Collagen Peptides Ameliorate Murine Chronic Colitis: Toward the Molecular Basis for Their Enhancement of Intestinal Epithelial Defenses Against Oxidative Stress

Collagen peptides are a promising nutraceutical therapeutic for ulcerative colitis. 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. Male C57BL/6 mice were subjected to three 10-day cycles of dextran sodium sulfate (DSS) (i.e., 4 days of DSS drinking and 6 days of recovery) to induce chronic colitis. Collagen peptides (150 and 300 mg/kg/day) derived from ginger protease-degraded gelatin hydrolysate dose-dependently improved clinical signs, colon histopathology, and biochemical markers of experimental chronic colitis. In Caco-2 cells, collagen peptides and their typical in vivo degradation products (i.e., prolyl-hydroxyproline, glycine, proline, and hydroxyproline) attenuated H2O2-induced lactate dehydrogenase release, intracellular oxidant burst, and cell viability loss with those free amino acids showing significantly weaker activities. Collagen peptides and prolyl-hydroxyproline, rather than glycine, proline, and hydroxyproline, activated cellular hypoxia-inducible factor-1 signaling that upregulated several heat-shock 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-colitis mechanism involves the enhancement of epithelial defenses against oxidative stress via hypoxia-inducible factor-1-dependent/-independent pathways.