Diet composition affects long-term zearalenone exposure on the gut-blood-liver axis metabolic dysfunction in mice

Zearalenone (ZEN), one of the most contaminated Fusarium toxins worldwide, is very common in contaminating wheat, corn oil and other foods. People are more vulnerable to ZEN exposure with more daily caloric intake, yet little is known about the combined effect of different dietary patterns with mycotoxins. This study aimed to compare the effects of long-term ZEN exposure on the overall biochemical landscape of the "gut-blood-liver axis" under normal diet and high-fat diet (HFD) using a combined multi-omics approach. The results indicated that ZEN exposure, possibly via the phenylalanine metabolic pathway, led to dysbiosis of mouse flora, suppression of short-chain fatty acids (SCFAS) metabolism, systemic inflammatory responses, and disturbances in serum and liver metabolism, which were exacerbated in synergy with HFD and ultimately led to a more severe state of lipid metabolism in the liver. We further found that ZEN exposure attenuated the indole-3-propionic acid (IPA) metabolic pathway, enhanced 2-hydroxybutyric acid metabolism in serum, and attenuated β-alanine metabolism in liver which was positively correlated with the abundance of Prevotellaceae UCG-004, Prevotellaceae UCG-001, and Prevotellaceae NK3B31 groups. The results highlighted the damaging effects of ZEN on the gut-blood-liver axis under different dietary patterns, which might serve as a reference for future studies exploring the combined effects of fungal toxins and multiple dietary patterns.