Integrated Data Mining and Animal Experiments to Investigate the Efficacy and Potential Pharmacological Mechanism of a Traditional Tibetan Functional Food Terminalia chebula Retz. in Hyperuricemia

Abstract

Background: Hyperuricemia (HUA), a common metabolic disorder associated with gout, renal dysfunction, and systemic inflammation, necessitates safer and more comprehensive therapeutic approaches. Traditional Tibetan medicine has a rich history of treating HUA. This study aimed to identify novel anti-hyperuricemic herb derived from traditional Tibetan medicine.

Methods: Traditional Tibetan medicine prescriptions for HUA were analyzed using data mining techniques, identifying T. chebula as a high-frequency herb. Its phytochemical composition was characterized by UPLC-QE-Orbitrap-MS. Hyperuricemic rat models were treated with T. chebula to assess its effects on serum uric acid (UA) levels, renal inflammation, intestinal barrier integrity, and gut microbiota composition. Molecular and histological analyses evaluated its impact on key biomarkers.

Results: Through data mining, we identified T. chebula as a promising candidate for HUA treatment. T. chebula demonstrated dose-dependent inhibition of xanthine oxidase (XOD) in vitro and significantly reduced serum UA levels and XOD activity in vivo. It restored gut barrier function by upregulating tight junction proteins (ZO-1, Occludin, Claudin-1) and reduced pro-inflammatory cytokines (IL-6, TNF-α). T. chebula improved renal function, reducing serum creatinine (Cre) and blood urea nitrogen (BUN) levels. Gut microbiota analysis revealed a favorable shift in microbial composition, with reductions in harmful bacteria (eg, Clostridium spp.) and increases in beneficial bacteria (eg, Roseburia). These effects aligned with the modulation of the gut-kidney axis.

Conclusion: This study highlights the multi-target therapeutic potential of T. chebula in HUA management. By regulating the gut-kidney axis, T. chebula alleviates systemic inflammation, enhances intestinal and renal health, and addresses critical aspects of HUA pathology. These findings underscore the value of integrating traditional medicine with modern scientific methodologies to develop innovative treatments.

Keywords: Terminalia chebula Retz.; data mining; hyperuricemia; intestinal flora; renal.

Graphical abstract

Figure 1

Data mining of Tibetan medicine prescriptions in the treatment of UA. (A) High-frequency Chinese medicines in prescriptions. (B) Herbs co-occurrence diagram. (C) Hierarchical cluster analysis of herbs. (D) The inhibitory activity of T. chebula on XOD in vitro.

Figure 2

Chemical composition analysis and identification of T. chebula. (A) Total ion chromatograms of T. chebula extract in positive mode. (B) Total ion chromatograms of T. chebula extract in negative mode. (C) The structure of the chemical composition identified in T. chebula..

Figure 3

The therapeutic effects of T. chebula on HUA rats. (A) Schematic experimental design for T. chebula treatment. (B) Body weight. (C) Serum UA. (D) Serum XOD activity. (E) Serum IL-6. (F) Serum TNF-α. Values are presented as mean ± SD (n = 6 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. **P< 0.05 vs Control group; ^#P < 0.05, ^##P < 0.05 vs Model group.

Figure 4

T. chebula protected renal function of hyperuricemic rats. (A) H&E staining and Masson staining of kidney tissue (blue denotes collagen fibers, bar = 50 µm). (B) Renal index. (C) Serum Cre. (D) Serum BUN. Values are presented as mean ± SD (n = 6 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. **P< 0.05 vs Control group; ^##P < 0.05 vs Model group.

Figure 5

T. chebula improved intestinal barrier integrity in hyperuricemic rats (A) H&E staining of gut (bar = 100 µm). (B) Serum DAO. (C) Serum D-Lac. (D) Serum LPS. Values are presented as mean ± SD (n = 6 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. **P< 0.05 vs Control group; ^##P < 0.05 vs Model group.

Figure 6

T. chebula improved tight junction proteins expression in intestinal. (A) ZO-1, Occludin, and Claudin-1 immunohistochemical staining in intestinal (bar = 50 µm). (B) Statistical analysis of the percentage of the ZO-1, Occludin, and Claudin-1 positively stained area. (C) ZO-1, Occludin, and Claudin-1 mRNA expression by RT-PCR. Values are presented as mean ± SD (n = 6 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. *P< 0.05, **P< 0.05 vs Control group; ^#P < 0.05, ^##P < 0.05 vs Model group.

Figure 7

The influence of T. chebula on the structure of intestinal flora in HUA rats. (A) Sob index. (B) Chao index. (C) Shannon index. (D) Simpson index. (E) The relative abundance of Firmicutes. (F) The relative abundance of Actinobacteriota. (G) The relative abundance of Desulfobacterota. (H) The relative abundance of Bacteroidota. Values are presented as mean ± SD (n = 4 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. *P< 0.05 Control group; ^#P < 0.05, ^##P < 0.05 vs Model group.

Figure 8

The influence of T. chebula on the species composition of intestinal flora in HUA rats at both the genus and phylum levels. (A) Percent of community abundance on Phylum level. (B) Percent of community abundance on Genus level. Values are presented as mean ± SD (n = 4 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test.

Figure 9

Changes of key gut microbiota among groups. (A) Spearman correlation analysis between intestinal flora and HUA index. (B) The relative abundance of Clostridium_innocuum_group. (C) The relative abundance of Erysipelatoclostridium. (D) The relative abundance of UBA1819. (E) The relative abundance of Subdoligranulum. (F) The relative abundance of Clostridium_sensu_stricto_1. (G) The relative abundance of DNF00809. (H) The relative abundance of Monoglobus. (I) The relative abundance of Roseburia. Values are presented as mean ± SD (n = 4 per group). Statistical significance was assessed using one-way ANOVA followed by Tukey’s HSD test. *P< 0.05, **P< 0.05 vs Control group; ^#P < 0.05, ^##P < 0.05 vs Model group.