Prophage-encoding engineered bacteria enable prophylactic lytic phage therapy for enteric infection in mice

Phage therapy is a promising antibacterial approach but it has limited efficacy against enteric bacterial infections, such as Salmonella enterica Typhimurium (STm). Here we hypothesized that establishing high concentrations of a pathogen-targeting phage in the gut before infection would prophylactically protect against future infection. To this end, we engineered non-pathogenic Escherichia coli to encode a prophage that produces obligately lytic phage progeny targeting STm while overcoming its host defence systems, including restriction-modification systems. We show that prophylactic gut colonization with this lytic phage-producing lysogen of E. coli produces high levels of lytic phage before infection, inhibits the establishment of STm after infection and improves survival in mouse models of STm-induced colitis. Using a mutant STm strain limited to intestinal colonization, we show that phage-producing E. coli consistently colonized, produced high phage levels and eliminated STm from the intestinal tract. Our findings present a proof-of-concept that prophylactic prophage therapy can protect against an enteric infection.