Pereira Fátima C, Ge Xiaowei, Kristensen Jannie Munk, Kirkegaard Rasmus H, Maritsch Klara, Zhu Yifan, Decorte Marie, Hausmann Bela, Berry David, Wasmund Kenneth, Schintlmeister Arno, Boettcher Thomas, Cheng Ji-Xin, Wagner Michael
Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, Vienna, Austria.
School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
bioRxiv. 2023 Nov 13:2023.11.12.566429. doi: 10.1101/2023.11.12.566429.
Increasing evidence shows that many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. 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 nervous system-targeted drugs on the gut microbiome. supplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. Importantly, we demonstrate that the impact of these drugs on microbial metabolism is much more pronounced than their impact on abundances, with low concentrations of drugs reducing the activity, but not the abundance of key microbiome members like or species. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Remarkably, entacapone-induced iron starvation selected for iron-scavenging organisms carrying antimicrobial resistance and virulence genes. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and identifies metal sequestration as a mechanism of drug-induced microbiome disturbance.
越来越多的证据表明，许多针对人类的药物会改变肠道微生物群，对宿主健康产生影响。然而，对于药物靶向微生物群的机制以及药物如何影响微生物功能，我们了解得要少得多。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技术，来研究两种广泛使用的靶向神经系统的药物对肠道微生物群的影响。向粪便样本中添加生理相关浓度的恩他卡朋或洛沙平琥珀酸盐，会显著影响多达三分之一的微生物种类的丰度。重要的是，我们证明这些药物对微生物代谢的影响比对丰度的影响更为显著，低浓度的药物会降低关键微生物组成员（如 或 物种）的活性，但不会降低其丰度。我们进一步证明，恩他卡朋因其能够络合和消耗可用铁而影响微生物群，并且通过补充微生物可利用铁的水平可以挽救微生物的生长。值得注意的是，恩他卡朋诱导的铁饥饿选择了携带抗微生物抗性和毒力基因的铁清除生物体。总的来说，我们的研究揭示了两种研究较少的药物对整个微生物群的影响，并确定金属螯合是药物诱导微生物群紊乱的一种机制。
