Antimicrobial peptides are host-encoded immune effectors that combat pathogens and shape the microbiome in plants and animals. However, little is known about how the host antimicrobial peptide repertoire is adapted to its microbiome. Here, we characterized the function and evolution of the antimicrobial peptide family of Diptera. Using mutations affecting the two () of , we reveal the specific role of for the pathogen and for the gut mutualist . The presence of or like genes across Diptera correlates with the presence of and in their environment. Moreover, and like sequences predict host resistance against infection by these bacteria across the genus . Our study explains the evolutionary logic behind the bursts of rapid evolution of an antimicrobial peptide family and reveals how the host immune repertoire adapts to changing microbial environments.
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