Cholera toxin promotes pathogen acquisition of host-derived nutrients

Abstract

Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection1. Cholera toxin (CT) is required for V. cholerae to cause severe disease and is also thought to promote transmission of the organism in that victims can shed many liters of diarrheal fluid that typically contains in excess of 1011 organisms per liter. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CT-mediated disease enhances pathogen growth and induces a distinct V. cholerae transcriptome signature that is indicative an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, a nutrient essential for growth2. The majority of iron in the mammalian host resides in a chelated form within the porphyrin structure of heme, and V. cholerae genetically encodes the ability to utilize heme as a source of iron3. We show that V. cholerae heme and vibriobactin utilization genes confer a growth advantage to the pathogen only when CT is produced. Furthermore, CT-induced capillary congestion pathology in the terminal ileum correlated with an increased bioavailability of luminal heme. CT-induced disease in the ileum also led to increased luminal concentrations of long-chain fatty acids (LCFAs) and L-lactate metabolites, as well as upregulation of V. cholerae iron-sulfur cluster-containing TCA cycle enzyme genes. Genetic analysis of V. cholerae suggested that heme and LCFA uptake-dependent growth of V. cholerae occurs during infection but only in a strain capable of producing CT in vivo. We conclude that CT-induced disease creates an iron-depleted metabolic niche in the gut that selectively promotes the explosive growth of this pathogen through acquisition of host-derived heme and fatty acids as nutrients.