Bacteriophage (phage) dramatically shape microbial community composition, redistribute nutrients via host lysis, and drive evolution through horizontal gene transfer. Despite their importance, much remains to be learned about phage in the human microbiome. We investigated gut microbiomes of humans from Bangladesh and Tanzania, two African baboon social groups, and Danish pigs, and report that many contain phage belonging to a clade with genomes >540 kb in length, the largest yet reported in the human microbiome and close to the maximum size ever reported for phage. We refer to these as Lak phage. CRISPR spacer targeting indicates that the Lak phage infect bacteria of the genus Prevotella . We manually curated to completion 15 distinct Lak phage genomes recovered from metagenomes. The genomes display several interesting features, including use of an alternative genetic code, large intergenic regions that are highly expressed, and up to 35 putative tRNAs, some of which contain enigmatic introns. Different individuals have distinct phage genotypes, and shifts in variant frequencies over consecutive sampling days reflect changes in relative abundance of phage sub-populations. Recent homologous recombination has resulted in extensive genome admixture of nine baboon Lak phage populations. We infer that Lak phage are widespread in gut communities that contain Prevotella species, especially in individuals in the developing world, and conclude that megaphage, with fascinating and underexplored biology, may be common but largely overlooked components of human and animal gut microbiomes.

Bacteriophages (phages) dramatically shape microbial community composition, redistribute nutrients via host lysis and drive evolution through horizontal gene transfer. Despite their importance, much remains to be learned about phages in the human microbiome. We investigated the gut microbiomes of humans from Bangladesh and Tanzania, two African baboon social groups and Danish pigs; many of these microbiomes contain phages belonging to a clade with genomes >540 kilobases in length, the largest yet reported in the human microbiome and close to the maximum size ever reported for phages. We refer to these as Lak phages. CRISPR spacer targeting indicates that Lak phages infect bacteria of the genus Prevotella. We manually curated to completion 15 distinct Lak phage genomes recovered from metagenomes. The genomes display several interesting features, including use of an alternative genetic code, large intergenic regions that are highly expressed and up to 35 putative transfer RNAs, some of which contain enigmatic introns. Different individuals have distinct phage genotypes, and shifts in variant frequencies over consecutive sampling days reflect changes in the relative abundance of phage subpopulations. Recent homologous recombination has resulted in extensive genome admixture of nine baboon Lak phage populations. We infer that Lak phages are widespread in gut communities that contain the Prevotella species, and conclude that megaphages, with fascinating and underexplored biology, may be common but largely overlooked components of human and animal gut microbiomes.