Abstract: Objective: To study the effect and molecular mechanism of ethanol extract from Hippocampus abdominalis on hyperuricemia in mice. Methods: The chemical components in the ethanol extract and the mouse serum were analyzed using high performance chemical isotope labeling (HP-CIL) technology. A mouse model of hyperuricemia was established by co-administration of potassium oxazinate and hypoxanthine. Serum levels of uric acid, creatinine, and uric acid nitrogen, as well as hepatic xanthine oxidase activity, were detected using commercial detection kits. HE staining was used to detect renal injury in mice. Western blot was used to detect protein expression levels. High throughput sequencing was used to analyze the changes in the gut microbiota in mice. Results: Chemical analysis identified 1 174 compounds in the hippocampal extract, among which peptides, amino acids, carboxylic acids, and fatty acids were the main ones. Eight compounds (tyrosyl-proline, isoleucyl-serine, threoninyl-alanine, tryptophyl-serine, prostaglandin D2, mataric acid, 4-pyridoxic acid, and citric acid) were exclusively present in the serum of hippocampal extract-treated mice compared with normal and hyperuricemic mice and these compounds were also were found in the extract, suggesting their absorption into the blood circulation. Compared with the model mice, the extract significantly reduced serum uric acid levels. It also significantly reduced serum creatinine, uric acid nitrogen levels and alleviated renal injury, indicating renal protection. The ethanol extract inhibited hepatic xanthine oxidase and suppressed the renal expression of uric acid reabsorption transporters (URAT1 and GLUT9), while promoting the expression of uric acid excretion transporters (ABCG2, OAT1, and OAT3) in kidney tissue, indicating that H. abdominalis extract may regulate the level of blood uric acid in mice by affecting uric acid production, excretion and reabsorption. Furthermore, the extract significantly modulated the abundance of gut microbiota in hyperuricemic mice, restoring it to nearly normal levels. This demonstrates that the extract can regulate blood uric acid levels by remodeling intestinal microecology. Conclusion: H. abdominalis ethanol extract significantly ameliorates hyperuricemia in mice by regulating xanthine oxidase activity, uric acid transporter expression, and the gut microbiota.

Key words: Hippocampus abdominalis; hyperuricemia; uric acid excretion proteins; uric acid reabsorption proteins; gut microbiota