Yan Jun Li1,2, Xiaochen Chen3, Tony K Kwan3, Yik Wen Loh3, Julian Singer3,2, Yunzi Liu3, Jin Ma1, Jian Tan4,5, Laurence Macia4,5, Charles R Mackay6, Steven J Chadban3,2,7, Huiling Wu1,2,7. 1. Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia huiling.wu@sydney.edu.au. 2. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia. 3. Kidney Node Laboratory, The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia. 4. Nutritional Immunometabolism Laboratory, The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia. 5. School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia. 6. Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia. 7. Renal Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 Prevotella and Bifidobacterium, 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. In vitro, SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. Diabeticmice 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. RESULTS:Diabeticmice 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 Prevotella and Bifidobacterium, 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 diabeticmice were protected from nephropathy, but not in the absence of GPR43 or GPR109A. In vitro, SCFAs modulated inflammation in renal tubular cells and podocytes under hyperglycemic conditions. CONCLUSIONS: 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.
Authors: Andrew J Brown; Susan M Goldsworthy; Ashley A Barnes; Michelle M Eilert; Lili Tcheang; Dion Daniels; Alison I Muir; Mark J Wigglesworth; Ian Kinghorn; Neil J Fraser; Nicholas B Pike; Jay C Strum; Klaudia M Steplewski; Paul R Murdock; Julie C Holder; Fiona H Marshall; Philip G Szekeres; Shelagh Wilson; Diane M Ignar; Steve M Foord; Alan Wise; Simon J Dowell Journal: J Biol Chem Date: 2002-12-19 Impact factor: 5.157
Authors: Anne Vrieze; Els Van Nood; Frits Holleman; Jarkko Salojärvi; Ruud S Kootte; Joep F W M Bartelsman; Geesje M Dallinga-Thie; Mariette T Ackermans; Mireille J Serlie; Raish Oozeer; Muriel Derrien; Anne Druesne; Johan E T Van Hylckama Vlieg; Vincent W Bloks; Albert K Groen; Hans G H J Heilig; Erwin G Zoetendal; Erik S Stroes; Willem M de Vos; Joost B L Hoekstra; Max Nieuwdorp Journal: Gastroenterology Date: 2012-06-20 Impact factor: 22.682
Authors: Vinicius Andrade-Oliveira; Mariane T Amano; Matheus Correa-Costa; Angela Castoldi; Raphael J F Felizardo; Danilo C de Almeida; Enio J Bassi; Pedro M Moraes-Vieira; Meire I Hiyane; Andrea C D Rodas; Jean P S Peron; Cristhiane F Aguiar; Marlene A Reis; Willian R Ribeiro; Claudete J Valduga; Rui Curi; Marco Aurelio Ramirez Vinolo; Caroline M Ferreira; Niels Olsen Saraiva Câmara Journal: J Am Soc Nephrol Date: 2015-01-14 Impact factor: 10.121
Authors: Nosratola D Vaziri; Jakk Wong; Madeleine Pahl; Yvette M Piceno; Jun Yuan; Todd Z DeSantis; Zhenmin Ni; Tien-Hung Nguyen; Gary L Andersen Journal: Kidney Int Date: 2012-09-19 Impact factor: 10.612
Authors: Kendle M Maslowski; Angelica T Vieira; Aylwin Ng; Jan Kranich; Frederic Sierro; Di Yu; Heidi C Schilter; Michael S Rolph; Fabienne Mackay; David Artis; Ramnik J Xavier; Mauro M Teixeira; Charles R Mackay Journal: Nature Date: 2009-10-29 Impact factor: 49.962
Authors: June Zhou; Roy J Martin; Richard T Tulley; Anne M Raggio; Kathleen L McCutcheon; Li Shen; Samuel Colby Danna; Sasmita Tripathy; Maren Hegsted; Michael J Keenan Journal: Am J Physiol Endocrinol Metab Date: 2008-09-16 Impact factor: 4.310
Authors: Gwen Tolhurst; Helen Heffron; Yu Shan Lam; Helen E Parker; Abdella M Habib; Eleftheria Diakogiannaki; Jennifer Cameron; Johannes Grosse; Frank Reimann; Fiona M Gribble Journal: Diabetes Date: 2011-12-21 Impact factor: 9.461
Authors: Premraj Rajkumar; William H Aisenberg; Omar W Acres; Ryan J Protzko; Jennifer L Pluznick Journal: PLoS One Date: 2014-10-23 Impact factor: 3.240