Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition
Kroon S., Malcic D., Weidert L., Bircher L., Boldt L., Christen P., Kiefer P., Sintsova A., Nguyen BD., Barthel M., Steiger Y., Clerc M., Herzog MKM., Chen C., Gül E., Guery B., Slack E., Sunagawa S., Vorholt JA., Maier L., Lacroix C., Hausmann A., Hardt WD.
Endotoxin-driven systemic immune activation is a common hallmark across various clinical conditions. During acute critical illness, elevated plasma lipopolysaccharide triggers non-specific systemic immune activation. In addition, a compositional shift in the gut microbiota, including an increase in gut-luminal opportunistic pathogens, is observed. Whether a causal link exists between acute endotoxemia and abundance of gut-luminal opportunistic pathogens is incompletely understood. Here, we model acute, pathophysiological lipopolysaccharide concentrations in mice and show that systemic exposure promotes a 100–10’000-fold expansion of Klebsiella pneumoniae, Escherichia coli, Enterococcusfaecium and Salmonella Typhimurium in the gut within one day, without overt enteropathy. Mechanistically, this is driven by a Toll-like receptor 4-dependent increase in gut-luminal oxygen species levels, which transiently halts microbiota fermentation and fuels growth of gut-luminal facultative anaerobic pathogens through oxidative respiration. Thus, systemic immune activation transiently perturbs microbiota homeostasis and favours opportunistic pathogens, potentially increasing the risk of infection in critically ill patients.