Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition

Endotoxin-driven systemic immune activation is a common hallmark across various clinical conditions. During acute critical illness, elevated plasma lipopolysaccharide can lead to non-specific systemic immune activation. In addition, acute critical illness associates with compositional shifts in the gut microbiota, including an increased abundance of gut-luminal opportunistic pathogens. However, whether there is a causal link between these phenomena is incompletely understood. To gain mechanistic insights, we model acute, pathophysiological concentrations of lipopolysaccharide in mice to assess the impact on microbiota homeostasis. We show that systemic lipopolysaccharide exposure promotes Klebsiella, Escherichia coli, Enterococcus and Salmonella Typhimurium to bloom in the murine gut by 100-10'000-fold within one day without overt enteropathy. Knockout mice, microbiota growth assays, transcriptomics, and metabolomics indicate that systemic lipopolysaccharide exposure transiently elevates gut-luminal oxygen species concentrations in a Toll-like receptor 4-dependent manner. This transiently halts microbiota fermentation of both mouse and human microbiota and fuels growth of gut-luminal facultative anaerobic pathogens through oxidative respiration. Thereby, lipopolysaccharide-triggered release of oxygen species transiently perturbs the microbiota and elicits blooms of opportunistic pathogens which may further promote intestinal sequelae and infections.