D-gluconate is the primary sugar acid that fuels Salmonella expansion
Monosaccharides fuel Salmonella Typhimurium colonization in the gut. Among these, sugar acids represent an underexplored class of carbon sources that are largely absent from the diet and generated through host-driven oxidative processes. Here, we systematically evaluated the degradation pathways of D-glucose- and D-galactose-derived sugar acids in S. Typhimurium. D-gluconate emerged as the dominant substrate supporting invasion in the streptomycin-pretreated mouse model. In ecological invasion assays, multimutants unable to metabolize D-glucose-derived sugar acids enabled a diluted wild-type population to reach comparable gut-luminal loads by day 1 post-infection, identifying these compounds as a key metabolic niche in the inflamed intestine. While dispensable during early colonization, sugar acid metabolism became critical for long-term persistence, with mutants exhibiting pronounced fitness attenuation in the gut but not in systemic sites. Quantification of gut luminal metabolites confirmed the presence of these sugar acids, particularly D-gluconate, at high millimolar concentrations. Notably, sugar acid utilization pathways were equally prevalent in E. coli from IBD patients and non-IBD controls, consistent with their pathobiont nature and suggesting that inflammation promotes expansion into this niche, analogous to the inflammation-driven use of anaerobic respiration with inorganic electron acceptors. Together, our findings position D-gluconate as an inflammation-dependent metabolite that promotes Enterobacteriaceae expansion in the inflamed gut.