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Circ Res. 2018 Oct 26;123(10):1164-1176. doi: 10.1161/CIRCRESAHA.118.313142.

Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential.

Author information

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.

KEYWORDS:

cardiovascular diseases; gastrointestinal microbiome; humans; metabolism; thrombosis

PMID:
30359185
PMCID:
PMC6223262
[Available on 2019-10-26]
DOI:
10.1161/CIRCRESAHA.118.313142

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