Intestinal Bacteriophage Therapy: Looking for Optimal Efficacy

Abstract

Several human intestinal microbiota studies suggest that bacteriophages, viruses infecting bacteria, play a role in gut homeostasis. Currently, bacteriophages are considered a tool to precisely engineer the intestinal microbiota, but they have also attracted considerable attention as a possible solution to fight against bacterial pathogens resistant to antibiotics. These two applications necessitate bacteriophages to reach and kill their bacterial target within the gut environment. Unfortunately, exploitable clinical data in this field are scarce. Here, we review the administration of bacteriophages to target intestinal bacteria in mammalian experimental models. While bacteriophage amplification in the gut was often confirmed, we found that in most studies, it had no significant impact on the load of the targeted bacteria. In particular, we observed that the outcome of bacteriophage treatments is linked to the behavior of the target bacteria toward each animal model. Treatment efficacy ranges from poor in asymptomatic intestinal carriage to high in intestinal disease. This broad range of efficacy underlines the difficulties to reach a consensus on the impact of bacteriophages in the gut and calls for deeper investigations of key parameters that influence the success of such interventions before launching clinical trials.

Keywords: enteric pathogens; gastrointestinal infection; intestinal colonization.

FIG 1

Three models recapitulate the variation of the bacterial populations in the gut of mammals receiving a phage treatment (red) compared to untreated controls (blue). Following phage introduction in animals colonized by their target bacteria, three models were defined: transit, coexistence, and infection. These models correspond to the outcomes directly linked to the behavior of bacteria toward animals. Either bacteria could not stably colonize an animal’s gut (transit model), or they colonized stably at high levels (coexistence model), or they induced an intestinal infection (infection model).

FIG 2

Several factors in the host, organ, and cell influence phage activity in the gut. The health state of the host (left) imposes a global physiological environment with prolonged consequences on the intestinal microbiota including phage-bacteria interactions. In the organ (middle), the cellular environment (immune cells, other microbes) affects bacterial physiology (pH, oxygen) with direct consequences on phage dynamics (prophage induction and bacterial susceptibility to phages). Finally, in the cell (right), different bacterial defense mechanisms will impact the outcome of phage-bacterium interactions. Epithelial cells, pink; mucus layer, gray; DNA molecules correspond to bacterial (blue) and phage (red) genetic material; CRISPR/Cas, clustered regularly interspaced short palindromic repeats/CRISPR associated.