Abstract
Salmonellosis and shigellosis remain major global health concerns, with Salmonella Typhimurium and Shigella flexneri classified as high-priority antibiotic-resistant pathogens by the World Health Organization. The development of new antibiotics is slow and challenging, underscoring the need for alternative therapeutic strategies. One promising approach involves leveraging gut microbiota-derived bacteria that confer colonization resistance against enteric pathogens. In this study, we screened a human gut microbiota culture collection and identified Bifidobacterium longum as the most effective species in inhibiting S. Typhimurium and S. flexneri in vitro. To evaluate its protective potential in vivo, we utilized Caenorhabditis elegans as a model system. Our findings demonstrate that B. longum significantly reduced pathogen burden and enhanced host survival following infection. Mechanistic analysis revealed that B. longum inhibits S. Typhimurium primarily through acidification, while S. flexneri suppression appears to involve a protein-mediated or heat-stable metabolite-dependent mechanism. Additionally, B. longum modulated host immune pathways, downregulating genes associated with the p38 MAPK and insulin/IGF-1 signaling pathways. These results highlight the potential of B. longum as a non-antibiotic therapeutic for controlling Salmonella and Shigella infections. However, further validation in mammalian models is required to assess its clinical relevance. IMPORTANCE: Gut infections caused by Salmonella and Shigella are major global health threats. As an alternative to novel drug discovery, which is time-consuming and faces several challenges, this study explores the potential of gut bacteria to protect against these pathogens. We identified Bifidobacterium longum, a common gut microbe, which can significantly reduce infection by both Salmonella and Shigella in a lab setting and in a simple animal model. The bacterium functions by creating an environment that is hostile to pathogens and by modulating the host's immune responses. These findings suggest that B. longum could be developed as a natural, non-antibiotic treatment to control or reduce these enteric pathogen infections. This approach opens the door to using probiotics as effective tools in the global fight against antibiotic resistance.