Salmonella Typhimurium screen identifies shifts in mixed-acid fermentation during gut colonization
How enteric pathogens adapt their metabolism to a dynamic gut environment is not yet fully understood. To investigate how Salmonella enterica Typhimurium (S.Tm) colonizes the gut, we conducted an in vivo transposon mutagenesis screen in a gnotobiotic mouse model. Our data implicate mixed-acid fermentation in efficient gut-luminal growth and energy conservation throughout infection. During initial growth, the pathogen utilizes acetate fermentation and fumarate respiration. After the onset of gut inflammation, hexoses appear to become limiting, as indicated by carbohydrate analytics and the increased need for gluconeogenesis. In response, S.Tm adapts by ramping up ethanol fermentation for redox balancing and supplying the TCA cycle with α-ketoglutarate for additional energy. Our findings illustrate how S.Tm flexibly adapts mixed fermentation and its use of the TCA cycle to thrive in the changing gut environment. Similar metabolic wiring in other pathogenic Enterobacteriaceae may suggest a broadly conserved mechanism for gut colonization.
Authors
- Wolf‐Dietrich Hardt (ORCID: https://orcid.org/0000-0002-9892-6420)
- Christopher Schubert (ORCID: https://orcid.org/0000-0002-7921-1470)
- Uwe Sauer (ORCID: https://orcid.org/0000-0002-5923-0770)
- Andreas Sichert (ORCID: https://orcid.org/0000-0002-1386-5535)
- Shinichi Sunagawa (ORCID: https://orcid.org/0000-0003-3065-0314)
- 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)
- Beat Christen (ORCID: https://orcid.org/0000-0002-9528-3685)
- Philipp Keller (ORCID: https://orcid.org/0000-0003-3962-5078)
- Emma Slack (ORCID: https://orcid.org/0000-0002-2473-1145)
- Bidong D. Nguyen (ORCID: https://orcid.org/0009-0009-8201-0387)
- Timothy G. Keys (ORCID: https://orcid.org/0000-0003-2921-0362)
- Manja Barthel (ORCID: https://orcid.org/0000-0001-6771-7661)
- Philipp Christen (ORCID: https://orcid.org/0000-0002-3139-2874)
- Miguelangel Cuenca (ORCID: https://orcid.org/0000-0003-3435-9102)
- Verena Lentsch (ORCID: https://orcid.org/0000-0001-7440-4604)
- Jana Näf
- Christoph Rutschmann
- Julien Huttman
- Clio Scheidegger
Institutions
- University of Stuttgart (DE)
- ETH Zurich (CH)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1016/j.chom.2024.08.015
- Citations
- 23
- Primary Topic
- Probiotics and Fermented Foods
- Type
- article
- Field-Weighted Citation Impact
- 8.01
Funders
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung