Large-scale biosynthetic analysis of human microbiomes reveals diverse protective ribosomal peptides

The human microbiome produces diverse metabolites that influence host health, yet the chemical landscape of ribosomally synthesized and post-translationally modified peptides (RiPPs)—a versatile class of bioactive compounds—remains underexplored. Here, we conduct a large-scale biosynthetic analysis of 306,481 microbial genomes from human-associated microbiomes, uncovering a broad array of yet-to-be-discovered RiPPs. These RiPPs are distributed across various body sites but show a specific enrichment in the gut and oral microbiome. Big data omics analysis reveals that numerous RiPP families are inversely related to various diseases, suggesting their potential protective effects on health. For a proof of principle study, we apply the synthetic-bioinformatic natural product (syn-BNP) approach to RiPPs and chemically synthesize nine autoinducing peptides (AIPs) for in vitro and ex vivo assay. Our findings reveal that five AIPs effectively inhibit the biofilm formation of disease-associated pathogens. Furthermore, when ex vivo testing gut microbiota from mice with inflammatory bowel disease, we observe that two AIPs can regulate the microbial community and reduce harmful species. These findings highlight the vast potential of human microbial RiPPs in regulating microbial communities and maintaining human health, emphasizing their potential for therapeutic development.