Liang Xue, Bittinger Kyle, Li Xuanwen, Abernethy Darrell R, Bushman Frederic D, FitzGerald Garret A
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Elife. 2015 Dec 23;4:e08973. doi: 10.7554/eLife.08973.
The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is probably the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin - thus, the drug-microbe interactions described here provide candidate mediators of individualized drug responses.
脊椎动物的肠道微生物群与异源生物化合物的代谢有关，这激发了对临床上重要药物的微生物驱动代谢的研究。在这里，我们研究了微生物群与吲哚美辛之间的相互作用，吲哚美辛是一种非甾体抗炎药（NSAID），可抑制环氧化酶（COX）-1和-2。在小鼠的急性和慢性暴露模型中，以临床相关剂量对吲哚美辛进行了测试，该剂量抑制了COX-1和COX-2衍生前列腺素的产生，并导致小肠（SI）损伤。深度测序分析表明，在两种给药模型中，吲哚美辛暴露都与肠道微生物群结构的改变有关。抗生素治疗对肠道微生物组的扰动改变了吲哚美辛的药代动力学和药效学，这可能是细菌β-葡萄糖醛酸酶活性降低的结果。人类在其微生物群及其对吲哚美辛的反应方面表现出相当大的个体差异——因此，这里描述的药物-微生物相互作用为个体化药物反应提供了候选介质。
