Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid-Mediated Activation of G Protein-Coupled Receptors GPR43 and GPR109A

• Published in: Journal of the American Society of Nephrology 2020-06, Vol.31 (6), p.1267-1281
• Main Authors: Li, Yan Jun, Chen, Xiaochen, Kwan, Tony K, Loh, Yik Wen, Singer, Julian, Liu, Yunzi, Ma, Jin, Tan, Jian, Macia, Laurence, Mackay, Charles R, Chadban, Steven J, Wu, Huiling
• Format: Article
• Language: English
• Subjects: Albuminuria - prevention & control; Animals; Basic Research; Diabetes Mellitus, Experimental - complications; Diabetic Nephropathies - prevention & control; Dietary Fiber - administration & dosage; Dysbiosis; Fatty Acids, Volatile - physiology; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled - physiology; Streptozocin
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2019101029

Studies have reported "dysbiotic" changes to gut microbiota, such as depletion of gut bacteria that produce short-chain fatty acids (SCFAs) through gut fermentation of fiber, in CKD and diabetes. Dietary fiber is associated with decreased inflammation and mortality in CKD, and SCFAs have been proposed to mediate this effect. To explore dietary fiber's effect on development of experimental diabetic nephropathy, we used streptozotocin to induce diabetes in wild-type C57BL/6 and knockout mice lacking the genes encoding G protein-coupled receptors GPR43 or GPR109A. Diabetic mice were randomized to high-fiber, normal chow, or zero-fiber diets, or SCFAs in drinking water. We used proton nuclear magnetic resonance spectroscopy for metabolic profiling and 16S ribosomal RNA sequencing to assess the gut microbiome. Diabetic mice fed a high-fiber diet were significantly less likely to develop diabetic nephropathy, exhibiting less albuminuria, glomerular hypertrophy, podocyte injury, and interstitial fibrosis compared with diabetic controls fed normal chow or a zero-fiber diet. Fiber beneficially reshaped gut microbial ecology and improved dysbiosis, promoting expansion of SCFA-producing bacteria of the genera and , which increased fecal and systemic SCFA concentrations. Fiber reduced expression of genes encoding inflammatory cytokines, chemokines, and fibrosis-promoting proteins in diabetic kidneys. SCFA-treated diabetic mice were protected from nephropathy, but not in the absence of GPR43 or GPR109A. , SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions. Dietary fiber protects against diabetic nephropathy through modulation of the gut microbiota, enrichment of SCFA-producing bacteria, and increased SCFA production. GPR43 and GPR109A are critical to SCFA-mediated protection against this condition. Interventions targeting the gut microbiota warrant further investigation as a novel renoprotective therapy in diabetic nephropathy.