Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition
Sanne Kroon, Dejan Malcic, Lena Weidert, Lea Bircher, Leonardo Boldt, Philipp Christen, Patrick Kiefer, Anna Sintsova, Bidong D. Nguyen, Manja Barthel, Yves Steiger, Mélanie Clerc, Mathias K.-M. Herzog, Carmen Chen, Ersin Gül, Benoît Guéry, Emma Slack, Shinichi Sunagawa, Julia A. Vorholt, Lisa Maier, Christophe Lacroix, Annika Hausmann, Wolf‐Dietrich Hardt
Abstract
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, Enterococcus faecium 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.