LAUSR

Significance Bacteriophages (phages) are viruses that infect bacteria. Phages are abundant in the gut and are compositionally unique across the human population. While phages are in constant evolutionary battle with bacteria, their potential evolution with the mammalian gut remains overlooked. Here, we test whether phages are capable of adapting directly to the mammalian “host.” Using a coculture of phages, bacteria, and a gut-like mucosa, we found that phage evolution was driven by de novo mutations and recombination. This contributed to a unique phage capsid mutation, lending enhanced phage persistence in the mucus layer. Our findings propose a potential coevolutionary mechanism between phages and the gut mucosa, which could contribute to the individuality of gut viromes.