Bidirectional interactions between indomethacin and the murine intestinal microbiota

Area of Science:

• Microbiology
• Pharmacology
• Gastroenterology

Background:

• Vertebrate gut microbiota metabolize xenobiotics, including medications.
• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, inhibit cyclooxygenase (COX) enzymes.
• Clinically relevant doses of indomethacin can cause gastrointestinal damage.

Purpose of the Study:

• To investigate the interactions between the gut microbiota and indomethacin.
• To understand how indomethacin affects the intestinal microbiota structure.
• To explore the role of microbial metabolism in indomethacin pharmacokinetics and pharmacodynamics.

Main Methods:

• Acute and chronic indomethacin exposure models in mice.
• Deep sequencing analysis of intestinal microbiota composition.
• Antibiotic treatment to perturb the gut microbiome.
• Assessment of indomethacin pharmacokinetics and pharmacodynamics.

Main Results:

• Indomethacin exposure altered the structure of the intestinal microbiota.
• Antibiotic treatment modified indomethacin pharmacokinetics and pharmacodynamics.
• Reduced bacterial β-glucuronidase activity was implicated in these alterations.
• Indomethacin suppressed prostaglandin production and caused small intestinal damage.

Conclusions:

• Gut microbiota composition influences indomethacin's effects.
• Bacterial β-glucuronidase activity is a key mediator in drug-microbe interactions.
• These findings suggest microbial influence on individualized drug responses to indomethacin.