Zearalenone (ZEA), a secondary metabolite from Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancers in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer promotive effect of ZEA. The aim of this study was to unveil the effect of ZEA on colon cancer progression and its underlying mechanism. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed that a 4-week ZEA intervention increased the tumor weight twofold. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB and KI67, and the phosphorylation levels of ERK1/2 and AKT. Metabolomics analysis of the serum revealed the levels of amino acids, including histidine, arginine, citrulline and glycine decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of 9 genera, such as Tuzzerella and Rikenella, etc. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid level and tumor weight. In addition, circulatory hippuric acid level was positively correlated with the tumor weight and the expression of oncogenic genes, including ROBO3, JAK3 and BEST4. Altogether, our results indicated that ZEA promoted colon cancer tumor progression through enhancing the BEST4/AKT/ERK1/2 pathway, lowering the circulatory amino acid concentration, alternating the gut microbiota composition, and suppressing the SCFA production.
