Interactions Between Akkermansia Species and Gastrointestinal Mucins

Abstract

Akkermansia is a genus of commensal, mucolytic bacteria that reside within the gastrointestinal mucin layer and thus interact closely with host tissues. Akkermansia species have garnered interest due to their probiotic capabilities and ability to modulate host health. Among human-associated Akkermansia species, Akkermansia muciniphila is the most prevalent and best characterized, yet the broader genus contains substantial functional diversity that remains poorly understood. Specifically, the knowledge of how Akkermansia adheres to mucin, how Akkermansia consumes mucin, and what key functional differences exist across Akkermansia species remains understudied. In this dissertation, I address these gaps in knowledge through an interdisciplinary approach. A multi-omic analysis provides insight into the functional capabilities of diverse Akkermansia species and defines mechanisms that enable A. muciniphila to thrive in the human microbiome relative to other Akkermansia species. I also demonstrate that PEPCTERM proteins, a unique class of mucin-binding proteins, are required for colonization in vivo and likely mediate mucin-binding through extracellular polysaccharides. Finally, I describe a fluorescence-assisted cell sorting (FACS) protocol developed to identify Akkermansia genes required for intracellular mucin accumulation, a unique method of mucin metabolism in Akkermansia. These studies elucidate functional differences among human-associated Akkermansia species and establish mechanistic links among mucin adhesion, internalization, and niche establishment. These insights into fundamental Akkermansia biology will be critical in the future optimization and development of Akkermansia-based probiotic platforms, harnessing the power of additional Akkermansia species beyond A. muciniphila.