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. [Display omitted] • Mixed-acid fermentation of hexoses fuels the initial growth of S.Tm SL1344 • Enzymes connecting glycolysis with the oxidative branch of the TCA cycle are redundant • Upon triggering inflammation, S.Tm adapts its mixed-acid fermentation • Responses to inflammation include ethanol fermentation and α-ketoglutarate import Bidong Nguyen and colleagues revealed the metabolic adaptations of Salmonella Typhimurium to changes in the gut environment during infection. These adaptations include the diversification of mixed-acid fermentation and the use of a partial TCA cycle in response to redox and nutritional changes induced by inflammation. [ABSTRACT FROM AUTHOR]