Predicting and manipulating drug inactivation by the human gut microbiome

The trillions of microorganisms in the human gastrointestinal tract are an underexplored aspect of pharmacology. Despite numerous examples of microbial effects on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the commonly prescribed cardiac glycoside, digoxin, by Eggerthella lenta. Whole genome transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, absent in non-metabolizing E. lenta strains, and predictive of the efficiency of digoxin inactivation by the human gut microbiome. Digoxin inactivation was further enhanced by microbial interactions and inhibited by arginine. Pharmacokinetic studies using gnotobiotic mice revealed that increasing dietary protein reduces the in vivo metabolism of digoxin by E. lenta, with significant changes to drug concentration in the urine and serum. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes. Overall design: RNA-Seq analysis of Eggerthella lenta cultured with or without digoxin.

人类胃肠道内的万亿级共生微生物是药理学领域尚未得到充分探索的重要方向。尽管已有大量研究证实微生物可对药物疗效与毒性产生影响，但学界对其背后的分子机制往往仍缺乏完整认知。本研究针对卵形真杆菌（Eggerthella lenta）对临床常用强心苷类药物（cardiac glycoside）地高辛（digoxin）的灭活作用进行了系统解析。通过全基因组转录组分析、比较基因组学与体外培养实验，我们发现一处可被地高辛诱导上调的细胞色素编码操纵子；该操纵子在无法代谢地高辛的卵形真杆菌菌株中缺失，且可用于预测人体肠道微生物组对地高辛的灭活效率。微生物群落间的相互作用可进一步增强地高辛的灭活过程，而精氨酸则会对该过程产生抑制作用。利用悉生小鼠（gnotobiotic）开展的药代动力学研究显示，提高膳食蛋白质摄入水平可降低卵形真杆菌在体内对地高辛的代谢活性，进而显著改变尿液与血清中的药物浓度。上述研究结果凸显了从人类基因组与微生物组双重视角开展药理学研究的重要性。整体实验设计：对添加或不添加地高辛的卵形真杆菌培养物进行RNA测序（RNA-Seq）分析。