Colonization resistance to enteric pathogens is one of the primary beneficial functions of the gut microbiota. Several mechanisms likely contribute to this phenomenon: restriction of nutrients, direct growth inhibition, and stimulation of the host’s defenses. Focusing on the enteric pathogen S. Typhimurium infecting mice, we are attempting to identify molecules and bacterial species that are responsible for protection. We isolated a consortium of anaerobic, spore-forming bacteria, mostly Clostridiales, from the mouse gut, which are capable of providing significant protection. We found that this was independent of major host immune pathways (MyD88/TRIF, IL-22 and RAG1). This suggests a direct mechanism of pathogen inhibition by these symbionts. We are currently isolating smaller groups and single strains from this consortium and determining their growth substrate preferences. Whole-genome sequencing and comparison of the protective strains should allow us to identify genes and pathways that are key to their function. In a separate but complementary approach, we are using in vitro screening to purify and identify molecules that are produced (or depleted) by the gut microbiota and that can affect S. Typhimurium growth. This unbiased, bioassay-guided fractionation approach has allowed us to partially purify a factor that is found in SPF mouse cecum and is bacteriostatic to S. Typhimurium in vitro. In the future this approach will be applied to other relevant pathogens.
Sponsored by the Host Microbiome Initiative