title: Bidirectional interactions between indomethacin and the murine intestinal microbiota.
abstract: 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.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Xue
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Bittinger
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Xuanwen
authors.initials: X
authors.lastname: Li
authors.affiliation: Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, United States.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Abernethy
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Frederic D
authors.identifier: http://orcid.org/0000-0003-4740-4056
authors.initials: FD
authors.lastname: Bushman
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D058448:Biota / Q000187:drug effects; D001711:Biotransformation; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D007213:Indomethacin / Q000378:metabolism*; D051379:Mice
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin
keywords: glucuronidation; human biology; indomethacin; medicine; microbiota; mouse; pharmacokinetics