Host-Derived Metabolites Modulate Transcription of Salmonella Genes Involved in L-Lactate Utilization during Gut Colonization

During Salmonella enterica serovar Typhimurium infection, host inflammation alters the metabolic environment of the gut lumen to favor the outgrowth of the pathogen at the expense of the microbiota. Inflammation-driven changes in host cell metabolism lead to the release of L-lactate and molecular oxygen from the tissue into the gut lumen. Salmonella utilizes lactate as an electron donor in conjunction with oxygen as the terminal electron acceptor to support gut colonization. Here, we investigated transcriptional regulation of the respiratory L-lactate dehydrogenase LldD in vitro and in mouse models of Salmonella infection. The two-component system ArcAB repressed transcription of L-lactate utilization genes under anaerobic conditions in vitro. The ArcAB-mediated repression of lldD transcription was relieved under microaerobic conditions. Transcription of lldD was induced by L-lactate but not D-lactate. A mutant lacking the regulatory protein LldR failed to induce lldD transcription in response to L-lactate. Furthermore, the lldR mutant exhibited reduced transcription of L-lactate utilization genes and impaired fitness in murine models of infection. These data provide evidence that the host-derived metabolites oxygen and L-lactate serve as cues for Salmonella to regulate lactate oxidation metabolism on a transcriptional level.