Enteric populations of Escherichia coli are likely to be resistant to phages due to O antigen expression.

内容摘要

Metagenomic data provide evidence that bacteriophage (phage) abound in the enteric microbiomes of humans. However, the contribution of these viruses in shaping the bacterial composition of the gut microbiome and how these phages are maintained remain unclear. We performed experiments with 756 combinations of 54 Escherichia coli and nine phage isolates from four fecal microbiota transplantation (FMT) doses and five laboratory phages as samples of non-dysbiotic human enteric microbiota. We also developed a mathematical model of the population and evolutionary dynamics of bacteria and phage. Our experiments predict that as a consequence of the production of the O antigen, most of the E. coli in the human enteric microbiome will be resistant to infections with the array of co-occurring phages. Our modeling suggests that phages are maintained in these enteric communities due to the high rates of transition between the O antigen-resistant and -sensitive states. Based on our observations and predictions from this theory, we postulate that the phage found in the human gut are likely to play a little role in shaping the strain composition of E. coli of healthy individuals. Although we only investigated E. coli, the mechanism of resistance described here is shared among most of the gram-negative bacteria. Evidence is provided that, as a consequence of O antigen-mediated resistance, the genetically diverse array of bacteriophage in the gut microbiome of humans plays little or no role in determining the densities and distribution of the genetically diverse strain E. coli in this habitat. Our mathematical model predicts and our experiments support the hypothesis that the phage present in the gut microbiome are maintained by replication on the minority of sensitive bacteria generated by the leakiness of O antigen-mediated resistance.IMPORTANCEBacteriophages (phages) are abundant in the human gut, yet whether these viruses shape the bacterial communities living there remains unresolved. Using Escherichia coli and phages isolated from the stool of healthy fecal microbiota transplantation (FMT) donors, together with a mathematical model, we show that the vast majority of gut E. coli are resistant to co-occurring phages because they express the O antigen, a surface structure that masks the receptors phages use to attach. Despite this widespread resistance, phages persist by replicating on a small, continually regenerated subpopulation of sensitive cells, a phenomenon we term leaky resistance. These findings suggest that phages play a little role in determining which E. coli strains dominate the healthy human gut. Because the O antigen is broadly expressed across gram-negative bacteria, this mechanism likely extends well beyond E. coli and helps explain why isolating therapeutic phages against many pathogens is difficult.