Many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, the mechanisms underlying these effects are not well known. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single-cell chemical imaging to investigate the impact of two widely prescribed drugs on the gut microbiome. Physiologically relevant concentrations of entacapone, a treatment for Parkinson’s disease, or loxapine succinate, used to treat schizophrenia, were incubated ex vivo with human faecal samples. Both drugs significantly impact microbial activity, more so than microbial abundance. Mechanistically, entacapone can complex and deplete available iron resulting in gut microbiome composition and function changes. Microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Further, entacapone-induced iron starvation selected for iron-scavenging gut microbiome members encoding antimicrobial resistance and virulence genes. These findings reveal the impact of two under-investigated drugs on whole microbiomes and identify metal sequestration as a mechanism of drug-induced microbiome disturbance.

许多人类靶向药物会改变肠道微生物组，从而对宿主健康产生影响。然而，这些影响背后的机制尚不清楚。在这里，我们结合了定量微生物组分析、长读长宏基因组学、稳定同位素探测和单细胞化学成像，以研究两种广泛使用的药物对肠道微生物组的影响。将治疗帕金森病的恩他卡朋或用于治疗精神分裂症的琥珀酸洛沙平的生理相关浓度与人类粪便样本进行离体孵育。这两种药物都对微生物活性有显著影响，比微生物丰度更严重。从机制上讲，恩他卡朋可以复杂化和消耗可用的铁，从而导致肠道微生物组的组成和功能发生变化。可以通过补充微生物群可及的铁水平来挽救微生物生长。此外，恩他卡朋诱导的铁饥饿被选择用于编码抗菌素耐药性和毒力基因的铁清除肠道微生物组成员。这些发现揭示了两种研究不足的药物对整个微生物组的影响，并将金属螯合确定为药物诱导的微生物组紊乱的机制。