Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin-mediated mitochondrial damage.

damages the colonic mucosa through the action of two potent exotoxins. Factors shaping pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and toxins target the mitochondria of CECs and enhance toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.