Evaluating the impact of pharmaceuticals on the human gut microbiome Raw sequence reads. Evaluating the impact of pharmaceuticals on the human gut microbiome

Drugs initially designed to specifically target human cells often can affect microbes as well. As a result of poor gastrointestinal absorption and/or biliary secretion, many of these drugs reach the large intestine where they encounter - and potentially interact with - hundreds to thousands of different microbial species that play important roles in various aspects of human physiology. Indeed, several cohort studies have reported significant associations between the use of medication and shifts in gut microbial composition and function. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. In this study we combined quantitative microbiome profiling and long-read metagenomics, stable isotope probing and single-cell chemical imaging to investigate the impact of two nervous system-targeted drugs on the gut microbiome.Ex vivosupplementation 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. 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. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and further identifies metal sequestration as a mechanism of drug-induced microbiome disturbance. Sequencing was performed at the Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna under the project IDs JMF-2103-29 and JMF-2208-05.

最初专为靶向人类细胞而设计的药物，往往也会对微生物产生影响。由于胃肠道吸收不良或胆汁排泄障碍，此类药物多会抵达大肠，在此处与数百乃至数千种不同的微生物物种接触并可能产生相互作用——而这些微生物在人类生理学的诸多方面均发挥着重要作用。诚然，多项队列研究已报道，药物使用与肠道微生物组的组成及功能改变之间存在显著关联。然而，目前关于药物靶向微生物组的具体机制，以及药物如何影响微生物功能的认知仍较为匮乏。本研究结合定量微生物组谱分析（quantitative microbiome profiling）、长读长宏基因组学（long-read metagenomics）、稳定同位素探针（stable isotope probing）与单细胞化学成像（single-cell chemical imaging），探究了两种靶向神经系统的药物对肠道微生物组的影响。将生理相关浓度的恩他卡朋（entacapone）或琥珀酸洛沙平（loxapine succinate）体外添加至粪便样本中，可显著改变样本中多达三分之一现存微生物物种的丰度。本研究进一步证实，恩他卡朋可通过络合并消耗可利用铁离子来影响微生物组，而补充微生物可利用的铁离子即可恢复微生物的生长。综上，本研究揭示了两种尚未被充分研究的药物对完整微生物组的影响，并进一步确认金属螯合作用是药物诱导微生物组紊乱的一种机制。测序工作由维也纳医科大学与维也纳大学联合微生物组中心（Joint Microbiome Facility）完成，项目编号为JMF-2103-29与JMF-2208-05。