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.

Computational Modeling of the Gut Microbiota Predicts Metabolic Mechanisms of RecurrentClostridioides difficileInfection

“…Consistent with these results, Cronobacter was most positively correlated with Enterobacteriaceae (proportionality coefficient  = +0.12) but negatively correlated with Bacteroides ( = -0.29) and several other taxa (e.g. Lachnospiraceae; Figure 5B) often reported to be CDI protective (64,65). Similarly, Bacteroides was negatively correlated with Enterobacteriaceae ( = -0.21), Gammaproteobacteria and Clostridiaceae ( Figure S10B), taxa which have been reported to be elevated in CDI (64,65,69).…”

“…By contrast, both abundance data and model-processed abundance data derived from post-index samples identified high Enterobacteriaceae, low Bacteroides clusters as having disproportionate numbers of recurrent samples. Numerous studies have identified Enterobacteriaceae as positively associated and Bacteroides as negatively associated with primary CDI (63)(64)(65) and to a lesser extent with subsequent reinfection (72,73). The analyses presented here suggest CDI recurrence is more dependent on community response to antibiotic therapy than on the community composition entering therapy.…”

“…Lachnospiraceae; Figure 5B) often reported to be CDI protective (64,65). Similarly, Bacteroides was negatively correlated with Enterobacteriaceae ( = -0.21), Gammaproteobacteria and Clostridiaceae ( Figure S10B), taxa which have been reported to be elevated in CDI (64,65,69).…”

Covalent attachment and Pro‐Pro endopeptidase (PPEP‐1)‐mediated release of Clostridium difficile cell surface proteins involved in adhesion

“…The spores survive the acid pH in the stomach and once they are exposed to primary bile acids, they can germinate into vegetative cells (Sorg and Sonenshein, ; Paredes‐Sabja et al ., ). Depending on the state of the host commensal flora, and the metabolites present in the gut (Ferreyra et al ., ), C. difficile may colonize and expand in the colon, producing daughter cells and toxins that are responsible for the pathogenesis (Hryckowian et al ., ). Patients that have undergone an antibiotic regime have a higher chance of suffering from a C. difficile infection (Rupnik et al ., ; Smits et al ., ).…”

“…Patients that have undergone an antibiotic regime have a higher chance of suffering from a C. difficile infection (Rupnik et al ., ; Smits et al ., ). The antibiotics cause a dysbiosis by killing bacteria of the microbiota that are important for resistance against C. difficile infection (Schubert et al ., ; Hryckowian et al ., ). Some microbiota are able to convert primary bile acids into secondary bile acids.…”