Trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite derived from trimethylamine (TMA)-containing nutrients that are abundant in a Western diet, enhances both platelet responsiveness and in vivo thrombosis potential in animal models and predicts incident atherothrombotic event risks in clinical studies. Here, utilizing a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme (CutC/D), we developed potent, time-dependent and irreversible inhibitors 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 days 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 a million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA/TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective non-lethal targeting of gut microbial enzymes linked to host disease, while limiting systemic exposure of the inhibitor in the host.

Barrington et al. examined the effect of four human diets (American, Mediterranean, Japanese, and Maasai/ketogenic) on metabolic health across four mouse...

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