The Commensal Microbiota Enhances ADP-Triggered Integrin αIIbβ3 Activation and von Willebrand Factor-Mediated Platelet Deposition to Type I Collagen

Abstract

The commensal microbiota is a recognized enhancer of arterial thrombus growth. While several studies have demonstrated the prothrombotic role of the gut microbiota, the molecular mechanisms promoting arterial thrombus growth are still under debate. Here, we demonstrate that germ-free (GF) mice, which from birth lack colonization with a gut microbiota, show diminished static deposition of washed platelets to type I collagen compared with their conventionally raised (CONV-R) counterparts. Flow cytometry experiments revealed that platelets from GF mice show diminished activation of the integrin αIIbβ3 (glycoprotein IIbIIIa) when activated by the platelet agonist adenosine diphosphate (ADP). Furthermore, washed platelets from Toll-like receptor-2 (Tlr2)-deficient mice likewise showed impaired static deposition to the subendothelial matrix component type I collagen compared with wild-type (WT) controls, a process that was unaffected by GPIbα-blockade but influenced by von Willebrand factor (VWF) plasma levels. Collectively, our results indicate that microbiota-triggered steady-state activation of innate immune pathways via TLR2 enhances platelet deposition to subendothelial matrix molecules. Our results link host colonization status with the ADP-triggered activation of integrin αIIbβ3, a pathway promoting platelet deposition to the growing thrombus.

Low-Grade Endotoxemia and Thrombosis in COVID-19

“…The biological plausibility of this finding relies on previous experimental study showing that low-grade endotoxemia amplifies thrombus growth through interaction with its receptor TLR4 at level of platelets or leucocytes ( 15 ). This finding is in agreement with previous reports showing that gut microbiota enhances thrombus growth through TLR2-dependent platelet activation ( 16 , 17 ). At this regard, Shin et al demonstrated in vitro and in vivo that bacterial lipoproteins promote thrombosis by clotting activation and endothelial leakage, which is a typical feature of COVID-19 ( 18 ).…”

Gut microbiota induces high platelet response in patients with ST segment elevation myocardial infarction after ticagrelor treatment

“…In the past decade, researchers have realized that gut microbiota are involved in the formation of many cardiac metabolic phenotypes and promote the development of atherosclerosis and other diseases ( Duttaroy, 2021 ). It has been found that platelets of sterile mice show reduced ADP-dependent PA, indicating that the presence of symbionts sensitizes ADP-induced platelet activation ( Kiouptsi et al, 2020 ). The underlying mechanism of these findings may be related to the activation of the innate immune pathway triggered by TLR2 ( Jäckel et al, 2017 ) or activation of integrin αIIbβ3 ( Kiouptsi et al, 2020 ).…”

“…It has been found that platelets of sterile mice show reduced ADP-dependent PA, indicating that the presence of symbionts sensitizes ADP-induced platelet activation ( Kiouptsi et al, 2020 ). The underlying mechanism of these findings may be related to the activation of the innate immune pathway triggered by TLR2 ( Jäckel et al, 2017 ) or activation of integrin αIIbβ3 ( Kiouptsi et al, 2020 ). Furthermore, the level of functional choline utilization C (cut C) in the gut microbiota can be transmitted through fecal transplantation, thereby enhancing platelet reactivity and thrombosis potential in the recipient ( Skye et al, 2018 ).…”

Targeting Trimethylamine N-Oxide: A New Therapeutic Strategy for Alleviating Atherosclerosis

“…A gut microbiota-derived metabolite, phenylacetylglutamine (PAGln), reportedly enhances platelet activation-related phenotypes and thrombosis potential ( 13 ). In addition, associated studies have noted that the gut microbiota also promotes arterial thrombosis through the following mechanisms: adhesion-induced platelet activation ( 14 ), direct or indirect enhancement of human platelet responsiveness to multiple agonists ( 15 , 16 ), enhancement of platelet deposition to subendothelial matrix molecules ( 17 ).…”