Bacteriophage Adaptation to a Mammalian Mucosa Reveals a Trans-Domain Evolutionary Axis

Abstract

The majority of viruses within the human gut are bacteriophages (phages) where they sustain top-down control and co-evolve with gut bacterial communities. Here, we probed beyond conventional phage-bacteria co-evolution to investigate the potential evolution between phages and the mammalian “host”. To that, we recapitulated a life-like mammalian gut mucosa using gut-on-a-chip devices and showed that the mucosa supports stable phage-bacteria co-existence. Next, we experimentally evolved phage populations within the gut-on-a-chip and discovered that phages adapt by de novo mutations and genetic recombination. We found that a mutation in the phage capsid protein Hoc – known to facilitate phage adherence to mucus – caused altered phage binding to fucosylated mucin glycans. We demonstrated that the altered glycan-binding phenotype provided a fitness advantage within the mucosal environment. Collectively, our findings revealed that phages – in addition to their evolutionary relationship with bacteria – are also able to evolve with the mammalian host.