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This study aimed to evaluate the protective effects and underlying mechanisms of collagen peptides in a murine model of chronic colitis and in human intestinal epithelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>Male C57BL\/6 mice were subjected to three 10\u2010day cycles of dextran sodium sulfate (DSS) (i.e., 4\u00a0days of DSS drinking and 6\u00a0days of recovery) to induce chronic colitis. Collagen peptides (150 and 300\u00a0mg\/kg\/day) derived from ginger protease\u2010degraded gelatin hydrolysate dose\u2010dependently improved clinical signs, colon histopathology, and biochemical markers of experimental chronic colitis. In Caco\u20102 cells, collagen peptides and their typical in vivo degradation products (i.e., prolyl\u2010hydroxyproline, glycine, proline, and hydroxyproline) attenuated H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced lactate dehydrogenase release, intracellular oxidant burst, and cell viability loss with those free amino acids showing significantly weaker activities. Collagen peptides and prolyl\u2010hydroxyproline, rather than glycine, proline, and hydroxyproline, activated cellular hypoxia\u2010inducible factor\u20101 signaling that upregulated several heat\u2010shock proteins and antioxidant enzymes, whereas glycine, proline, and hydroxyproline boosted cellular glutathione production by directly or indirectly increasing substrate supply. Collagen peptides were protective against chronic colitis, and their anti\u2010colitis mechanism involves the enhancement of epithelial defenses against oxidative stress via hypoxia\u2010inducible factor\u20101\u2010dependent\/\u2010independent pathways.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.70177","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:19:47Z","timestamp":1752124787000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Collagen Peptides Ameliorate Murine Chronic Colitis: Toward the Molecular Basis for Their Enhancement of Intestinal Epithelial Defenses Against Oxidative Stress"],"prefix":"10.1002","volume":"69","author":[{"given":"Suqin","family":"Zhu","sequence":"first","affiliation":[{"name":"Institute of Nutrition and Health School of Public Health Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Health School of Public Health Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangguang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Health School of Public Health Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Health School of Public Health Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hainan\/Haikou Research &amp; Development Center for Biopeptide Engineering Hainan Huayan Collagen Technology Co., Ltd  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Yu","sequence":"additional","affiliation":[{"name":"Yantai New Era Health Industry Daily Chemical Co., Ltd  Yantai Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lerong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yantai New Era Health Industry Daily Chemical Co., Ltd  Yantai Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhai","family":"She","sequence":"additional","affiliation":[{"name":"Guangdong Aquatic Resources Industrialization Engineering Technology Research Center Guangzhou Luxe Seafood Enterprises Ltd.  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