Gut microbiota regulate hepatic von Willebrand Factor synthesis and arterial thrombosis via Toll-like receptor-2

The symbiotic gut microbiota plays pivotal roles in host physiology. Despite expanding evidence of metabolic alterations contributing to the development of cardiovascular diseases, microbiota-triggered molecular pattern recognition signaling mechanisms which impacting thrombosis are poorly defined. Here, we show that germ-free (GF) mice and mice deficient in the Toll-like receptor 2 (Tlr2) 2 have reduced thrombus growth following carotid arteryafter injury relative to conventionally-raised (CONV-R) wild-type (WT) mice. Tlr2-/- mice raised under GF conditions were indistinguishable from GF WT mice, but colonization of GF WT and GF conventionalized Tlr2-/- mice with a microbiota restored the significant difference in platelet deposition. We identify reduced plasma levels of von Willebrand Factor plasma levels (VWF) and its reduced synthesis specifically in hepatic endothelial cells as the critical factor that determines defective Tlr2-/- platelet deposition in vivo. Platelets from Tlr2-/- mice displayed reduced integrin-mediated VWF binding and diminished adhesion to extracellular matrices in vitro, as seen with thrombosis-protected heterozygous Vwf+/- mice. Administration of VWF rescued defective platelet deposition in Tlr2-/- mice without affecting platelet deposition in WT mice. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters synthesis of pro-adhesive VWF by the liver endothelium and favors platelet-dependent vascular thrombosis.