Tailoring a Functional Synthetic Microbial Community Alleviates Fusobacterium nucleatum-infected Colorectal Cancer via Ecological Control.

Abstract

Polymorphic microbiomes play important roles in colorectal cancer (CRC) occurrence and development. In particular, Fusobacterium nucleatum (F. nucleatum) is prevalent in patients with CRC, and eliminating it is beneficial for treatment. Here, multiple metagenomic sequencing cohorts are combined with multiomics to analyze the microbiome and related functional alterations. Furthermore, local human metagenome and metabolomics are used to discover commensal consortia. A synthetic microbial community (SynCom) is then designed by metabolic network reconstruction, and its performance is validated using coculture experiments and an AOM-DSS induced mouse CRC model. The sequencing result shows that F. nucleatum is more abundant in both the feces and tumor tissues of CRC patients. It causes alterations through various pathways, including microbial dysbiosis, lipid metabolism, amino acid metabolism, and bile acid metabolism disorders. The designed SynCom contains seven species with low competition interrelationship. Furthermore, the SynCom successfully inhibits F. nucleatum growth in vitro and achieves colonization in vivo. Additionally, it promotes F. nucleatum decolonization, and enhances tryptophan metabolism and secondary bile acid conversion, leading to reduced lipid accumulation, decreased inflammatory reaction, and enhanced tumor inhibition effect. Overall, the bottom-up designed SynCom is a controllable and promising approach for treating F. nucleatum-positive CRC.