Pharmacological reduction of neutrophil infiltration reduces Clostridioides difficile infection severity.

Clostridioides difficile is the leading cause of nosocomial infections and an urgent public health threat. This bacterial pathogen is challenging to treat due to antibiotic resistance and high recurrence rates, highlighting the need for additional therapeutic strategies. Host inflammatory responses are major drivers of disease severity during C. difficile infection (CDI), yet few therapeutic strategies target these pathways. Here, we show that the prostaglandin E1 (PGE1) analog misoprostol markedly reduces CDI severity by modulating host immune responses. During CDI, misoprostol decreases circulating neutrophils and limits infiltration into the colon, reducing epithelial damage, intestinal pathology, and infection severity. Additionally, misoprostol reduces serum granulocyte colony-stimulating factor (G-CSF), an important cytokine in neutrophil mobilization, controlling neutrophil levels during CDI. Together, these findings highlight neutrophil infiltration as a key driver of C. difficile-associated disease and identify innate immune modulation as a potential host-directed therapeutic strategy.IMPORTANCEClostridioides difficile remains a leading cause of antibiotic-associated diarrhea worldwide and a major healthcare burden. While antibiotics are commonly used to treat CDI, high antibiotic resistance and recurrence rates highlight the need for additional therapeutic approaches. Here, we demonstrate that modulation of the innate immune response can mitigate disease severity. Administration of the prostaglandin analog misoprostol reduces neutrophil availability during CDI, resulting in decreased inflammation and improved outcomes. These findings suggest that fine-tuning neutrophil responses may present a promising host-directed strategy to improve CDI outcomes.