Microbiota-constrained bacterial density limits phage infection in the gut and allows persistence of susceptible cells.

With the rise of antibiotic resistance, bacteriophage-based treatments against bacterial infections have regained momentum. However, phage therapy has so far shown only moderate success in complex environments like the mammalian gut, where phages are particularly promising tools for microbiome engineering and specific elimination of opportunistic pathogens. Here, we use different murine models of intestinal colonization to quantitatively assess the minimal population size of susceptible Escherichia coli cells that is required for phage replication in the gut (replication threshold). We found that the composition of the intestinal microbiota is a key factor shaping phage-bacteria interactions by restricting the carrying capacity of susceptible host cells. We further demonstrate that the replication threshold enables coexistence of susceptible and resistant bacteria in phage-treated mice, with implications for phage-based applications in complex environments like the gut.