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.

The human symbiont Mucispirillum schaedleri: causality in health and disease.

Trillions of bacteria inhabit the mammalian gastrointestinal tract. In the majority of hosts, these symbionts contribute largely to beneficial functions promoting microbe-host homeostasis. However, an increasing number of human diseases is associated with altered microbiota composition and enrichment of certain bacterial species. A well-known example of this is Mucispirillum schaedleri, which has been associated with inflammatory conditions in the intestine. Mucispirillum spp. belong to the phylum Deferribacteres and are prevalent but low abundant members of the rodent, pig and human microbiota. Recently, M. schaedleri was causally linked to the development of Crohn's disease-like colitis in immunodeficient mice. While this study certifies a considerable pathogenic potential, the same organism can also promote health in the immunocompetent host: M. schaedleri protects from Salmonella enterica serovar Typhimurium (S. Tm)-induced colitis by interfering with the expression of the pathogen´s invasion machinery. In this review, we summarize the current knowledge on the mammalian gut symbiont M. schaedleri and its role in intestinal homeostasis and discuss open questions and perspectives for future research.