Microbial transplantation with human gut commensals containing CutC is sufficient to transmit enhanced platelet reactivity and thrombosis potential

SummaryGut microbes influence cardiovascular disease (CVD) and thrombosis risks through the production of trimethylamine-N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA), the precursor to TMAO, is rate limiting in the metaorganismal TMAO pathway in most humans, and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the choline utilization C/D genes (cutC/D) in multiple human commensals. However, direct demonstration that the catalytically active cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported. Herein, we use gnotobiotic mice and a series of microbial colonization studies employing either a high TMA producing stable human fecal polymcrobial community, or a defined CutC deficient background microbial community coupled with a CutC expressing human commensal ± genetic functional deletion of its cutC genes (i.e. Clostridium sporogenes cutC), to show that microbial cutC dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.