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 (OMM14) 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 challenge with both phage cocktails. Surprisingly, OMM14 mice were also susceptible 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. Concluding, our work shows that phages that dynamically modulate the density of protective members of the gut microbiota can provide opportunities for invasion of bacterial pathogens, in particular at early time points after phage application. This suggests, that phages targeting protective members of the microbiota may increase the risk for Salmonella infection. Author summary: Metagenomic studies revealed that bacteria and their specific viruses, bacteriophages (phages), are the most abundant and diverse community of microbes in the human intestines. However, functional studies for identifying the role of phages in shaping intestinal bacterial communities are still lacking. A fundamental function of the intestinal microbiota is colonization resistance (CR) to the invasion of intestinal pathogens such as Salmonella. Here, we use a simplified gnotobiotic mouse model and two phage cocktails to investigate the impact of phages in a bacterial community, on their target strains and on CR. We found, that oral application of phages leads to a decrease in CR against Salmonella. Thus, ingestion of phages might be a risk factor predisposing to bacterial infections and could explain interpersonal variability of infection susceptibility. We report a previously unanticipated impact of phages related to the impairment of CR against gastrointestinal infections. [ABSTRACT FROM AUTHOR]