Nonsteroidal anti-inflammatory drugs can work with Clostridioides difficile toxins to target mitochondria of epithelial cells, leading to increased severity of infection that can be long-lasting.
Nonsteroidal anti-inflammatory drugs (NSAIDs) worsen Clostridioides difficile infection (CDI) by disrupting colonic epithelial cells, damaging the mitochondria, a new study suggests.
The study, published in
“It has long been appreciated that NSAIDs like aspirin, indomethacin, and naproxen negatively affect the gut, both in patients with C difficile infection and other conditions like inflammatory bowel disease (IBD),” study author Joseph P. Zackular, PhD, of Children's Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine at Perelman School of Medicine at the University of Pennsylvania, told Contagion. “Long-term NSAID use can lead to stomach ulcers and intestinal injuries, like bleeding and perforation of the intestinal tissue.
“Our work has shed light on the mechanisms underlying this phenomenon in C difficile infection. We demonstrate that NSAIDs sensitize colonic epithelial cells to the effect of the toxins produced by C difficile. Specifically, we show that this effect is driven by off-target effects of NSAIDs on cellular mitochondria in the gut leading to enhanced damage and disease severity during C difficile infection.”
CDI in the colon produces exotoxins TcdA and TcdB, which can lead to cell death. The study involved an in vitro model with indomethacin as a representative NSAID. It found that epithelial cell barrier permeability was increased more when TcdB encountered indomethacin than in the presence of either individually.
“Our initial hypothesis was that the NSAID-mediated exacerbation of disease was caused by the effect of NSAIDs on their canonical targets—COX enzymes,” Zackular said. “However, to our surprise, we found that off-target effects of NSAIDs were responsible for this phenomenon. We showed that NSAIDs can localize to the mitochondria of epithelial cells and disrupt several functions that leads to increased mortality, epithelial cell damage and permeability, and inflammation during CDI.”
The study provides better understanding of why NSAIDs are harmful for patients with CDI and a baseline for more research into the mitochondrial functions during CDI.
“It is already established that NSAIDs treatment should be avoided for patients suspected of having CDI,” Zackular said. “Our work shows that the effect of NSAIDs can be long lasting, exacerbating C difficile infection in mice even days after discontinuation of treatment. Thus, we simply advise clinicians to evaluate the necessity of NSAID use in both patients suspected of having an active C difficile infection, as well as patients who are at increased risk of C difficile infection.”
Further research may explore how the effects of NSAIDs on mitochondria may play a role in other diseases like irritable bowel disease and colorectal cancer and on injuries to the small intestine.
“Our next steps are to further define how mitochondrial functions impact C difficile infection and other inflammatory diseases of colon,” Zackular said. “Moreover, we are very interested in understanding the role that the gut microbiota plays in shaping the effect of NSAIDs in the gut, especially in C difficile infection.”
