Overconsumption of low-digestible sugars can increase susceptibility to Salmonella Typhimurium infection

Low-digestible carbohydrates (LDCs), including dietary fibers and sugars that resist absorption, are generally considered beneficial for the gut microbiota. However, we show that acute overconsumption of certain LDCs, particularly low-digestible sugars (LDSs), such as arabinose, lactulose, and polyols commonly used as sugar substitutes, can compromise colonization resistance against the common foodborne pathogen Salmonella enterica serovar Typhimurium. LDS overconsumption results in elevated fecal pathogen loads, systemic dissemination, and colitis in infected mice. Mechanistic analysis of arabinose overconsumption revealed that rapid fermentation acidifies the intestinal environment, perturbs the microbiota, alters gut-luminal short-chain fatty acid levels and elevated amino acid availability, which can support pathogen growth. Additionally, this perturbation impacts virulence by broadening tissue tropism (e.g. expansion to small intestine) and selecting for invasive Salmonella . Unlike antibiotic perturbations, Salmonella colonization requires SPI-1 and SPI-2 Type-III-secretion systems, linking virulence to pathogen fitness. These findings reveal how dietary perturbations can impact the gut ecosystem in ways that not only compromise colonization resistance but also enhance pathogen virulence.