⁹Department for Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany

,

Andre J. van der Ven

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

,

Quirijn de Mast

¹Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

²Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

› Institutsangaben

Abstract

Background Considerable variation exists in platelet reactivity to stimulation among healthy individuals. Various metabolites and metabolic pathways influence platelet reactivity, but a comprehensive overview of these associations is missing. The gut microbiome has a strong influence on the plasma metabolome. Here, we investigated the association of platelet reactivity with results of untargeted plasma metabolomics and gut microbiome profiling.

Methods We used data from a cohort of 534 healthy adult Dutch volunteers (the 500 Functional Genomics study). Platelet activation and reactivity were measured by the expression of the alpha-granule protein P-selectin and the binding of fibrinogen to the activated integrin αIIbβ3, both in unstimulated blood and after ex vivo stimulation with platelet agonists. Plasma metabolome was measured using an untargeted metabolic profiling approach by quadrupole time-of-flight mass spectrometry. Gut microbiome data were measured by shotgun metagenomic sequencing from stool samples.

Results Untargeted metabolomics yielded 1,979 metabolites, of which 422 were identified to play a role in a human metabolic pathway. Overall, 92/422 (21.8%) metabolites were significantly associated with at least one readout of platelet reactivity. The majority of associations involved lipids, especially members of eicosanoids, including prostaglandins and leukotrienes. Dietary-derived polyphenols were also found to inhibit platelet reactivity. Validation of metabolic pathways with functional microbial profiles revealed two overlapping metabolic pathways (“alanine, aspartate, and glutamate metabolism” and “arginine biosynthesis”) that were associated with platelet reactivity.

Conclusion This comprehensive overview is an resource for understanding the regulation of platelet reactivity by the plasma metabolome and the possible contribution of the gut microbiota.

Keywords

metabolome - microbiome - platelet - platelet reactivity

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Referenzen

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