Study on the mechanism of Orthosiphon aristatus (Blume) Miq. in the treatment of hyperuricemia by microbiome combined with metabonomics

Abstract

Ethnopharmacological relevance: Growing evidence indicates that hyperuricemia is closely associated with gut microbiota dysbiosis. Orthosiphon aristatus (Blume) Miq. (O. aristatus), as a traditional Chinese medicine, has been widely used to treat hyperuricemia in China. However, the mechanism by which O. aristatus treats hyperuricemia has not been clarified.

Aim of the study: In this study, we investigated whether the molecular mechanism underlying the anti-hyperuricemia effect of O. aristatus is related to the regulation of gut microbiota by 16S rDNA gene sequencing combined with widely targeted metabolomics.

Materials and methods: Hyperuricemia was induced in rats by administration of 10% fructose and 20% yeast, and the uricosuric effect was assessed by measuring the uric acid (UA) levels in serum and cecal contents. Intestinal morphology was observed by hematoxylin and eosin (HE) staining. To explore the effects of O. aristatus on the gut microbiota and its metabolites, we utilized 16S rDNA gene sequencing combined with widely targeted metabolomics. Furthermore, metabolic pathway enrichment analysis was performed on the screened differential metabolites. The real time quantitative polymerase chain reaction (RT-PCR) and western blotting (WB) were used to detect the expression of relevant proteins in the key pathway.

Results: Our results indicated that O. aristatus intervention decreased serum UA levels and increased the UA levels in cecal contents in hyperuricemic rats. Additionally, O. aristatus improved intestinal morphology and altered the composition of the gut microbiota and its metabolites. Specifically, 16S rDNA revealed that O. aristatus treatment significantly reduced the abundance of unidentified-Ruminococcaceae and Lachnospiraceae-NK4A136-group. Meanwhile, widely targeted metabolomics showed that 17 metabolites, including lactose, 4-oxopentanoate and butyrate, were elevated, while 55 metabolites, such as flavin adenine dinucleotide and xanthine, were reduced. Metabolic pathway enrichment analysis found that O. aristatus was mainly involved in purine metabolism. Moreover, RT-PCR and WB suggested that O. aristatus could significantly up-regulate the expression of UA excretion transporter ATP-binding cassette subfamily G member 2 (ABCG2) in the intestine.

Conclusion: O. aristatus exerts UA-lowering effect by regulating the gut microbiota and ABCG2 expression, indicating that this herb holds great promise in the treatment of hyperuricemia.

Keywords: Gut microbiota; Hyperuricemia; Metabonomics; Orthosiphon aristatus (Blume) Miq.; Purine metabolism.