Histidine alleviates copper-induced intestinal inflammation through oxidative stress-mediated mitochondrial damage and the Hif1α-Tnfα/Il1β pathway.

Introduction: Copper (Cu) is an essential trace element for vertebrates, but excessive intake can induce intestinal toxicity. Whether nutritional intervention can alleviate Cu overload-induced intestinal damage and the underlying mechanisms remain unclear. In this study, we combined Methods: Rainbow trout (weight: 7.24 ± 0.03 g) were fed diets containing 3.11 mg Cu/kg and 6.89 g His/kg (Control), 12.69 mg Cu/kg and 6.71 g His/kg (Cu), 3.24 mg Cu/kg and 10.94 g His/kg (His), 12.37 mg Cu/kg and 10.87 g His/kg (Cu+His) for 8 weeks. Intestinal epithelial cells (IECs) were isolated from rainbow trout and incubated for 24-h in Cu (10 μM) and His (2.5 mM) solution. Histopathology, ultrastructural structure, oxidative stress, mitochondrial damage, and inflammation were determined in the intestine and IECs; fluorescence staining (DCFH-DA and JC-1), immunoblotting, immunofluorescence, siRNA, and ChIP were performed on IECs. Results: Our research results indicate that Cu can induce intestinal oxidative stress, which in turn leads to mitochondrial dysfunction and activation of the Hif1α-Tnfα/Il1β signaling axis, ultimately exacerbating intestinal inflammatory responses. In contrast, co-treatment with Cu and histidine markedly attenuated the intestinal inflammatory phenotype. Mechanistically, histidine exerts anti-inflammatory effects by inhibiting oxidative stress, improving mitochondrial function and suppressing Hif1α, thereby preventing the occurrence of intestinal inflammation. Discussion: This study is the first to elucidate the mechanism by which histidine alleviates Cu-induced intestinal inflammation and delineated the critical regulatory role of mitochondrial damage and the Hif1α-Tnfα/Il1β pathway in this process within a fish model. It provides a new theoretical basis for mitigating heavy metal toxicity through nutritional intervention.