Development of a gut microbe-targeted non-lethal therapeutic to inhibit thrombosis potential without enhanced bleeding

Trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite derived from trimethylamine (TMA)-containing nutrients abundant in a Western diet, enhances both platelet responsiveness and in vivo thrombosis potential and predicts incident atherothrombotic event risks in clinical studies. 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 significantly reduced plasma TMAO levels for up to 3 days with limited systemic exposure in the host. This was achieved by the selective accumulation of inhibitor within intestinal microbes to millimolar levels, a concentration over a million-fold higher than needed for therapeutic effect. In animal models, inhibition of microbial TMA/TMAO generation rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The present studies reveal 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 inhibitor systemic exposure in the host

氧化三甲胺（Trimethylamine-N-oxide, TMAO）是一类依赖肠道菌群的代谢物，源自西式饮食中富含三甲胺（trimethylamine, TMA）的营养底物。该代谢物可增强血小板反应性与体内血栓形成潜能，且在临床研究中可预测动脉血栓事件的发生风险。本研究采用靶向产TMA的核心微生物酶（CutC/D）的机制型抑制剂策略，开发出强效、时间依赖性且不可逆的抑制剂，此类抑制剂不会影响共生菌群的生存活力。在动物模型中，单次口服给药可显著降低血浆TMAO水平长达3天，且宿主全身暴露量极低。该效果通过抑制剂在肠道微生物内选择性蓄积至毫摩尔级浓度实现，该浓度较治疗所需有效浓度高出百万倍以上。动物实验结果显示，抑制微生物产TMA/TMAO可逆转饮食诱导的血小板反应性增强与血栓形成，且未观察到毒性反应或出血风险升高。本研究证实，靶向肠道微生物产TMA/TMAO的机制型抑制作用可降低血栓形成潜能——这是心脏病中的关键不良并发症。同时，本研究还提供了一种通用策略，可实现与宿主疾病相关的肠道微生物酶的选择性非致死性靶向干预，同时大幅降低抑制剂在宿主体内的全身暴露。