Trimethylamine-N-oxide (TMAO), a derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.

三甲胺-N-氧化物（TMAO）是肠道微生物代谢物三甲胺（TMA）的衍生物，已被确定为促进动脉粥样硬化的独立危险因素。有证据表明，小檗碱（BBR）可用于治疗肥胖、糖尿病和动脉粥样硬化，但其机制尚不清楚，主要是因为其口服生物利用度较差。在这里，我们发现 BBR 减弱了用补充胆碱的饲料喂养的 C57BL/6J 和 ApoE KO 小鼠的 TMA/TMAO 产生，并减轻了 ApoE KO 小鼠的动脉粥样硬化病变区域。通过体内单剂量 d9-胆碱给药证明 BBR 调节的肠道微生物群可抑制 TMA/TMAO 产生。盲肠内容物的宏基因组分析表明，BBR 改变了肠道微生物群组成、微生物组功能和cutC / cntA基因丰度。此外，BBR 在体外和来自胆碱喂养小鼠和人类志愿者粪便样本的肠道微生物群中，可抑制 TMA 产生细菌中胆碱向 TMA 的转化，这一结果通过将 TMA 产生细菌移植到体内而得到证实。老鼠。这些结果为 BBR 抗动脉粥样硬化作用的机制提供了新的见解，BBR 通过肠道微生物群重塑抑制共生微生物 TMA 的产生。