Frontiers in immunology · 2026
Histidine alleviates copper-induced intestinal inflammation through oxidative stress-mediated mitochondrial damage and the Hif1α-Tnfα/Il1β pathway.
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Zhong Chongchao, Chen Fang, Lu Shaoxia, Han Shicheng, Liu Hongbai, Wang Chang'an
Аннотация
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 in vivo animal experiments with in vitro cell models to investigate the protective effect of histidine against Cu-induced intestinal inflammation and its molecular mechanisms.
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.
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.