Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Garret A. FitzGerald

Abstract

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 β-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 β-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.

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Pharmacology Commons

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