A microbiota-tryptophol-AhR axis mediates the gut-kidney protective effects of Hushen Tongfengtai Granules in hyperuricemic nephropathy.

BACKGROUND

Hyperuricemia (HUA) may result in hyperuricemic nephropathy (HN), and gut dysbiosis with barrier dysfunction can worsen disease progression. Hushen Tongfengtai granules (HSTFT), a traditional Chinese herbal prescription, have been used clinically to mitigate HUA and related renal injury. However, the mechanisms behind their effects remain to be explored.

OBJECTIVE

To find HSTFT to mitigate HN through mechanisms dependent on gut microbiota.

METHODS

Fecal metagenomics and UPLC-ESI-MS/MS metabolomics were employed to identify key microbial taxa and metabolites modulated by HSTFT. Antibiotic-treated mice were used to investigate the gut microbiota-dependent mechanisms of HSTFT. In vivo and in vitro experiments were further conducted to validate the ameliorative effects of HSTFT on gut dysbiosis and barrier dysfunction in HUA mice.

RESULTS

HSTFT could improve renal injury and intestinal barrier dysfunction in HUA. Fecal metagenomic analysis revealed enrichment of Bifidobacterium breve. Antibiotic depletion could abolish the therapeutic efficacy of HSTFT, while Bifidobacterium breve (B.breve) recolonization could restore intestinal and renal protection. Metabolomic analysis identified tryptophol as a key HSTFT-associated metabolite. Exogenous tryptophol (TOL) recapitulated the protective effects and may activate the aryl hydrocarbon receptor (AhR) pathway. The AhR antagonist CH223191 could inhibit the TOL/HSTFT-mediated protective effects on intestinal barrier integrity and renal function.

CONCLUSION

HSTFT could ameliorate HN by enhancing intestinal barrier integrity and renal protection, with the underlying mechanism involving upregulation of intestinal B.breve and its metabolite TOL via AhR pathway activation.