Abstract: FR-PO154
Dietary Fiber-Derived Microbial Metabolites Prevent Acute and Chronic Kidney Ischemia-Reperfusion Injury (IRI) through G Protein-Coupled Receptor GPR43
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Gilbert, Alexander, The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
- Chitsaz, Anita, The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
- Zhu, Guozhen, The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
- Singer, Julian J., The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
- Chadban, Steven J., The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
- Wu, Huiling, The University of Sydney Charles Perkins Centre, Sydney, New South Wales, Australia
Background
Short-chain fatty acids (SCFAs) derived from gut microbial fermentation of fiber exert anti-inflammatory effects and have been found to attenuate the development of inflammatory diseases. We investigated the impact of dietary fiber on kidney IRI in a murine model.
Methods
C57BL/6 mice were fed a high fiber diet (HFD) and controls received normal chow (NC). Kidney ischemia was induced for 22 min followed by reperfusion. Samples were collected 24 hours and 28 days after reperfusion. Kidney histology and gene expression was examined. Stool was assessed by 16S rRNA sequencing (gut microbiome) and 1H NMR spectroscopy (SCFAs).
Results
HFD mice were protected against acute and chronic kidney IRI, with lower serum creatinine, less tubular damage, and tubulo-interstitial infiltrate accumulation compared with NC controls (p<0.05). HFD mice had less proteinuria and interstitial fibrosis at 28 days. HFD significantly reduced pro-inflammatory cytokines, chemokines and fibrosis-related gene expression within IRI-kidney compared with NC controls (p<0.05-0.01). Kidney IRI-associated dysbiosis and significant expansion of pathobionts was evident in NC-IRI mice compared to NC sham-operated controls (p<0.05-0.001), however this was attenuated in HFD-IRI mice (p<0.05-0.001). HFD-IRI mice also exhibited significant expansion of SCFA-producing bacteria compared to NC controls. Pearson correlation analyses showed that at a family level, Enterobacteriaceae and Clostridia_vadinBB60_group were most strongly associated with kidney injury. In contrast, SCFA producers were associated with better kidney histology and function. Consistent with changes in the gut microbiome, HFD mice had significantly higher serum acetate and fecal SCFA concentrations. HFD provided significantly less protection in GPR43-/- mice compared to wild type HFD-IRI-mice, though HFD remained protective in GPR109A-/- mice.
Conclusion
Dietary fiber protects against acute and chronic kidney IRI through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production, ameliorating IRI-associated dysbiosis. This protection is partially mediated through GPR43.
Funding
- Government Support – Non-U.S.