Pangenomic analysis identifies correlations between <i>Akkermansia</i> species and subspecies and human health outcomes

Abstract

<b>Aim:</b> <i>Akkermansia</i> are common members of the human gastrointestinal microbiota. The prevalence of these mucophilic bacteria, especially <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>), correlates with immunological and metabolic health. The genus <i>Akkermansia</i> in humans includes species with significantly larger genomes than <i>A. muciniphila</i>, leading us to postulate that this added genetic content may influence how they impact human metabolic and immunological health. <b>Methods:</b> We conducted a pangenomic analysis of 234 <i>Akkermansia</i> complete or near-complete genomes. We also used high-resolution species and subspecies assignments to reanalyze publicly available metagenomic datasets to determine if there are relationships between <i>Akkermansia</i> species and <i>A. muciniphila</i> clades with various disease outcomes. <b>Results:</b> Analysis of genome-wide average nucleotide identity, 16S rRNA gene identity, conservation of core <i>Akkermansia</i> genes, and analysis of the fatty acid composition of representative isolates support the partitioning of the genus <i>Akkermansia</i> into several species. In addition, <i>A. muciniphila sensu stricto</i>, the most prevalent <i>Akkermansia</i> species in humans, should be subdivided into two subspecies. For a pediatric cohort, we observed species-specific correlations between <i>Akkermansia</i> abundance with baseline obesity or after various interventions. For inflammatory bowel disease cohorts, we identified a decreased abundance of <i>Akkermansia</i> in patients with ulcerative colitis or Crohn's disease, which was species and subspecies-dependent. In patients undergoing immune checkpoint inhibitor therapies for non-small cell lung carcinoma, we observed a significant association between one <i>A. muciniphila</i> subspecies and survival outcomes. <b>Conclusion:</b> Our findings suggest that the prevalence of specific <i>Akkermansia</i> species and/or subspecies can be crucial in evaluating their association with human health, particularly in different disease contexts, and is an important consideration for their use as probiotics.