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人类肠道细菌对治疗药物的生物积累
2021-09-10 16:09

德国欧洲分子生物学实验室Contact Kiran R. Patil、Athanasios Typas和Peer Bork研究组合作揭示人类肠道细菌对治疗药物的生物积累。该项研究成果发表在2021年9月8日出版的《自然》上。

他们研究了 25 种代表性肠道细菌菌株对 15 种结构不同药物的消耗。这揭示了 70 种细菌与药物之间的相互作用,其中 29 种以前没有报道过。超过一半的新相互作用可归因于生物积累。也就是说,细菌在细胞内储存药物而不对其进行化学修饰,并且在大多数情况下不会影响细菌的生长。例如,他们通过点击化学、热蛋白质组分析和代谢组学研究了广泛使用的抗抑郁药度洛西汀的生物积累的分子基础。

他们发现度洛西汀与多种代谢酶结合并改变相应细菌的代谢物分泌。当在特定的积累和非积累微生物群落中进行测试时,度洛西汀通过代谢交叉影响显著改变了群落的组成。他们在动物模型中进一步验证了他们的发现,表明生物积累细菌减弱了秀丽隐杆线虫对度洛西汀的行为反应。

总之,他们的结果表明,肠道细菌的生物积累可能是改变药物可用性和细菌代谢的常见机制,可能以个体方式对微生物群组成、药代动力学、副作用和药物反应产生影响。

据悉,肠道中的细菌可以调节治疗药物的可用性和功效。然而,药物与细菌之间相互作用的系统图谱直到最近才开始研究,提出的主要潜在机制是微生物对药物的化学转化(生物转化)。

附:英文原文

Title: Bioaccumulation of therapeutic drugs by human gut bacteria

Author: Klnemann, Martina, Andrejev, Sergej, Blasche, Sonja, Mateus, Andre, Phapale, Prasad, Devendran, Saravanan, Vappiani, Johanna, Simon, Bernd, Scott, Timothy A., Kafkia, Eleni, Konstantinidis, Dimitrios, Zirngibl, Katharina, Mastrorilli, Eleonora, Banzhaf, Manuel, Mackmull, Marie-Therese, Hvelmann, Felix, Nesme, Leo, Brochado, Ana Rita, Maier, Lisa, Bock, Thomas, Periwal, Vinita, Kumar, Manjeet, Kim, Yongkyu, Tramontano, Melanie, Schultz, Carsten, Beck, Martin, Hennig, Janosch, Zimmermann, Michael, Svin, Daniel C., Cabreiro, Filipe, Savitski, Mikhail M., Bork, Peer, Typas, Athanasios, Patil, Kiran R.

Issue&Volume: 2021-09-08

Abstract: Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria–drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

DOI: 10.1038/s41586-021-03891-8

Source: https://www.nature.com/articles/s41586-021-03891-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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