Microbiota-Derived Hydrogen Fuels Salmonella Typhimurium Invasion of the Gut Ecosystem

•Initially, S. Typhimurium (S. Tm) grows in the unperturbed gut (ecosystem invasion)•S. Tm hyb hydrogenase is required for ecosystem invasion•Hyb allows S. Tm to use microbiota-derived hydrogen as an energy source•Subversion of a microbiota metabolite fuels gut ecosystem invasion by S. Tm

SummaryThe intestinal microbiota features intricate metabolic interactions involving the breakdown and reuse of host- and diet-derived nutrients. The competition for these resources can limit pathogen growth. Nevertheless, some enteropathogenic bacteria can invade this niche through mechanisms that remain largely unclear. Using a mouse model for Salmonella diarrhea and a transposon mutant screen, we discovered that initial growth of Salmonella Typhimurium (S. Tm) in the unperturbed gut is powered by S. Tm hyb hydrogenase, which facilitates consumption of hydrogen (H2), a central intermediate of microbiota metabolism. In competitive infection experiments, a hyb mutant exhibited reduced growth early in infection compared to wild-type S. Tm, but these differences were lost upon antibiotic-mediated disruption of the host microbiota. Additionally, introducing H2-consuming bacteria into the microbiota interfered with hyb-dependent S. Tm growth. Thus, H2 is an Achilles’ heel of microbiota metabolism that can be subverted by pathogens and might offer opportunities to prevent infection.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (231 K)Download as PowerPoint slide