Elucidating the Diversity and Potential Function of Ribosomally Synthesized and Post-translationally Modified Peptides in the Human Microbiome

The human microbiome possesses a vast potential for producing ribosomally synthesized and post-translationally modified peptides (RiPPs) that can impact human health and disease. Understanding the RiPPs-mediated microbe-microbe and microbe-host interactions holds significant implications for human health. However, the RiPP biosynthetic potential in human microbiome and their associations with human disease remain largely uncharacterized. In this study, we systematically analyzed 306,481 human microbiota-associated genomes, revealing a wide diversity of RiPPs that are mostly unknown. RiPP biosynthesis is found in various body sites and exhibits niche-specific enrichment in the gut and oral microbiome. Through a comparative metatranscriptomic analysis, 30 RiPP families with potentially antibacterial and signaling activities are found to be related to multiple diseases. Nine RiPPs, namely autoinducing peptides (AIPs), negatively associated with multiple diseases are chemically synthesized and experimentally validated for their bioactivity. Five AIPs can effectively inhibit biofilm formation by disease-associated pathogens such as Clostridioides difficile . These findings highlight the vast potential of human microbial RiPPs in regulating microbial communities and maintaining human health, emphasizing their potential for therapeutic development.