|UPenn's Xue Liang|
The gut microbiome has been an area of intensive study in medicine over the last decade and plays a big role in the metabolism of dozens of drugs. Now new research shows that the widely used class of nonsteroidal anti-inflammatory drugs (NSAIDs) also interacts with gut bacteria, which in turn reduces the effectiveness of NSAIDs.
Researchers at the Perelman School of Medicine at the University of Pennsylvania published their findings in the journal eLife, headed up by first author Xue Liang of Garret FitzGerald's lab.
They gave clinically relevant doses of an NSAID similar to ibuprofen and naproxen--called indomethacin--to mice in a short- and long-term period. As expected they saw a reduction in prostaglandins synthesis via the cyclooxygenase (COX) enzymes, which provides the classical anti-inflammatory characteristics of NSAIDs. However, they also saw damage to the lining of the small intestines in both short and long term exposure.
The damage to the intestinal tract after the indomethacin exposure included permeation, ulceration, bleeding and perforation of the tract. They also deep sequenced the genes expressed in the gut bacteria and found that after NSAID treatment there is a shift in bacterial composition toward pro-inflammatory bacteria.
The team further showed that gut microbiota is required for effective metabolism of indomethacin by depleting gut bacteria with antibiotics, prior to treatment. The researchers will next ask whether changing gut bacteria is causing or is the effect of gastrointestinal (GI) problems following indomethacin treatment.
Since selective COX-2 inhibition is known to show fewer GI issues, the researchers will also try to discern if specific COX-1 or COX-2 inhibition (the two major COX enzymes) effect gut microbiota composition differently.
In the era of personalized medicine, Liang says, "the drug-microbe interactions in this study provide clear cut candidate mediators of individualized drug responses to be studied in the future."