Salmonella enterica serovar Typhimurium is a pervasive enteric pathogen and an ongoing global threat to public health. Ecological studies in the Salmonella impacted gut remain underrepresented in the literature, discounting the microbiome mediated interactions that may inform Salmonella physiology during colonization and infection. To understand the microbial ecology of Salmonella remodeling of the gut microbiome, here we performed multi-omics approaches on fecal microbial communities from untreated and Salmonella-infected mice. Reconstructed genomes recruited metatranscriptomic and metabolomic data providing a strain-resolved view of the expressed metabolisms of the microbiome during Salmonella infection. This data informed possible Salmonella interactions with members of the gut microbiome that were previously uncharacterized. Salmonella-induced inflammation significantly reduced the diversity of transcriptionally active members in the gut microbiome, yet increased gene expression was detected for 7 members, with Luxibacter and Ligilactobacillus being the most active. Metatranscriptomic insights from Salmonella and other persistent taxa in the inflamed microbiome further expounded the necessity for oxidative tolerance mechanisms to endure the host inflammatory responses to infection. In the inflamed gut lactate was a key metabolite, with microbiota production and consumption reported amongst transcriptionally active members. We also showed that organic sulfur sources could be converted by gut microbiota to yield inorganic sulfur pools that become oxidized in the inflamed gut, resulting in thiosulfate and tetrathionate that supports Salmonella respiration. Advancement of pathobiome understanding beyond inferences from prior amplicon-based approaches can hold promise for infection mitigation, with the active community outlined here offering intriguing organismal and metabolic therapeutic targets.

Gut microbiome carbon and sulfur metabolisms support Salmonella during pathogen infection