Background Akkermansia muciniphila is 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. muciniphila remains understudied and that of closely related species, except for A. glycaniphila, unexplored. Results We present a large-scale population genomics analysis of the Akkermansia genus 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 Akkermansia strains 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, Akkermansia candidate 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 Akkermansia when cognate predicted bacteriophages are present, suggesting ecological interactions. A. muciniphila further 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 Akkermansia genus in humans. This variability should be considered in the ongoing experimental and metagenomic efforts to characterize the health-associated properties of A. muciniphila and related bacteria.

BackgroundHumans have coevolved with microbial communities to establish a mutually advantageous relationship that is still poorly characterized and can provide a better understanding of the human microbiome. Comparative metagenomic analysis of human and non-human primate (NHP) microbiomes offers a promising approach to study this symbiosis. Very few microbial species have been characterized in NHP microbiomes due to their poor representation in the available cataloged microbial diversity, thus limiting the potential of such comparative approaches.ResultsWe reconstruct over 1000 previously uncharacterized microbial species from 6 available NHP metagenomic cohorts, resulting in an increase of the mappable fraction of metagenomic reads by 600%. These novel species highlight that almost 90% of the microbial diversity associated with NHPs has been overlooked. Comparative analysis of this new catalog of taxa with the collection of over 150,000 genomes from human metagenomes points at a limited species-level overlap, with only 20% of microbial candidate species in NHPs also found in the human microbiome. This overlap occurs mainly between NHPs and non-Westernized human populations and NHPs living in captivity, suggesting that host lifestyle plays a role comparable to host speciation in shaping the primate intestinal microbiome. Several NHP-specific species are phylogenetically related to human-associated microbes, such as Elusimicrobia and Treponema, and could be the consequence of host-dependent evolutionary trajectories.ConclusionsThe newly reconstructed species greatly expand the microbial diversity associated with NHPs, thus enabling better interrogation of the primate microbiome and empowering in-depth human and non-human comparative and co-diversification studies.

Omics technologies have revolutionized microbiome research allowing the characterization of complex microbial communities in different biomes without requiring their cultivation. As a consequence, there has been a great increase in the generation of omics data from metagenomes and metatranscriptomes. However, pre-processing and analysis of these data have been limited by the availability of computational resources, bioinformatics expertise and standardized computational workflows to obtain consistent results that are comparable across different studies. Here, we introduce MIntO (Microbiome Integrated meta-Omics), a highly versatile pipeline that integrates metagenomic and metatranscriptomic data in a scalable way. The distinctive feature of this pipeline is the computation of gene expression profile through integrating metagenomic and metatranscriptomic data taking into account the community turnover and gene expression variations to disentangle the mechanisms that shape the metatranscriptome across time and between conditions. The modular design of MIntO enables users to run the pipeline using three available modes based on the input data and the experimental design, including de novo assembly leading to metagenome-assembled genomes. The integrated pipeline will be relevant to provide unique biochemical insights into microbial ecology by linking functions to retrieved genomes and to examine gene expression variation. Functional characterization of community members will be crucial to increase our knowledge of the microbiome’s contribution to human health and environment. MIntO v1.0.1 is available at https://github.com/arumugamlab/MIntO.