1. Microbiology and Infectious Disease

Bidirectional interactions between indomethacin and the murine intestinal microbiota

  1. Xue Liang
  2. Kyle Bittinger
  3. Xuanwen Li
  4. Darrell R Abernethy
  5. Frederic D Bushman
  6. Garret A FitzGerald  Is a corresponding author
  1. Univ. of Pennsylvania, United States
  2. University of Pennsylvania, United States
  3. Food and Drug Administration, United States
https://doi.org/10.7554/eLife.08973
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  1. Xue Liang
  2. Kyle Bittinger
  3. Xuanwen Li
  4. Darrell R Abernethy
  5. Frederic D Bushman
  6. Garret A FitzGerald
(2015)
Bidirectional interactions between indomethacin and the murine intestinal microbiota
eLife 4:e08973.
https://doi.org/10.7554/eLife.08973
  2. Download BibTeX
  3. Download .RIS

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 likely 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.

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Author details

  1. Xue Liang

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, Univ. of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Kyle Bittinger

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Xuanwen Li

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Darrell R Abernethy

    Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Frederic D Bushman

    Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Garret A FitzGerald

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    garret@upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Wendy S Garrett, Harvard School of Public Health, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#803903) of the University of Pennsylvania. Throughout the study, every effort was made to minimize suffering.

Version history

  1. Received: May 26, 2015
  2. Accepted: December 16, 2015
  3. Accepted Manuscript published: December 23, 2015 (version 1)
  4. Version of Record published: February 2, 2016 (version 2)

Copyright

© 2015, Liang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xue Liang
  2. Kyle Bittinger
  3. Xuanwen Li
  4. Darrell R Abernethy
  5. Frederic D Bushman
  6. Garret A FitzGerald
(2015)
Bidirectional interactions between indomethacin and the murine intestinal microbiota
eLife 4:e08973.
https://doi.org/10.7554/eLife.08973

Share this article

https://doi.org/10.7554/eLife.08973

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