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. The host inflammatory response is a major driver of C. difficile -associated disease and associated with worse clinical outcomes. Currently, few strategies targeting the inflammatory response have been leveraged to treat CDI. Here, we show that administration of the prostaglandin E ₁ (PGE ₁ ) 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.