Bidirectional interactions between indomethacin and the murine intestinal microbiota

TLDR

The vertebrate gut microbiota are known to metabolize xenobiotics, prompting investigation into microbe‑driven processing of clinically relevant drugs. This study examined how the intestinal microbiota interact with indomethacin, a COX‑1/2‑inhibiting NSAID. Indomethacin was administered at clinically relevant doses in acute and chronic mouse models, suppressing COX‑derived prostaglandins and inducing small‑intestinal damage. Deep sequencing revealed indomethacin altered microbiota composition, antibiotic‑mediated microbiome disruption modified its pharmacokinetics and pharmacodynamics—likely via reduced β‑glucuronidase activity—and human microbiota variability may underlie individualized drug responses.

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.