The immunomodulatory metabolite butyrate ameliorates renal fibrosis by restoring gut barrier integrity and suppressing the TGF-β1/Smad3 pathway.

Abstract

Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, with the gut-kidney axis implicated in its pathophysiology. This study investigated the role of the gut microbiota-derived metabolite, butyrate, in renal fibrosis. We analyzed the gut microbiota in CKD patients and a unilateral ureteral obstruction (UUO) mouse model, performed targeted metabolomics, and assessed gut barrier function. The therapeutic effects of oral sodium butyrate were evaluated in vivo, while direct mechanisms were explored in vitro using TGF-β1-stimulated HK-2 renal tubular cells. We found that both CKD patients and UUO mice exhibited gut dysbiosis with a depletion of the butyrate-producer Faecalibacterium prausnitzii, leading to systemic butyrate deficiency and compromised gut barrier integrity. Oral sodium butyrate administration significantly ameliorated renal fibrosis, improved renal injury, and restored gut barrier integrity in UUO mice. In vitro, butyrate attenuated TGF-β1-induced fibrotic responses by inhibiting Smad3 phosphorylation, an effect mimicked by a histone deacetylase (HDAC) inhibitor. In conclusion, gut dysbiosis-driven butyrate deficiency contributes to renal fibrosis progression. Supplementation with butyrate represents a promising therapeutic strategy, acting dually by restoring gut barrier integrity and directly suppressing the renal pro-fibrotic TGF-β1/Smad3 pathway via its HDAC inhibitory function.