Anaerobic nitrate reduction divergently governs population expansion of the enteropathogen Vibrio cholerae

To survive and proliferate in the absence of oxygen, many enteric pathogens can undergo anaerobic respiration within the host by using nitrate (NO₃^-) as an electron acceptor^1,2. In these bacteria, NO₃^- is typically reduced by a nitrate reductase to nitrite (NO₂^-), a toxic intermediate that is further reduced by a nitrite reductase³. However, Vibrio cholerae, the intestinal pathogen that causes cholera, lacks a nitrite reductase, leading to NO₂^- accumulation during nitrate reduction⁴. Thus, V. cholerae is thought to be unable to undergo NO₃^--dependent anaerobic respiration⁴. Here, we show that during hypoxic growth, NO₃^- reduction in V. cholerae divergently affects bacterial fitness in a manner dependent on environmental pH. Remarkably, in alkaline conditions, V. cholerae can reduce NO₃^- to support population growth. Conversely, in acidic conditions, accumulation of NO₂^- from NO₃^- reduction simultaneously limits population expansion and preserves cell viability by lowering fermentative acid production. Interestingly, other bacterial species such as Salmonella typhimurium, enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium also reproduced this pH-dependent response, suggesting that this mechanism might be conserved within enteric pathogens. Our findings explain how a bacterial pathogen can use a single redox reaction to divergently regulate population expansion depending on the fluctuating environmental pH.