Leech protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites.

Background: Hyperuricemia (HUA) is a public health concern that needs to be solved urgently. The lyophilized powder of has been shown to significantly alleviate HUA; however, its underlying metabolic regulation remains unclear.

Aim: To explore the underlying mechanisms of in HUA based on modulation of the gut microbiota and host metabolism.

Methods: A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections. The mice received oral drugs or saline. Additionally, 16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome, respectively. The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay.

Results: The protein extract of lyophilized powder (49 mg/kg) showed an enhanced anti-trioxypurine ability than that of allopurinol (5 mg/kg) ( < 0.05). A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of powder, which included the genera of , , , , , , , and . Furthermore, 22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of powder, which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism, sphingolipid metabolism, galactose metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites.

Conclusion: The proteins in powder were effective for HUA. Mechanistically, they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.