Clostridium difficile exploits a host metabolite produced during toxin-mediated infection

Abstract

Several enteric pathogens can gain specific metabolic advantages over other members of the microbiota by inducing host pathology and inflammation. The pathogen Clostridium difficile (Cd) is responsible for a toxin-mediated colitis that causes 15,000 deaths in the U.S. yearly1, yet the molecular mechanisms by which Cd benefits from toxin-induced colitis remain understudied. Up to 21% of healthy adults are asymptomatic carriers of toxigenic Cd2, indicating that Cd can persist as part of a healthy microbiota; antibiotic-induced perturbation of the gut ecosystem is associated with transition to toxin-mediated disease. To understand how Cd metabolism adapts from a healthy gut to the inflamed conditions its toxins induce, we used RNA-seq to define the metabolic state of wild-type Cd versus an isogenic mutant lacking toxins in a mouse model. Combining bacterial and mouse genetics, we demonstrate that Cd utilizes sorbitol derived from both diet and host. Host-derived sorbitol is produced by the enzyme aldose reductase, which is expressed by diverse immune cells and is upregulated during inflammation, including during Cd toxin-mediated disease. This work highlights a mechanism by which Cd can utilize a host-derived nutrient generated during toxin-induced disease by an enzyme not previously associated with infection.