Host-Derived Metabolites Modulate Transcription of <i>Salmonella</i> Genes Involved in <scp>l</scp> -Lactate Utilization during Gut Colonization

Abstract

During <i>Salmonella enterica</i> 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. <i>Salmonella</i> 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 <i>in vitro</i> and in mouse models of <i>Salmonella</i> infection. The two-component system ArcAB repressed transcription of l-lactate utilization genes under anaerobic conditions <i>in vitro</i> The ArcAB-mediated repression of <i>lldD</i> transcription was relieved under microaerobic conditions. Transcription of <i>lldD</i> was induced by l-lactate but not d-lactate. A mutant lacking the regulatory protein LldR failed to induce <i>lldD</i> transcription in response to l-lactate. Furthermore, the <i>lldR</i> 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 <i>Salmonella</i> to regulate lactate oxidation metabolism on a transcriptional level.