Lytic phages lead to targeted and sustained depletion of Akkermansia muciniphila in the gut microbiome

Natural bacteriophages are major regulators of gut bacterial populations, but their capacity to impose sustained, taxon-selective control over individual commensals in the gut remains unclear. Here, we establish a collection of isolated lytic phages targeting Akkermansia muciniphila, a mucosa-associated and context-dependent gut commensal, and demonstrate their utility as precision perturbation tools. We isolated 27 phages representing two distinct vOTUs within the class Caudoviricetes, neither of which had close cultured representatives in public databases. The phages lysed susceptible A. muciniphila strains at low multiplicities of infection and showed no detectable activity against other tested gut bacteria. Selected phages reproducibly depleted A. muciniphila across distinct stool-derived in vitro communities, demonstrating that the magnitude of structural disruption scales with the target's baseline abundance. Oral gavage of the optimized cocktail PC6 achieved targeted and sustained suppression in A. muciniphila-colonized and human microbiota-associated mouse models, with infective phages recoverable from feces. Shotgun metagenomics revealed changes in a limited subset of taxa and functional pathways, comprising both shared and donor-specific responses, without broad loss of pathway-level diversity. These findings expand the collection of cultured phages that infect A. muciniphila and provide a tractable strategy for causally probing the ecological roles of defined gut commensals.

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