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帕金森病药物恩他卡朋通过铁螯合作用破坏肠道微生物组平衡。

The Parkinson's disease drug entacapone disrupts gut microbiome homoeostasis via iron sequestration.

机构信息

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, UK.

出版信息

Nat Microbiol. 2024 Dec;9(12):3165-3183. doi: 10.1038/s41564-024-01853-0. Epub 2024 Nov 21.

DOI:10.1038/s41564-024-01853-0
PMID:39572788
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11602724/
Abstract

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.

摘要

许多针对人类的药物会改变肠道微生物组，从而对宿主健康产生影响。然而，这些影响的机制尚不清楚。在这里，我们结合定量微生物组分析、长读长宏基因组学、稳定同位素示踪和单细胞化学成像，研究了两种广泛使用的药物对肠道微生物组的影响。生理相关浓度的恩他卡朋（一种治疗帕金森病的药物）或琥珀酸洛沙平（用于治疗精神分裂症的药物）在体外与人类粪便样本孵育。这两种药物都显著影响微生物的活性，而不是微生物的丰度。从机制上讲，恩他卡朋可以与可用铁形成复合物并耗尽铁，导致肠道微生物组组成和功能发生变化。通过补充微生物可利用铁的水平可以挽救微生物的生长。此外，恩他卡朋诱导的铁饥饿选择了编码抗菌药物耐药性和毒力基因的铁掠夺肠道微生物组成员。这些发现揭示了两种研究较少的药物对整个微生物组的影响，并确定金属螯合是药物诱导微生物组紊乱的一种机制。

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