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Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.
journal contribution
posted on 2019-03-22, 20:21 authored by Stanley HazenTrimethylamine 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.