An animal study from the Perelman School of Medicine at the University of Pennsylvania has found that a nonsteroidal anti-inflammatory drug (NSAID) changed the composition and diversity of gut microbes as a result of which how the drug is broken down changed and hindered its effectiveness.
It is known that gut bacteria that comprises the gastrointestinal microbiome have a significant role to play in the metabolism of most chemicals humans ingest. To be precise, gut bacteria are involved in the digestion of over 30 U.S. Food and Drug Administration (FDA) approved drugs. This is one of the motivating factors behind studies of microbe-driven breakdown of clinically important drugs. The findings of the study were published this month in the journal eLife.
Interactions between gut bugs in mice and the NSAID indomethacin (similar to ibuprofen and naproxen) inhibit the action of cyclooxygenases (COX) -1 and -2. NSAIDs block these COX enzymes and reduce fatty acids called prostaglandins in the body revealed Xue Liang, PhD, first author of the study and a postdoctoral researcher in the lab of senior author Garret A FitzGerald, MD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Institute for Translational Medicine and Therapeutics. He added that because of this characteristic of NSAIDs, they reduce inflammation, pain, and fever. But, prostaglandins are also known to protect stomach lining cells and promote blood clotting and since they are reduced, NSAIDs can give rise to ulcers and bleeding in the stomach.
As a part of the study, the team of researchers tested indomethacin in mice at clinically relevant doses during both acute and chronic exposure. It was found that both doses suppressed production of prostaglandins and caused damage to the small intestine of the mice, similar to the upper and lower gastrointestinal complications induced by NSAIDs in humans. Increased permeability, ulceration, bleeding, and perforation in the intestinal tract were some of the damage induced.
When deep gene sequencing of gut microbiota was done, it was found that exposure to both doses of indomethacin in animal experiments shifted the composition of intestinal bacteria towards a pro-inflammatory structure. It led to the expansion of Peptococcaceae species and Erysipelotrichaceae species in the gut microbiota, as well as the underrepresentation of the S24-7 species in fecal microbiota.
To further the study, the researchers had to test the impact of intestinal microbes on the metabolism of indomethacin. For this the team used antibiotics to deplete the microbiota and then compared metabolism in treated and control mice. It was found that the antibiotic suppression of intestinal bacteria significantly reduced activity by the bacteria enzyme ?-glucuronidase. Indomethacin reabsorption into the circulation was reduced due to the absence of the enzyme and it resulted in increased elimination, a shortened half-life, and reduced exposure to the drug. All this resulted in reduction of the drug's ability to suppress pro-inflammatory prostaglandins.
Liang opined that there are considerable individual differences in the composition of the gut bacteria in humans due to age, diet, time of day, etc., and a result their responses to indomethacin can be varying. He further added that the drug-microbe interactions in this study provide clear-cut candidate mediators of individualized drug responses to be studied in the future.
In the next leg of their study, the researchers are keen on investigating whether gut microbiota composition would be differently influenced by COX-1- or COX-2-specific inhibition, as COX-2 inhibitors show less gastrointestinal complications. They also aim to find whether taking this NSAID at different times of day might lead to higher efficacy and less side effects in animal models and eventually in humans. Other areas to explore include finding if alterations in gut microbiota composition are a driver or a passenger in gastrointestinal ailments, after the ingestion of indomethacin.