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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>in vivo<\/jats:italic>\n                      animal experiments with\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell models to investigate the protective effect of histidine against Cu-induced intestinal inflammation and its molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rainbow trout (weight: 7.24 \u00b1 0.03\u00a0g) were fed diets containing 3.11 mg Cu\/kg and 6.89\u00a0g His\/kg (Control), 12.69 mg Cu\/kg and 6.71\u00a0g His\/kg (Cu), 3.24 mg Cu\/kg and 10.94\u00a0g His\/kg (His), 12.37 mg Cu\/kg and 10.87\u00a0g His\/kg (Cu+His) for 8 weeks. Intestinal epithelial cells (IECs) were isolated from rainbow trout and incubated for 24-h in Cu (10 \u03bcM) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our research results indicate that Cu can induce intestinal oxidative stress, which in turn leads to mitochondrial dysfunction and activation of the Hif1\u03b1-Tnf\u03b1\/Il1\u03b2 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 Hif1\u03b1, thereby preventing the occurrence of intestinal inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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 Hif1\u03b1-Tnf\u03b1\/Il1\u03b2 pathway in this process within a fish model. It provides a new theoretical basis for mitigating heavy metal toxicity through nutritional intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1960076","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:32:33Z","timestamp":1791174753000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Histidine alleviates copper-induced intestinal inflammation through oxidative stress-mediated mitochondrial damage and the Hif1\u03b1-Tnf\u03b1\/Il1\u03b2 pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Chongchao","family":"Zhong","sequence":"first","affiliation":[{"name":"Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences","place":["Harbin, Heilongjiang, 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