Microbial cutC-dependent TMA/TMAO production by human gut commensals is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host.
Does colonization with gut microbes expressing the cutC gene increase platelet reactivity and thrombosis potential in germ-free mice?
The microbial choline TMA-lyase pathway, specifically the cutC gene, directly enhances platelet reactivity and thrombosis potential, identifying it as a potential therapeutic target for atherothrombotic heart disease.
RATIONALE: Gut microbes influence cardiovascular disease 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 cutC/D (choline utilization C/D) genes in multiple human commensals. OBJECTIVE: Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported. METHODS AND RESULTS: Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC). CONCLUSIONS: Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
Skye et al. (Thu,) conducted a other in Thrombosis potential. Microbial colonization with CutC-expressing human commensal vs. CutC-deficient background microbial community or Clostridium sporogenes Δ cutC was evaluated on Platelet reactivity and thrombosis potential. Microbial cutC-dependent TMA/TMAO production by human gut commensals is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host.