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, Melanie Clerc, Mathias K.-M. Herzog, Carmen Chen, Ersin Gül, Benoit Guery, Emma Slack, Shinichi Sunagawa, Julia A. Vorholt, Lisa Maier, Christophe Lacroix, Annika Hausmann () and Wolf-Dietrich Hardt ()
Additional contact information
Sanne Kroon: Department of Biology, ETH Zürich
Dejan Malcic: Department of Biology, ETH Zürich
Lena Weidert: Department of Biology, ETH Zürich
Lea Bircher: ETH Zürich
Leonardo Boldt: University of Tübingen
Philipp Christen: Department of Biology, ETH Zürich
Patrick Kiefer: Department of Biology, ETH Zürich
Anna Sintsova: Department of Biology, ETH Zürich
Bidong D. Nguyen: Department of Biology, ETH Zürich
Manja Barthel: Department of Biology, ETH Zürich
Yves Steiger: Department of Biology, ETH Zürich
Melanie Clerc: Department of Biology, ETH Zürich
Mathias K.-M. Herzog: Department of Biology, ETH Zürich
Carmen Chen: Lausanne University Hospital and University of Lausanne
Ersin Gül: Department of Biology, ETH Zürich
Benoit Guery: Lausanne University Hospital and University of Lausanne
Emma Slack: ETH Zürich
Shinichi Sunagawa: Department of Biology, ETH Zürich
Julia A. Vorholt: Department of Biology, ETH Zürich
Lisa Maier: University of Tübingen
Christophe Lacroix: ETH Zürich
Annika Hausmann: Department of Biology, ETH Zürich
Wolf-Dietrich Hardt: Department of Biology, ETH Zürich

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57979-0

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