Salmonella enterica serovar Typhimurium induces intestinal
inflammation to create a niche that fosters the outgrowth of the pathogen over the gut microbiota. Under inflammatory conditions, Salmonella utilizes terminal electron acceptors generated as byproducts of intestinal
inflammation to generate cellular energy through respiration. However, the electron donating reactions in these electron transport chains are poorly understood. Here, we investigated how
formate utilization through the respiratory
formate dehydrogenase-N (FdnGHI) and
formate dehydrogenase-O (FdoGHI) contribute to gut colonization of Salmonella. Both
enzymes fulfilled redundant roles in enhancing fitness in a mouse model of Salmonella-induced
colitis, and coupled to tetrathionate,
nitrate, and
oxygen respiration. The
formic acid utilized by Salmonella during
infection was generated by its own
pyruvate-formate lyase as well as the gut microbiota. Transcription of
formate dehydrogenases and
pyruvate-formate lyase was significantly higher in bacteria residing in the mucus layer compared to the lumen. Furthermore,
formate utilization conferred a more pronounced fitness advantage in the mucus, indicating that
formate production and degradation occurred predominantly in the mucus layer. Our results provide new insights into how Salmonella adapts its energy metabolism to the local microenvironment in the gut. IMPORTANCE Bacterial pathogens must not only evade immune responses but also adapt their metabolism to successfully colonize their host. The microenvironments encountered by enteric pathogens differ based on anatomical location, such as small versus large intestine, spatial stratification by host factors, such as mucus layer and
antimicrobial peptides, and distinct commensal microbial communities that inhabit these microenvironments. Our understanding of how Salmonella populations adapt its metabolism to different environments in the gut is incomplete. In the current study, we discovered that Salmonella utilizes
formate as an electron donor to support respiration, and that
formate oxidation predominantly occurs in the mucus layer. Our experiments suggest that spatially distinct Salmonella populations in the mucus layer and the lumen differ in their energy metabolism. Our findings enhance our understanding of the spatial nature of microbial metabolism and may have implications for other enteric pathogens as well as commensal host-associated microbial communities.