A systematic investigation of lactic acid bacteria-derived biosynthetic gene clusters reveals diverse antagonistic bacteriocins in the human microbiome

Lactic acid bacteria (LAB) produce various bioactive secondary metabolites (SMs), which endow LAB with a protective role for the host. However, the biosynthetic potentials of LAB-derived SMs remain elusive, particularly in their diversity, abundance, and distribution in the human microbiome. To gain an insight into the biosynthetic capacity of LAB, we analyzed the biosynthetic gene clusters (BGCs) from 31,977 LAB genomes and 748 human microbiome metagenomes, identifying 130,051 BGCs. The found BGCs were clustered into 2,849 gene cluster families (GCFs), most of which are species-specific, niche-specific, and uncharacterized yet. We found that most LAB BGCs encoded bacteriocins with pervasive antagonistic activities predicted by machine learning models, potentially playing protective roles in the human microbiome. Class II bacteriocins, the most abundant LAB SMs, are particularly enriched and predominant in vaginal microbiomes. Together with experimental validation, our metagenomic and metatranscriptomic analysis showed that class II bacteriocins with antagonistic potential might regulate microbial communities in the vagina, thereby contributing to homeostasis. These discoveries of the diverse and prevalent antagonistic SMs are expected to stimulate the mechanism study of LAB’s protective roles in the host and highlight the potential of LAB as a new source of antibacterial SMs.