Thromb Haemost
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
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
3  Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia
,
Melanie Schirmer
4  Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
,
Rahajeng N. Tunjungputri
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
3  Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia
,
Hera Vlamakis
4  Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
5  Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, United States
,
Cecilia Chiriac
6  National Institute of Research and Development for Biological Sciences, Institute of Biological Research, Cluj-Napoca, Romania
7  Department of Aquatic Microbial Ecology, Institute of Hydrobiology, Biology Centre of the Academy of Sciences of the Czech Republic, České Budějovice, Czech Republic
,
Edwin Ardiansyah
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
M. Hussein Gasem
3  Center for Tropical and Infectious Diseases, Faculty of Medicine, Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia
8  Department of Internal Medicine, Faculty of Medicine Diponegoro University-Dr. Kariadi Hospital, Semarang, Indonesia
,
Leo A. B. Joosten
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
Philip G. de Groot
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
Ramnik J. Xavier
4  Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
5  Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, Massachusetts, United States
,
Mihai G. Netea
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
9  Department for Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
,
Andre J. van der Ven
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
,
Quirijn de Mast
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
› Author Affiliations
Funding N.V. was supported by the Indonesia Endowment Fund for Education (LPDP) given by the Ministry of Finance of the Republic of Indonesia. M.G. Netea was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. The Human Functional Genomics Project was supported by a European Research Council (ERC) Consolidator grant (ERC 310372). [Fig. 5] was made using Biorender (BioRender—biorender.com).

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.

Supplementary Material



Publication History

Received: 18 January 2021

Accepted: 28 June 2021

Publication Date:
30 June 2021 (online)

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