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Gut microbiome interactions with drug metabolism, efficacy, and toxicity

  • Ian D. Wilson
    Correspondence
    Reprint requests: Ian D. Wilson, Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
    Affiliations
    Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK
    Search for articles by this author
  • Jeremy K. Nicholson
    Affiliations
    Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK
    Search for articles by this author
Published:August 13, 2016DOI:https://doi.org/10.1016/j.trsl.2016.08.002
      The gut microbiota has both direct and indirect effects on drug and xenobiotic metabolisms, and this can have consequences for both efficacy and toxicity. Indeed, microbiome-driven drug metabolism is essential for the activation of certain prodrugs, for example, azo drugs such as prontosil and neoprontosil resulting in the release of sulfanilamide. In addition to providing a major source of reductive metabolizing capability, the gut microbiota provides a suite of additional reactions including acetylation, deacylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, and importantly, in the context of certain types of drug-related toxicity, conjugates hydrolysis reactions. In addition to direct effects, the gut microbiota can affect drug metabolism and toxicity indirectly via, for example, the modulation of host drug metabolism and disposition and competition of bacterial-derived metabolites for xenobiotic metabolism pathways. Also, of course, the therapeutic drugs themselves can have effects, both intended and unwanted, which can impact the health and composition of the gut microbiota with unforeseen consequences.

      Abbreviations:

      ADMET (absorption, distribution, metabolism, excretion, toxicity), AHR (aryl hydrocarbon receptor), AUC (area under the curve), BVU ((E)-5-(2-bromovinyl) uracil), CAR (constitutive androstane receptor), cMOAT (Canalicular multispecific organic anion transporter 1), cgr (cardiac glycoside reductase), CYP450s (cytochromes P450), DPD (dihydropyrimidine dehydrogenase), DNA (deoxyribonucleic acid), EPHXs (epoxide hydrolases), DMI’s (drug-microbiome interactions), FDA (Food and Drug Administration), GF (germ free), GSTs (glutathione transferases), 5-FU (5-fluorouracil), GI (gastro intestinal), GPX2 (glutathione peroxidase), GST (glutathione S-transferase), LC-MS/MS (liquid chromatography-tandem mass spectrometry), Mdr 1a (multidrug resistance protein 1), MRP2 (multidrug resistance-associated protein 2), mRNA (messenger ribonucleic acid), NATs (N-acetyl transferases), Nrf-2 (nuclear factor erythroid 2-related factor), NSAIDs (non-steroidal anti-inflammatory drugs), OTU (operational taxonomic unit), PPI (proton pump inhibitors), PXR (pregnane-receptor), RMs (reactive metabolites), SPF (specific pathogen free), SULTs (sulphotransferases), UGT (UDP-glucuronosyltransferase), UDP (uridine diphosphate)
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