Sarah M Skye1,2, Weifei Zhu1,2, Kymberleigh A Romano1,2,3, Chun-Jun Guo4, Zeneng Wang1,2, Xun Jia1, Jennifer Kirsop1,2, Bridget Haag1, Jennifer M Lang5,6, Joseph A DiDonato1,2, W H Wilson Tang1,2,7, Aldons J Lusis5,6, Federico E Rey3, Michael A Fischbach1,4, Stanley L Hazen2,7. 1. From the Department of Cellular and Molecular Medicine, Lerner Research Institute (S.M.S., W.Z., K.A.R., Z.W., X.J., J.K., B.H., J.A.D., W.H.W.T., S.L.H.), Cleveland Clinic, OH. 2. Center for Microbiome and Human Health, Lerner Research Institute (S.M.S., W.Z., K.A.R., Z.W., J.K., J.A.D., W.H.W.T., S.L.H.), Cleveland Clinic, OH. 3. Department of Bacteriology, University of Wisconsin-Madison (K.A.R., F.E.R.), David Geffen School of Medicine, University of California, Los Angeles. 4. Department of Bioengineering and ChEM-H, Stanford University, CA (C.-J.G., M.A.F.), David Geffen School of Medicine, University of California, Los Angeles. 5. Department of Human Genetics (J.M.L., A.J.L.), David Geffen School of Medicine, University of California, Los Angeles. 6. Department of Medicine (J.M.L., A.J.L.), David Geffen School of Medicine, University of California, Los Angeles. 7. Department of Cardiovascular Medicine (W.H.W.T., S.L.H.), Cleveland Clinic, OH.
Abstract
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.
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 cholineTMA-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 cholineTMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
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