Gut symbiont-derived ursodeoxycholic acid promotes fatty acid oxidation to protect against renal ischemia-reperfusion injury.

Abstract

Renal ischemia-reperfusion injury (IRI) is a common complication of renal surgery that currently lacks effective prevention or treatment strategies. The gut microbiota and their metabolites are closely associated with kidney injury. However, the exact mechanisms underlying this link are unclear. Here, we find that renal IRI reduces ursodeoxycholic acid (UDCA), a metabolite of Eubacterium limosum (E. limosum), in mice cecal content and serum. Conversely, supplementation with either E. limosum or UDCA prevents these mice from IRI. Mechanistically, UDCA directly binds and activates peroxisome proliferator-activated receptor-gamma (PPARγ) to increase fatty acid oxidation, inducing ATP production and reducing lipid accumulation in proximal tubular epithelial cells, ultimately protecting the kidney against IRI. Importantly, while renal IRI in patients markedly lowers their serum UDCA, patients with higher pre-IRI UDCA or E. limosum level develop less severe IRI. Collectively, our findings highlight the rationale of using UDCA and E. limosum for the prevention or treatment of renal IRI.