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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.

Original publication

DOI

10.1016/j.chom.2024.08.015

Type

Journal article

Journal

Cell host & microbe

Publication Date

10/2024

Volume

32

Pages

1758 - 1773.e4

Addresses

Institute of Microbiology, Department of Biology, ETH Zürich, Zürich, Switzerland. Electronic address: nguyenb@ethz.ch.

Keywords

Gastrointestinal Tract, Animals, Mice, Inbred C57BL, Mice, Salmonella typhimurium, Ethanol, Acetates, Fumarates, DNA Transposable Elements, Germ-Free Life, Mutagenesis, Fermentation, Citric Acid Cycle, Gluconeogenesis, Gastrointestinal Microbiome