Comprehensive Biosynthetic Analysis of Human Microbiome Reveals Diverse Protective Ribosomal Peptides

The human microbiome holds tremendous potential for generating specialized peptides, specifically ribosomally synthesized and post-translationally modified peptides (RiPPs), significantly affecting human health by mediating interactions with other microbes and the human host. However, the capacity of our microbiome to produce these peptides and their links with human health are poorly understood. This study systematically analyzes 306,481 human microbiota-associated genomes, 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, guided by biosynthetic prediction, nine autoinducing peptides (AIPs) were chemically synthesized for in vitro and ex vivo assay. Our findings revealed that five AIPs effectively inhibited the biofilm formation of disease-associated pathogens, with one demonstrating significant anti-inflammatory capabilities. Furthermore, when ex vivo testing gut bacteria from mice with inflammatory bowel disease, we observed that two AIPs could 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.