1Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia, 3800. email@example.com
Clostridium difficile is an important nosocomial pathogen and the leading cause of infectious diarrhoea in hospitals worldwide. Susceptibility to infection with this bacterium is induced by antibiotic treatment or disruption of the normal gastrointestinal microbiota. Infection with toxigenic C. difficile strains causes extensive colonic inflammation, epithelial tissue damage and rapid fluid loss, which manifests as diarrhoea.
C. difficile damages the colonic epithelium via the action of toxins, and this damage must be repaired for optimal gut function. Using an animal infection model and colonic organoids, we investigated infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair. We show that intestinal integrity is altered by C. difficile infection, with a disruption in colonic adherens-junctions and crypt polarity seen, correlating with induction of a pro-inflammatory response. Colonic stem cells are also compromised which diminishes their ability to repair the injured epithelium, shown by a reduction in the growth of colonic organoids from infected animals. The recruitment and exploitation of host proteins during infection was also examined.
These results enhance our current understanding of C. difficile disease pathogenesis and identify new targets for therapeutics to aid gut repair following toxin-mediated damage or to reduce disease severity, which is particularly relevant for recurrent C. difficile infection.