The human microbiome as a source of novel bioactive natural products: structures, bioactivities, and biosynthetic insights.

The human microbiome, comprising trillions of microorganisms in distinct anatomical locations such as the gut, oral cavity, skin, and vagina, has emerged as a source of bioactive natural products with diverse scaffolds. Through co-evolution with the host, the human microbiome produces small molecules tailored to physicochemical environments that contribute to immune regulation, epithelial barrier maintenance, pathogen defense, and neurochemical signaling. Recent advances in metagenomics, single-cell genomics, synthetic biology, and integrated omics approaches have enabled rapid discovery and structural elucidation of biosynthetic gene clusters (BGCs) and metabolites. Cultivation-driven and genome mining strategies combined with omics analyses have improved the efficiency of discovering microbiome-derived drug leads. These metabolites mediate competitive and cooperative interactions within microbial ecosystems and hold high promise for therapeutic applications such as immunomodulators, anti-infectives, and neuroactive agents. This review outlines the structural features, biosynthetic pathways, and bioactivities of key metabolites across major microbial niches, together with strategies for their discovery, highlighting their potential in advancing drug development and human health.