Bacteriophages targeting protective commensals impair resistance against Salmonella Typhimurium infection in gnotobiotic mice

Gut microbial communities protect the host against a variety of major human gastrointestinal pathogens. Bacteriophages (phages) are ubiquitous in nature and frequently ingested via food and drinking water. Moreover, they are an attractive tool for microbiome engineering due to the lack of known serious adverse effects on the host. However, the functional role of phages within the gastrointestinal microbiome remain poorly understood. Here, we investigated the effects of microbiota-directed phages on infection with the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm), using a gnotobiotic mouse model (OMM12) for colonization resistance (CR). We show that phage cocktails targeting Escherichia coli and Enterococcus faecalis acted in a strain-specific manner. They transiently reduced the population density of their respective target before establishing coexistence for up to 9 days. Infection susceptibility to S. Tm was markedly increased at an early time point after phage challenge. Surprisingly, OMM12 mice were more susceptible 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. The presence of phages that dynamically modulates the density of protective members of the gut microbiota provides opportunities for invasion of bacterial pathogens.