High-throughput transcriptomics of 409 bacteria-drug pairs reveals drivers of gut microbiota perturbation.
High-throughput transcriptomics of 409 bacteria-drug pairs reveals drivers of gut microbiota perturbation.
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409 个细菌-药物对的高通量转录组学揭示了肠道微生物群扰动的驱动因素。
DOI：
10.1038/s41564-023-01581-x
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发表时间：
2024
影响因子：
28.3
通讯作者：
Wang,HarrisH
中科院分区：
文献类型：
--
作者：
Ricaurte,Deirdre;Huang,Yiming;Sheth,RaviU;Gelsinger,DiegoRivera;Kaufman,Andrew;Wang,HarrisH
许多药物会扰乱肠道微生物群，可能会导致负面的健康后果。然而，大多数微生物-药物反应的机制还没有从基因水平上阐明。利用高通量细菌转录本，我们系统地表征了常见的人类肠道细菌对最常见的口服药物的基因表达谱。在400个药物-微生物对中，观察到了显著且可重现的转录反应，包括参与多药耐药、代谢物转运、酒石酸盐代谢和核黄素生物合成的途径。重要的是，我们发现他汀介导的AcrAB-TolC外排泵在类杆菌属物种中的上调增强了微生物对维生素A和次级胆汁酸的敏感性。此外，服用辛伐他汀的患者体内携带acrAB-tolC基因的肠道细菌会耗尽，这表明药物与外排的相互作用会产生附带毒性，从而耗尽患者微生物群中含有泵的微生物。这项研究为进一步了解药物介导的微生物区系变化的驱动因素，以便更好地进行临床干预提供了资源。
Many drugs can perturb the gut microbiome, potentially leading to negative health consequences. However, mechanisms of most microorganism–drug responses have not been elucidated at the genetic level. Using high-throughput bacterial transcriptomics, we systematically characterized the gene expression profiles of prevalent human gut bacteria exposed to the most frequently prescribed orally administered pharmaceuticals. Across >400 drug–microorganism pairs, significant and reproducible transcriptional responses were observed, including pathways involved in multidrug resistance, metabolite transport, tartrate metabolism and riboflavin biosynthesis. Importantly, we discovered that statin-mediated upregulation of the AcrAB-TolC efflux pump in Bacteroidales species enhances microbial sensitivity to vitamin A and secondary bile acids. Moreover, gut bacteria carryingacrAB-tolCgenes are depleted in patients taking simvastatin, suggesting that drug–efflux interactions generate collateral toxicity that depletes pump-containing microorganisms from patient microbiomes. This study provides a resource to further understand the drivers of drug-mediated microbiota shifts for better informed clinical interventions.