The pig as a preclinical model for human phage therapy of polybacterial enteric infections.

BACKGROUND: Diarrhoeal disease remains a leading cause of morbidity and mortality among children in low-and-medium-income countries (LMIC). Polybacterial infections and increasing antimicrobial resistance complicate treatment, underscoring the need for alternative approaches. Bacteriophage therapy offers a targeted treatment capable of combating multiple pathogens simultaneously. Here, we report use of a bacteriophage cocktail targeting Enterotoxigenic E. coli, Salmonella and Campylobacter in a polybacterial porcine model of infant enteric disease. METHODS: Weaned pigs were challenged with all three pathogens and subsequently treated with a cocktail of three phages. Pathogen loads, phage titres, clinical scores and fecal microbiome composition were measured and compared with untreated pathogen-challenged controls and unchallenged sentinel animals. RESULTS: Phage-treated pigs exhibited significant reductions in E. coli and Salmonella burdens, each decreasing by >1.8 log10 CFU/g relative to unchallenged controls (p < 0.05). Treatment produced corresponding increased in bacteriophage titres and led to significant improvements in clinical scores. Conversely, Campylobacter loads remained largely unchanged following phage administration. Microbiome analysis showed differences between challenged and unchallenged pigs (p = 0.09), and between pathogen-challenged and phage-treated pigs (p = 0.5), although these were not statistically significant. CONCLUSION: This study demonstrates the first use of phage therapy to target polybacterial enteric infections in a pig model of human disease. Simultaneous reductions in pathogen load and improved clinical outcomes highlight the potential of bacteriophage cocktails as treatments for bacterial enteric infections of relevance to children in low and middle-income countries, and to livestock health.