It is widely accepted that Clostridium difficile exploits dysbiosis and leverages inflammation to thrive in the gut environment, where it can asymptomatically colonize humans or cause a toxin-mediated disease ranging in severity from frequent watery diarrhea to pseudomembranous colitis or toxic megacolon. Here, we synthesize recent findings from the gut microbiota and enteric pathogenesis fields to inform the next steps toward a better understanding of C. difficile infection (CDI). In this review, we present a model in which the lifestyle of C. difficile is dictated by the metabolic state of the distal gut ecosystem. Contributions by C. difficile (specifically the production and action of the large glycosylating toxins TcdA and TcdB), the microbiota, and the host dictate whether the gut environment is supportive to the pathogen. Mechanistic, metabolic pathway-focused approaches encompassing the roles of all of these players are helping to elucidate the molecular ecology of the distal gut underlying a diseased or healthy ecosystem. A new generation of therapeutic strategies that are more targeted (and palatable) than fecal microbiota transplants or broad-spectrum antibiotics will be fueled by insight into the interspecies (host-microbe and microbe-microbe) interactions that differentiate healthy from pathogen-infested microbiotas.
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