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 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.
Authors
- Christophe Lacroix (ORCID: https://orcid.org/0000-0003-4360-2020)
- Wolf‐Dietrich Hardt (ORCID: https://orcid.org/0000-0002-9892-6420)
- Benoît Guéry (ORCID: https://orcid.org/0000-0002-6526-0714)
- Shinichi Sunagawa (ORCID: https://orcid.org/0000-0003-3065-0314)
- Mélanie Clerc (ORCID: https://orcid.org/0000-0003-1195-4558)
- Julia A. Vorholt (ORCID: https://orcid.org/0000-0002-6011-4910)
- Anna Sintsova (ORCID: https://orcid.org/0000-0003-4075-6366)
- Patrick Kiefer (ORCID: https://orcid.org/0000-0002-9159-0848)
- Mathias K.-M. Herzog (ORCID: https://orcid.org/0000-0002-0097-2526)
- Emma Slack (ORCID: https://orcid.org/0000-0002-2473-1145)
- Ersin Gül (ORCID: https://orcid.org/0000-0003-2873-8034)
- Lea Bircher (ORCID: https://orcid.org/0009-0006-7526-9276)
- Lisa Maier (ORCID: https://orcid.org/0000-0002-6473-4762)
- Carmen Chen (ORCID: https://orcid.org/0009-0004-8304-5825)
- Bidong D. Nguyen (ORCID: https://orcid.org/0009-0009-8201-0387)
- Sanne Kroon (ORCID: https://orcid.org/0000-0002-5722-0763)
- Manja Barthel (ORCID: https://orcid.org/0000-0001-6771-7661)
- Philipp Christen (ORCID: https://orcid.org/0000-0002-3139-2874)
- Annika Hausmann (ORCID: https://orcid.org/0000-0001-8852-3444)
- Yves Steiger (ORCID: https://orcid.org/0000-0002-8048-250X)
- Leonardo Boldt (ORCID: https://orcid.org/0009-0009-7743-605X)
- Dejan Malcic
- Lena Weidert
Institutions
- Novo Nordisk Foundation (DK)
- ETH Zurich (CH)
- Institute for Biomedical Engineering (CH)
- University of Tübingen (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1038/s41467-025-57979-0
- Citations
- 12
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 9.57
Funders
- National Science Foundation
- European Commission
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Botnar Research Centre for Child Health, University of Basel