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Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.

ABSTRACT: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.

SUBMITTER: Roberts AB

PROVIDER: S-EPMC6129214 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.

Roberts Adam B AB Gu Xiaodong X Buffa Jennifer A JA Hurd Alex G AG Wang Zeneng Z Zhu Weifei W Gupta Nilaksh N Skye Sarah M SM Cody David B DB Levison Bruce S BS Barrington William T WT Russell Matthew W MW Reed Jodie M JM Duzan Ashraf A Lang Jennifer M JM Fu Xiaoming X Li Lin L Myers Alex J AJ Rachakonda Suguna S DiDonato Joseph A JA Brown J Mark JM Gogonea Valentin V Lusis Aldons J AJ Garcia-Garcia Jose Carlos JC Hazen Stanley L SL

Nature medicine 20180806 9

Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme ...[more]

PMID: 30082863

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Dataset Information

Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.

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Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.

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