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 of a cohort of 534 healthy adult Dutch volunteers (500FG 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 as well as 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 1979 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. Conclusions This comprehensive overview is an important resource for understanding the regulation of platelet reactivity by the plasma metabolome and the possible contribution of the gut microbiota.

中文翻译：

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非靶向血浆代谢组和肠道微生物组分析为健康个体血小板反应性的调节提供了新见解

背景 在健康个体中，血小板对刺激的反应性存在很大差异。各种代谢物和代谢途径影响血小板反应性，但缺少对这些关联的全面概述。肠道微生物组对血浆代谢组有很大影响。在这里，我们调查了血小板反应性与非靶向血浆代谢组学和肠道微生物组分析结果的关联。方血液以及用血小板激动剂进行离体刺激后。通过四极飞行时间质谱法使用非靶向代谢分析方法测量血浆代谢组。肠道微生物组数据是通过粪便样本的鸟枪法宏基因组测序测量的。结果 非靶向代谢组学产生了 1979 种代谢物，其中 422 种被鉴定为在人类代谢途径中发挥作用。总体而言，92/422 (21.8%) 代谢物与至少一种血小板反应性读数显着相关。大多数关联涉及脂质，尤其是类花生酸成员，包括前列腺素和白三烯。还发现膳食来源的多酚会抑制血小板反应性。用功能性微生物特征验证代谢途径揭示了两个重叠的代谢途径（'丙氨酸，天冬氨酸，和谷氨酸代谢”和“精氨酸生物合成”）与血小板反应性相关。结论 这一全面的概述是了解血浆代谢组对血小板反应性的调节以及肠道微生物群的可能贡献的重要资源。