A Bacteriophage Cocktail Eliminates Salmonella Typhimurium from the Human Colonic Microbiome while Preserving Cytokine Signaling and Preventing Attachment to and Invasion of Human Cells by Salmonella In Vitro

Nontyphoidal Salmonella strains continue to be a major cause of foodborne illness globally. One intriguing approach to reducing the risk of salmonellosis is the direct ingestion of phages targeting Salmonella to enhance natural gut resilience and provide protection during foodborne disease outbreaks. We evaluated the ability of a prophylactically administered bacteriophage cocktail, the foodborne outbreak pill (FOP) targeting Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella, to resolve a Salmonella infection in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME), a simulated gut platform populated by the human intestinal microbiome of healthy donors. The FOP preparation eliminated Salmonella enterica serovar Typhimurium from the colon compartment of the SHIME platform but health-associated metabolites, such as short-chain fatty acids and lactate, remained stable or increased in a donor-dependent manner. In studies of human intestinal cells, pretreatment of Salmonella Typhimurium with the FOP cocktail preserved lipopolysaccharide-stimulated signaling in a Caco-2–THP-1 Transwell system and prevented destruction of the Caco-2 monolayer by Salmonella. Adhesion and invasion of intestinal epithelial cells by Salmonella–a critical factor in Salmonella pathogenesis–was blunted when the bacteria were incubated with the FOP preparation before addition to the monolayer. The FOP phage cocktail was effective for (i) eliminating Salmonella from a simulated human gut without disturbing the indigenous microbiota and (ii) reducing the risk of invasion by Salmonella into the intestinal epithelia. These results suggest that the FOP preparation may be of value for reducing the risk of salmonellosis in humans, e.g., during foodborne disease outbreaks.