Abstract
Clostridium difficile infection (CDI) is the number one hospital-acquired infection in the United States. CDI is more common and severe in inflammatory bowel disease patients. Here, we studied the mechanism by which prior colitis exacerbates CDI. Mice were given dextran sulfate sodium (DSS) colitis, recovered for 2 weeks, and then were infected with C. difficile. Mortality and CDI severity were increased in DSS-treated mice compared to controls. Severe CDI is dependent on CD4+ T cells, which persist after colitis-associated inflammation subsides. Adoptive transfer of Th17 cells to naive mice is sufficient to increase CDI-associated mortality through elevated IL-17 production. Finally, in humans, the Th17 cytokines IL-6 and IL-23 associate with severe CDI, and patients with high serum IL-6 are 7.6 times more likely to die post infection. These findings establish a central role for Th17 cells in CDI pathogenesis following colitis and identify them as a potential target for preventing severe disease.
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•C. difficile infection is more severe in mice with prior DSS-induced colitis•Severe disease depends on CD4+ T cells that persist beyond recovery from colitis•Transfer of Th17 cells to naive mice worsens C. difficile severity via IL-17 production•In C. difficile patients, high IL-23 and IL-6 levels correlate with disease severity
C. difficile infection is more common and severe in patients with inflammatory bowel disease. Saleh et al. demonstrate that colitis induces a population of Th17 cells that persists beyond the resolution of inflammation. These cells lead to increased disease severity and host mortality after infection with C. difficile.