A phase-variable capsule facilitates <i>Akkermansia muciniphila</i> colonization of the intestinal mucus layer

ABSTRACT Akkermansia muciniphila is a mucophilic commensal bacterium that significantly impacts metabolic and immune homeostasis. However, the bacterial factors involved in colonization of the gastrointestinal tract are not well understood. Here, we clarify the role of capsular polysaccharides (CPS) in Akkermansia ( Akk ) colonization. We show that Akkermansia species have multiple cps loci, with cps1 being the most conserved across species. We find that cps1 is regulated by phase variation via invertible genetic elements, leading to population diversity during growth in culture media, mice, and humans. An A. muciniphila mutant that cannot produce capsular polysaccharides successfully colonized the intestines of mice but showed a reduced ability to interact with the mucus layer. Additionally, this mutant tended to form biofilms and increased aggregation on abiotic surfaces and within the gastrointestinal lumen. Our findings suggest that the A. muciniphila capsule acts as a phase-variable regulator of colonization by balancing planktonic mucus-associated states and biofilm formation. IMPORTANCE Akkermansia muciniphila , a member of the human gut microbiota, is associated with improved metabolic and immune health. However, the bacterial factors that allow this organism to thrive in the intestine and interact with the host are not fully understood. We identify capsular polysaccharides as key regulators of A. muciniphila association with mucin-rich layers in the gastrointestinal tract and its proximity to the intestinal lining. Furthermore, capsule synthesis in Akkermansia is controlled by epigenetic switches; hence, a small but significant fraction of bacteria lack a capsule. These capsule-free bacteria cluster and are prone to forming biofilms. Therefore, capsular phase variation enables A. muciniphila to switch between different colonization states, underscoring the role of A. muciniphila glycans in adapting to the gut environment.