Identification of pyroglutamyl peptides with anti-colitic activity in Japanese rice wine, sake, by oral administration in a mouse model

Two pyroglutamyl peptides with anti-colitic activity were identified in Japanese rice wine, sake, by oral administration of a small dose (0.1-1.0 mg/kg body weight) and in vivo activity-guided fractionation. Compounds in sake were fractionated by preparative isoelectric focusing followed by preparative reversed phase-liquid chromatography. Anti-colitic activity was evaluated using a dextran sulphate sodium (DSS)-induced colitis mouse model. The final active fraction contained three pyroglutamyl peptides: pyroglutamyl-tyrosine (pyroGlu-Tyr), pyroglutamyl-asparaginyl-isoleucine (pyroGlu-Asn-Ile) and pyroglutamyl-asparaginyl-isoleucyl-asparagyl-asparaginyl-proline (pyroGlu-Asn-Ile-Asp-Asn-Pro). Orally administrating artificially synthesized pyroGlu-Tyr (1.0 mg/kg body weight) and pyroGlu-Asn-Ile (0.1 and 1.0 mg/kg body weight) exhibited a significant protective effect against colitis in mice, whereas pyroGlu-Asn-Ile-Asp-Pro showed no significant effect. Additionally, administrating pyroGlu-Asn-Ile normalized colitis-induced colonic dysbiosis, whereas pyroGlu-Tyr did not. These results suggest that identified pyroglutamyl peptides exhibited an anti-colitic activity via different mechanisms.