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.

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