Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2

Abstract

The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 ()-deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, , and heterozygous mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus growth.

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

“…31 Further study showed that host hepatic flavin monooxygenase 3 participates in gut microbiota-dependent changes in platelet responsiveness in vivo. The symbiotic gut microbiota alter the synthesis of proadhesive von Willebrand factor via Toll-like receptor-2 signaling and favor platelet integrin-dependent thrombus growth.…”

The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols

“…A number of clinical and animal studies have provided strong evidence that links different species of microbiota with the development of CVDs and thrombosis (Kiouptsi & Reinhardt, 2018). Gut microbiota also regulates the hepatic synthesis and plasma level of von Willebrand factor (VWF) via toll-like receptor 2 (TLR2) and leads to defective thrombus growth in mice (Jäckel et al, 2017). Moreover, clinical studies have suggested an involvement of innate immune pathways in gut microbiota-mediated CVDs (Ridker et al, 2017).…”

The intestinal microbiome potentially affects thrombin generation in human subjects

“…Microbiota products reach the portal circulation, the main site of coagulation protein synthesis . In work by others, germ‐free mice showed reduced synthesis of von Willebrand factor in hepatic endothelial cells, which was mediated by toll‐like receptor‐2 signaling in the portal circulation. This finding supports the concept that the intestinal microbiome can modulate thrombosis‐related gene transcription in the liver and subsequently affect the circulation.…”