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Bidirectional interactions between indomethacin and the murine intestinal microbiota / Liang, Xue.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Nong, Mu, author.
- Language:
- English
- Subjects (All):
- Pharmacology.
- 0419.
- Local Subjects:
- Pharmacology.
- 0419.
- Genre:
- Academic theses.
- Physical Description:
- 1 electronic resource (155 pages)
- Contained In:
- Dissertation Abstracts International 77-02B(E).
- Place of Publication:
- Ann Arbor : ProQuest Dissertations & Theses, 2015.
- Language Note:
- English
- Summary:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, antipyretic, and anti-inflammatory effects. However, NSAIDs commonly induce gastrointestinal toxicity by mechanisms that are incompletely understood, and the efficacy and side effects of these drugs exhibit significant inter-individual variability, which is partially explained by pharmacogenetics.
- The vertebrate intestinal microbiota have a highly diverse enzymatic system and hence have been implicated in the metabolism of various xenobiotics, including clinically important drugs. The composition of intestinal microbiota exhibits considerable inter-individual differences, and dysbiosis has been associated with the pathogenesis of many diseases.
- The present study is designed to elucidate the interactions between the microbiota and indomethacin, an NSAID that inhibits cyclooxygenases (COX) -1 and 2. At a dose that caused small intestinal damage, orally administered indomethacin was distributed in the circulation and in the intestinal tract, and suppressed the production of both COX-1 and COX-2 derived prostaglandins in vivo. Deep sequencing analysis showed that indomethacin altered the composition and diversity of the large intestinal and fecal microbiota, shifting it towards a pro-inflammatory phenotype. Depletion of the intestinal microbiota by antibiotic treatment increased indomethacin elimination, and decreased its half-life and volume of distribution. This involves the de-glucuronidation mediated by the beta-glucuronidase-expressing bacteria in the intestinal microbiota. Therefore, the intestinal microbiota may be a potential source of inter-individual variability in the pharmacokinetics and/or pharmacodynamics of indomethacin.
- This study also found that the total fecal microbial load, as well as the relative abundances of Bacteroidetes and Firmicutes oscillated during the light-dark cycle. This oscillation requires a functional host circadian clock, since deletion of Bmal1, a gene encoding a core molecular clock component, abolished this rhythmicity. The fecal microbiota composition was also altered by Bmal1-deletion. In addition, the relative abundances of several beta-glucuronidase-expressing bacteria oscillate diurnally, suggesting the involvement of intestinal microbiota in the chronopharmacology of indomethacin.
- The indomethacin-microbiota interactions described here provide candidate mechanisms for pathogenesis of GI toxicity, individualized drug responses, as well as the circadian variation of drug kinetics and effects.
- Notes:
- Source: Dissertation Abstracts International, Volume: 77-02(E), Section: B.
- Advisors: Garret A. FitzGerald Committee members: Jeffrey S. Barrett; Tilo Grosser; Katherine L. Nathanson; Gary D. Wu.
- Ph.D. University of Pennsylvania 2015.
- Local Notes:
- School code: 0175
- ISBN:
- 9781339052274
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