Regulatory Roles of Quercetin in Alleviating Fructose‐Induced Hepatic Steatosis: Targeting Gut Microbiota and Inflammatory Metabolites

While fructose is a key dietary component, concerns have been raised about its potential risks to the liver. This study aimed to assess quercetin's protective effects against fructose-induced mouse hepatic steatosis. Thirty-two male C57BL/6J mice were randomly allocated into four groups: control, high fructose diet (HFrD), HFrD supplemented with low-dose quercetin (HFrD+LQ), and HFrD supplemented with high-dose quercetin (HFrD+HQ). Biochemical, pathological, immune, and metabolic parameters were assessed. Quercetin treatment significantly reduced liver fat percentages in mice on a high fructose diet, with the most notable reduction observed in the HFrD+HQ group. Histological examination confirmed this reduction, revealing diminished lipid droplets and decreased inflammation and steatosis in hepatocytes. Compared to the high fructose group, interleukin-1 β and tumor necrosis factor alpha were significantly decreased, serum aspartate aminotransferase concentrations were markedly reduced, and blood high-density lipoprotein concentrations were substantially elevated after quercetin intervention (<i>p</i> < 0.05). Total bilirubin and triglyceride levels, which were significantly altered following high fructose intervention and reversed after quercetin intervention. Following the administration of 100 mg/kg quercetin, the Firmicutes/Bacteroidetes ratio was significantly reduced compared to the high fructose group. At the genus level, <i>Erysipelotrichaceae_uncultured</i>, <i>Faecalibaculum</i>, <i>Odoribacter</i>, <i>and Allobaculum</i> were significantly decreased (<i>p</i> < 0.05), <i>Lacnospiraceae NK4A136 group</i>, <i>Parabacteroides</i>, and <i>Alloprevotella</i> significantly increased (<i>p</i> < 0.05). However, the 50 mg/kg quercetin treatment only decreased the abundance of <i>Erysipelotrichaceae_uncultured</i> (<i>p</i> < 0.05). In addition, quercetin significantly enhanced the content of propionic acid and total acid (<i>p</i> < 0.05). Moreover, the intestinal flora showed a significant correlation with the hepatic health-related phenotype in mice. Both 50 and 100 mg/kg quercetin treatments significantly mitigated liver fat deposition in mice with fructose-induced hepatic steatosis. However, the higher dose of quercetin (100 mg/kg) demonstrated a more pronounced effect in reducing liver inflammation, likely due to its impact on gut microbiota regulation. This suggests quercetin's potential as a therapeutic agent for fructose-related hepatic steatosis, emphasizing the importance of dose considerations.