Sublethal systemic LPS exposure promotes intestinal opportunistic pathogen blooms

The cause of opportunistic pathogen infections in patients with systemic immune activation often remains unresolved. The intestinal microbiota serves as a gut-luminal reservoir for opportunistic pathogens, from where they can translocate to systemic sites. Systemic immune activation is associated with perturbations in the intestinal microbiota and increased risk of systemic infection with opportunistic pathogens. However, the causal link between these phenomena remains unclear. To address this, we employ a mouse model of sublethal systemic lipopolysaccharide (LPS) exposure, quantify intestinal growth of clinically relevant opportunistic pathogens, and use a related gut pathogen, Salmonella Typhimurium, to dissect the underlying mechanisms. We show that systemic LPS exposure opens an intestinal niche for Enterococcus, Klebsiella, Escherichia coli and Salmonella blooms. Knockout mice, microbiota growth assays, transcriptomics, metabolomics, and oxygen species measurements indicate that systemic immune activation elevates intestinal oxygen species levels in a Toll-like receptor 4 (TLR4)-dependent manner. This acutely halts microbiota fermentation and enables oxidative respiration by facultative anaerobic bacteria both in mouse and human microbiota, fuelling luminal opportunistic pathogen blooms and increasing the likelihood of systemic spread. LPS-triggered release of oxygen species, its growth-halting effect on the microbiota and the associated blooms of opportunistic pathogens provide a mechanism underlying the onset of systemic infections in sepsis patients.