Abstract
Akkermansia muciniphila is a commensal, mucophilic anaerobic bacterium that influences human host physiology. Although additional prominent Akkermansia species have been identified in humans, their responses to mucin-rich environments remain poorly understood. We conducted a comparative analysis of four representative human isolates: A. muciniphila, A. biwaensis, A. massiliensis, and A. durhamii, focusing on proteins involved in mucin degradation, cell-surface components, and species-specific secreted metabolites during growth in mucin. Our results reveal unique adaptations of A. muciniphila to exploit mucin-rich environments, including higher expression of key mucin-degrading proteins during growth in mucin compared to other Akkermansia species. We also demonstrate that A. muciniphila expresses a significantly greater number of secreted PEPCTERM proteins, which contribute to host colonization. The expression of pili-associated proteins varied across species, with non- muciniphila species producing more predicted pili, suggesting the ability to colonize additional niches. Lastly, we find that small peptides previously linked to host and microbiome modulation in the GI tract are over-represented in the metabolomes of non- muciniphila species. Conversely, A. muciniphila produces more hydroxylated fatty acids, indicating potential mechanisms for modulating host health. These findings highlight genetic and regulatory mechanisms that may explain A. muciniphila 's dominance in the human gut.