Modulation of Host-Microbe Metabolism by Cholera Toxin

Abstract

In order for successful fecal-oral transmission, enteric bacterial pathogens have to successfully compete with the intestinal microbiota and reach high concentrations during infection. Vibrio cholerae requires cholera toxin (CT) to cause diarrheal disease, which is thought to promote the fecal-oral transmission of the pathogen. Besides inducing diarrheal disease, the catalytic activity of CT also alters host intestinal metabolism, which promotes the growth of V. cholerae during infection through the acquisition of host-derived nutrients. Furthermore, recent studies have found that CT-induced disease activates a niche-specific suite of V. cholerae genes during infection, some of which may be important for fecal-oral transmission of the pathogen. Our group is currently exploring the concept that CT-induced disease promotes the fecal-oral transmission of V. cholerae by modulating both host and pathogen metabolism. Furthermore, the role of the intestinal microbiota in pathogen growth and transmission during toxin-induced disease merits further investigation. These studies open the door to investigating whether other bacterial toxins also enhance pathogen growth and transmission during infection, which may shed light on the design of novel therapeutics for intervention or prevention of diarrheal diseases.

Keywords: Vibrio cholerae; cholera; cholera toxin; diarrheal disease; enteric pathogens; gut microbiota; host-pathogen interactions; metabolism; pathogenesis; transmission.

FIG 1

(A and B) Model for modulation of host-microbe metabolism by cholera toxin. The intestinal microbiota in the small intestine and host factors regulate intestinal metabolism, thereby maintaining gut homeostasis. During infection, Vibrio cholerae colonizes the ileum of the small intestine and produces high levels of cholera toxin (CT). CT activates adenylate cyclase, which increases cellular levels of 3′,5′-cyclic AMP (cAMP) and leads to changes in a plethora of metabolic functions that are regulated by the cAMP-dependent protein kinase (PKA). Increased cAMP induces lipolysis and can cause extensive breakdown of lipids in cells, leading to secretion of free long-chain fatty acids (LCFAs) and likely glycerol. CT-mediated increase in cAMP also induces anaerobic glycolysis, leading to reduced consumption of oxygen and increased production of l-lactate. Modulation of host metabolism causes dysbiosis of the small intestine microbiota and drives the growth V. cholerae during infection by acquisition of host-derived nutrients, including heme (from capillary congestion) when iron becomes limiting. These CT-induced processes drive luminal expansion and transmission of V. cholerae during infection. The role of the microbiota and other host factors, such as cAMP-responsive element-binding protein H (CREBH) in the context of CT-induced remodeling of host-pathogen and host-microbe metabolism remains poorly understood.