Unveiling the Dark Side of Flavonoid: Rutin Provokes Hepatotoxicity in Low-Dose 2-Amino-3-methylimidazo [4,5-f] Quinoline-Exposed Mice via Regulating Gut Microbiota and Liver Metabolism

2-Amino-3-methylimidazole [4,5-f] quinoline (IQ) is a kind of heterocyclic amine (HCAs) with high carcinogenicity in hot processed meat. Rutin (Ru) is a flavonoid compound with anti-inflammatory and antioxidant properties. However, whether Ru is scatheless under IQ-stimulated potential unhealthy conditions, especially liver function, in vivo, is unknown. In this study, we explored the effects and underlying mechanism of Ru on liver injury induced by a low dose of IQ in mice. Results showed that Ru supplement led to liver injury upon low-dose IQ alone administration, as shown by histological analysis, inflammatory, and serum biochemical indexes. Additionally, nontargeted metabolomics analysis revealed that coexposure of Ru and IQ disrupted liver metabolic balance, leading to significant changes in metabolites and metabolic pathways, hinting at a possible relationship with intestinal microbiota. Furthermore, the 16S rRNA sequencing data indicated that a combination of Ru and IQ caused gut microbiota dysbiosis and decreased the level of short-chain fatty acids (SCFAs). Correlation analysis between gut microbiota, SCFAs, liver metabolites, and liver damage markers highlighted the crucial role of the gut-liver axis in IQ and Ru coexposure-induced liver injury in vivo. In general, this study offers a valuable perspective on flavones and HCA compounds in the realms of food safety and human health.