Lipid accumulation inhibition strategies alleviate Fusobacterium nucleatum-infected colorectal cancer

Fusobacterium nucleatum (F. nucleatum) is prevalent in colorectal cancer (CRC), and it can promote proliferation and induce chemoresistance via multiple pathways. The development of treatment strategies for F. nucleatum-infected CRC is of great importance. Shotgun metagenomic and metabolomic analyses of human feces, as well as metabolomic analysis of human blood, were performed to reveal the dysbiosis and metabolic dysregulation in CRC. Furthermore, the effects of Bifidobacterium animalis (B. animalis) on F. nucleatum and CRC were assessed in vitro and in vivo. Using a mouse CRC model, the function of bile salt hydrolase (BSH) in B. animalis was verified through heterologous expression in Escherichia coli (E. coli). Bile acids and drug library screening experiments were performed to inhibit F. nucleatum and tumor proliferation. We identified an increase in F. nucleatum, enrichment of lipid metabolites, and depletion of Bifidobacterium in CRC patients. Furthermore, B. animalis inhibited F. nucleatum and CRC cells growth in an acid-dependent manner and reduced F. nucleatum-induced tumor increasement in mice. Mechanistically, F. nucleatum caused lipid accumulation, exacerbated inflammation, and intestinal barrier disruption, whereas B. animalis alleviated these changes, increased the Simpson diversity index, reduced lipid metabolites, and altered secondary bile acid composition in mice. Moreover, E. coli-BSH and ursodeoxycholic acid (UDCA) inhibited F. nucleatum-induced lipid accumulation and FASN/CPT1/NF-κB upregulation. Additionally, they alleviated F. nucleatum-related intestinal tumorigenesis in vivo. Targeting F. nucleatum-infected CRC cells and subcutaneous tumors in mice, penfluridol or the combination of orlistat and 5-FU exhibited superior inhibitory effects compared to 5-FU alone. F. nucleatum and lipid metabolites are enriched in CRC patients. Furthermore, BSH-expressing E. coli, UDCA, and penfluridol can alleviate F. nucleatum-induced lipid accumulation and tumor growth in mice. Video Abstract.