A Gut Odyssey: The Impact of the Microbiota on Clostridium difficile Spore Formation and Germination

The Gram-positive, anaerobic, spore-forming bacterium Clostridium difficile is the leading cause of health care–associated infections and gastroenteritis-associated deaths in the United States [1]. C. difficile-associated disease is primarily toxin-mediated, although the organism’s natural antibiotic resistance and propensity to cause disease recurrence can lead to severe clinical complications, such as pseudomembranous colitis and toxic megacolon [2]. Antibiotic exposure potentiates C. difficile infections (CDI) by disrupting the colonization resistance conferred by the normal gut microbiota [3–5], while spore formation allows C. difficile to outlast antibiotic therapies and persist in the environment. The remarkable success of fecal microbiota transplantation (FMT) in treating severe recurrent CDI provides the most direct evidence that our gut microbiota protects us from C. difficile invasion [4–6]. While the most effective antibiotic-based therapies lead to an ~20% CDI recurrence rate [1], FMT has an ~95% cure rate [6]. However, since FMT may cause unforeseen complications [4,7], there is obvious interest in determining the mechanisms that control colonization resistance in order to produce more targeted therapies. Several mechanisms have been suggested by which the microbiota antagonizes C. difficile, including increased competition for resources, inhibition of germination and/or vegetative growth, and enhancement of host defense mechanisms [3,5]. In this Pearl, we focus on how the microbiota alters the developmental life cycle of C. difficile during infection.