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

Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile 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 C. difficile 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 C. difficile toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.

Pain killers: the interplay between nonsteroidal anti-inflammatory drugs and Clostridioides difficile infection.

Clostridioides difficile is one of the leading causes of nosocomial infections worldwide. Increases in incidence, severity, and healthcare cost associated with C. difficile infection (CDI) have made this pathogen an urgent public health threat worldwide. The factors shaping the evolving epidemiology of CDI and impacting clinical outcomes of infection are not well understood, but involve tripartite interactions between the host, microbiota, and C. difficile. In addition to this, emerging data suggests an underappreciated role for environmental factors, such as diet and pharmaceutical drugs, in CDI. In this review, we discuss the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and eicosanoids in CDI.

From Nursery to Nursing Home: Emerging Concepts in Clostridioides difficile Pathogenesis.

Clostridioides difficile is a Gram-positive, spore-forming, anaerobic bacterium that infects the human gastrointestinal tract, causing a wide range of disorders that vary in severity from mild diarrhea to toxic megacolon and/or death. Over the past decade, incidence, severity, and costs associated with C. difficile infection (CDI) have increased dramatically in both the pediatric and adult populations. The factors driving this rapidly evolving epidemiology remain largely unknown but are likely due in part to previously unappreciated host, microbiota, and environmental factors. In this review, we will cover the risks and challenges of CDI in adult and pediatric populations and examine asymptomatic colonization in infants. We will also discuss the emerging role of diet, pharmaceutical drugs, and pathogen-microbiota interactions in C. difficile pathogenesis, as well as the impact of host-microbiota interactions in the manifestation of C. difficile-associated disease. Finally, we highlight new areas of research and novel strategies that may shed light on this complex infection and provide insights into the future of microbiota-based therapeutics for CDI.