ABSTRACT Clostridioides difficile has emerged as a noteworthy pathogen in patients with inflammatory bowel disease (IBD). Patients with IBD who develop concurrent C. difficile infection (CDI) experience increased morbidity and mortality. IBD is associated with intestinal inflammation and alterations of the gut microbiota, both of which can diminish colonization resistance to C. difficile. Here, we describe the development of a mouse model to explore the role that IBD-induced changes of the gut microbiome play in the observed susceptibility to C. difficile. Helicobacter hepaticus, a normal member of the mouse gut microbiota, triggers pathologic inflammation in the distal intestine akin to human IBD in mice that lack intact IL-10 signaling. Development of IBD resulted in a distinct intestinal microbiota community compared to antibiotic-treated mice and non-IBD controls. We demonstrate that mice with H. hepaticus-induced IBD were susceptible to C. difficile colonization in the absence of other perturbations, such as antibiotic treatment. Concomitant IBD and CDI was associated with significantly worse disease than observed in animals with colitis alone. Specific pathogen-free IL-10-deficient mice retained the ability to resist C. difficile colonization in experiments that employed an isogenic mutant of H. hepaticus that triggers an attenuated intestinal inflammation, despite changes in microbiota community structure. These studies in a novel mouse model of IBD and CDI emphasize the dual importance of host responses and alterations of the gut microbiota in susceptibility to C. difficile colonization and infection in the setting of IBD.
IMPORTANCE The incidence of CDI continues to increase significantly among patients with IBD, independent of antibiotic use, yet the relationship between IBD and increased risk for CDI remains to be understood. Our study sought to describe and utilize an antibiotic-independent mouse model to specifically explore the relationship between the IBD-associated gut and susceptibility to C. difficile colonization and CDI development. We demonstrate that the development of IBD is sufficient to render mice susceptible to C. difficile colonization and results in significantly worse disease than IBD alone. Furthermore, this model requires both IBD-induced inflammation and associated microbiota alterations to permit C. difficile colonization. This model recapitulates human IBD and CDI comorbidity and will aid in developing new clinical approaches to predict, diagnose, and treat C. difficile infection in the IBD population.