A comprehensive analysis of human gut microbial biosynthesis gene clusters unveiling the dominant role of <i>Paenibacillus</i>

The secondary metabolites produced by the gut microbiota serve as crucial signaling molecules and substrates for gastrointestinal metabolic reactions, thereby playing a pivotal role in human physiological and pathological processes. In this study, we explore the complex symbiotic relationship between the gut microbiota and the human host by systematically annotating the biosynthetic gene clusters (BGCs) across 4,744 human gut microbiota genomes, sourced from the Unified Human Gastrointestinal Genome database. Our comprehensive analysis compares the differential biosynthetic potentials of microbiota from diverse continents and phyla while also elucidating the biosynthetic profiles of gut archaea. Notably, our findings identify <i>Paenibacillus</i> as a dominant genus within the human gut microbiota, characterized by its extensive biosynthetic capacity. This study presents the first global atlas of BGCs within the human gut microbiome, offering valuable insights into gut-derived secondary metabolic pathways and their intricate interactions with host physiology. These results lay the groundwork for future investigations into the microbiota's role in health and disease, underscoring the importance of understanding microbiota-derived metabolites in microbiology and gastroenterology.IMPORTANCEThis study provides a comprehensive analysis of biosynthetic gene clusters in the human gut microbiome, revealing a vast diversity of natural products with potential therapeutic applications. We identified <i>Paenibacillus</i> as a key genus with exceptional biosynthetic capabilities, including the production of leinamycin, a potent anticancer compound previously thought to be exclusive to <i>Streptomyces</i>. The findings highlight the gut microbiome as a rich, untapped resource for novel drug discovery, particularly in cancer therapy and immune modulation.