Goat gut microbiome as a reservoir for microorganism-encoded short peptides: regulation by host development age and nematode challenge

Short peptides are a promising class of antimicrobial agents with efficacy against multidrug-resistant pathogens. While host-derived defense peptides from animals and plants have been widely characterized, the landscape of microbial-encoded short peptides, particularly those with antimicrobial activity that can mitigate antibiotic resistance, remains underexplored. In this study, we identified 1147 novel microorganism-encoded short peptides (MSPs) from the goat gut microbiome, most of which lack homology to existing database entries. The microbial communities producing these MSPs were altered by the developmental stage of the goat, whereas the overall composition and diversity of these populations remained unchanged during nematode infection, despite significant correlations between certain MSPs and type 2 immunity. Notably, two MSPs demonstrated potent antimicrobial activity with lower cytotoxicity, exhibiting remarkable efficacy against methicillin-resistant Staphylococcus aureus and Streptococcus agalactiae. Collectively, our findings establish the goat gastrointestinal tract microbiome as a distinctive and promising reservoir for the discovery of antimicrobial and immunoregulatory peptides.