Identification of potential colorectal-cancer-protective bioactive natural compounds in the human gut microbiome

Abstract Increasing evidence links the gut microbiome to the development and progression of colorectal cancer (CRC). Despite the remarkable diversity of microbial biosynthetic gene clusters (BGCs), no CRC-protective bioactive natural compounds originating from gut microbiome BGCs have yet been detected. Here, we investigated BGCs within de novo gut metagenome-assembled species reconstructed from 559 individuals, including healthy controls, adenoma and CRC patients. Comparative analysis revealed distinct BGC patterns across groups, with four BGCs being significantly enriched in healthy individuals. One of these was predicted to be involved in the biosynthesis of a metabolite closely related to the anticancer compound curacin-A. Notably, this BGC was also overrepresented in healthy centenarians, suggesting a role in achieving long-term cancer-free health. Our findings highlight the importance of exploring gut microbiome BGCs as a source of novel bioactive molecules for cancer prevention and treatment, as well as for other health purposes.