Cholera-toxin-induced disease generates epithelial-cell-derived L-lactate that promotes Vibrio cholerae growth in the...

Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. Here, we show that CT-induced disease leads to the upregulation of mammalian lactate dehydrogenase A (LDHA), an enzyme that catalyzes the conversion of pyruvate to L-lactate, in small intestinal epithelial cells. In a suckling mouse model, the bacterial L-lactate dehydrogenase (LldD) confers a fitness advantage to V. cholerae but not to the ΔctxAB mutant incapable of producing CT. Finally, mice lacking epithelial-cell-specific LDHA have reduced luminal L-lactate concentrations, and the fitness advantage conferred by LldD is significantly reduced in these mice, demonstrating that epithelial-derived L-lactate is a major contributor to CT-dependent pathogen expansion. These findings identify epithelial-derived L-lactate as a host-derived metabolite generated in the small intestine during cholera disease that directly fuels V. cholerae growth during infection, uncovering a mechanism by which CT confers a fitness advantage to the pathogen during disease.