The emerging metabolic view of Clostridium difficile pathogenesis

Abstract

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.

Figure 1. A metabolism-centric model for the range of C. difficile lifestyles within the distal gut

Toxigenic C. difficile can persist in a range of environments in the distal gut. Future work to elucidate the mechanisms underlying these states will inform the development of novel interventions for the mitigation of CDI. (A) The microbiota of a healthy human may or may not contain toxigenic C. difficile. In asymptomatically colonized individuals, the roles played by C. difficile in the intestinal ecosystem remain unclear. (B) The dysbiosis resulting from an exogenous disturbance (e.g., antibiotics) allows for C. difficile colonization and/or outgrowth in the distal gut in the absence of toxin production. At this stage, the gut ecosystem may return to a healthy stable state or C. difficile may express the large glycosylating toxins TcdA and TcdB. (C) C. difficile toxins lead to inflammation in the distal gut environment and are responsible for C. difficile-mediated disease. The mechanisms by which this inflammation favors C. difficile remain unclear but may involve direct (e.g. privileged use of oxidized carbon sources or electron acceptors) or indirect effects (e.g. altered community composition enabling a competitive advantage for existing nutrients). The goal of therapeutic intervention in the context of symptomatic CDI is to facilitate the path from a diseased to a healthy state. This may occur either through a transient intermediate dysbiotic state (e.g. antibiotic treatment) or by bypassing dysbiosis to stability (“smart” therapeutic targeting pathogen or its virulence factors, e.g. the selenoorganic compound Ebselen [49]). Prophylactic measures (e.g. dietary MAC consumption or targeted anti-virulence agents) may be taken to favor the healthy microbiota state in all individuals, especially those at risk for developing CDI.