Genomic diversity and ecology of human-associated Akkermansiaspecies in the gut microbiome revealed by extensive metagenomic assembly

Background: Akkermansia muciniphilais a human gut microbe with a key role in the physiology of the intestinal mucus layer and reported associations with decreased body mass and increased gut barrier function and health. Despite its biomedical relevance, the genomic diversity of A. muciniphilaremains understudied and that of closely related species, except for A. glycaniphila, unexplored. Results: We present a large-scale population genomics analysis of the Akkermansiagenus using 188 isolate genomes and 2226 genomes assembled from 18,600 metagenomes from humans and other animals. While we do not detect A. glycaniphila, the Akkermansiastrains in the human gut can be grouped into five distinct candidate species, including A. muciniphila, that show remarkable whole-genome divergence despite surprisingly similar 16S rRNA gene sequences. These candidate species are likely human-specific, as they are detected in mice and non-human primates almost exclusively when kept in captivity. In humans, Akkermansiacandidate species display ecological co-exclusion, diversified functional capabilities, and distinct patterns of associations with host body mass. Analysis of CRISPR-Cas loci reveals new variants and spacers targeting newly discovered putative bacteriophages. Remarkably, we observe an increased relative abundance of Akkermansiawhen cognate predicted bacteriophages are present, suggesting ecological interactions. A. muciniphilafurther exhibits subspecies-level genetic stratification with associated functional differences such as a putative exo/lipopolysaccharide operon. Conclusions: We uncover a large phylogenetic and functional diversity of the Akkermansiagenus in humans. This variability should be considered in the ongoing experimental and metagenomic efforts to characterize the health-associated properties of A. muciniphilaand related bacteria.