Fusobacterium nucleatum enhances cholesterol biosynthesis in colorectal cancer via miR-130a-3p-mediated AMPK inhibition, a process counteracted by butyrate

Fusobacterium nucleatum (Fn) has been implicated in various diseases, including colorectal cancer (CRC). This study elucidates Fn's contribution to cholesterol synthesis and the underlying link with CRC, as well as butyrate's counteracting effects in this process. Cells and mouse models were treated with Fn followed/accompanied by butyrate treatments to investigate the interplay between butyrate and Fn's oncogenic properties. Transcriptomics analysis pinpointed Fn's profound impact on cholesterol biosynthesis genes and pathways. Fn treatment upregulated the expression of genes involved in cholesterol synthesis (FDPS, FDFT1, and SQLE) and increased SREBF2 activity in cells and mouse intestines, elevating cholesterol levels in cells, intestines, and sera. Fn upregulated miR-130a-3p, identified through transcriptomics and target prediction, through nuclear factor-κB activation. miR-130a-3p subsequently downregulated AMPKα/β1 expression to activate SREBF2 and upregulate cholesterol biosynthesis genes. These effects were predominantly mitigated by butyrate. Notably, analysis of TCGA data revealed that fusobacterial abundance correlated significantly with the expression of FDPS, FDFT1, SQLE, and AMPKα/β1 in CRC. Fn abundance and miRNA expression in human stools were quantified using qPCR and RT-qPCR. Fecal miR-130a-3p levels increased progressively from normal subjects through adenoma patients to CRC patients, correlating significantly with fecal Fn abundance. Additionally, heightened fecal Fn abundance was associated with an increased incidence of hypercholesterolemia in CRC patients. Fn promotes cholesterol biosynthesis by upregulating miR-130a-3p, which downregulates AMPK proteins and activates SREBF2. This study highlights the influence of gut bacteria on host cholesterol synthesis. Targeted modulation of gut microbiota to reduce cholesterol may represent a promising preventive strategy for CRC.