Clostridioides difficile is a major cause of healthcare-associated diarrhea in adult patients. Laboratory diagnosis of C. difficile infection (CDI) is challenging as there is no single test combining high sensitivity and specificity, rapid turnaround time and cost efficiency. They also offer no or little correlation with the clinical outcome. Recently, host-based methods have shown satisfactory performance for the diagnosis of infectious diseases. The aim of this study was to discover CDI-specific host biomarkers that correlate with disease stage and severity.