Gut symbiont-derived ursodeoxycholic acid promotes fatty acid oxidation to protect against renal ischemia-reperfusion injury
Ming Xie, Jun Zheng, Yu Yao, Qishen Yang, Zhipeng Zhou, Jingwen Xue et al. · 2025 · 7 citationsRead the paper
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.
What the full text shows
Working prototype- UDCA binds directly to human recombinant PPARγ protein with strong affinity. — Kd = 1.82 × 10⁻⁸ M (In vitro SPR analysis)
- Pretreatment with E. limosum or UDCA reduces renal injury markers (SCr, BUN, NGAL) and tubular apoptosis. (Mouse model of renal ischemia-reperfusion injury (IRI))
- UDCA protects HK-2 cells from hypoxia/reoxygenation (H/R) injury by increasing oxygen consumption rate (OCR) and ATP production. (In vitro human proximal tubular cell line (HK-2))
- Higher preoperative serum UDCA and fecal E. limosum levels correlate with less severe renal injury post-surgery. (Cohort of 41 patients with renal IRI)
- UDCA-mediated protection is abolished by PPARγ inhibition or knockdown. (In vivo (T0070907 inhibitor) and in vitro (sh-PPARγ))
- Renal IRI reduces the relative abundance of E. limosum and serum UDCA levels. (Mice and human patients)
- Setup
- 41 human patients, mouse models (SPF, GF, and ABX-treated), and human HK-2 cell lines.
- How
- The study used 16S rRNA sequencing and metabolomics to identify E. limosum and UDCA, followed by mouse IRI models and HK-2 cell H/R models. Molecular docking, SPR, and PPARγ inhibition/knockdown were used to determine the UDCA-PPARγ-FAO mechanism.
- Limitations
- Lack of off-clamp partial nephrectomy control groups in the human cohort. · Potential contribution of other UDCA-producing bacteria (e.g., Ruminococcus, Clostridium) not fully excluded.
Summarized by Gemma 4 from the open-access full text · 8 Oct 2026. Read it