Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms

Author(s):Show less -

Felizardo, Raphael J. F. ^{[1, 2, 3]} ; de Almeida, Danilo C. ^{[1, 3]} ; Pereira, Rafael L. ^[4] ; Watanabe, Ingrid K. M. ^{[1, 3]} ; Doimo, Nayara T. S. ^[5] ; Ribeiro, Willian R. ^[6] ; Cenedeze, Marcos A. ^[1] ; Hiyane, Meire I. ^[3] ; Amano, Mariane T. ^{[3, 5]} ; Braga, Tarcio T. ^[3] ; Ferreira, Caroline M. ^[6] ; Parmigiani, Raphael B. ^[7] ; Andrade-Oliveira, Vinicius ^[3] ; Volpini, Rildo A. ^[8] ; Vinolo, Marco Aurelio R. ^[9] ; Marino, Eliana ^[2] ; Robert, Remy ^[2] ; Mackay, Charles R. ^[2] ; Camara, Niels O. S. ^{[1, 3]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Med, Nephrol Div, Sao Paulo - Brazil

^[2] Monash Univ, Dept Biochem & Mol Biol, Biodiscovery Inst, Clayton, Vic - Australia

^[3] Univ Sao Paulo, Fac Med, Inst Biomed Sci 4, Dept Immunol, Sao Paulo - Brazil

^[4] Univ Fed Parana, Dept Physiol, Curitiba, Parana - Brazil

^[5] Hosp Sirio Liban es, Ctr Mol Oncol, Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, Dept Pharmaceut Sci, Diadema - Brazil

^[7] Idengene Med Diagnost, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, LIM12, Sao Paulo - Brazil

^[9] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Campinas - Brazil

• Document type: Journal article
• Source: FASEB JOURNAL; v. 33, n. 11, p. 11894-11908, NOV 2019.
• Web of Science Citations: 0

Abstract

Butyrate is a short-chain fatty acid derived from the metabolism of indigestible carbohydrates by the gut microbiota. Butyrate contributes to gut homeostasis, but it may also control inflammatory responses and host physiology in other tissues. Butyrate inhibits histone deacetylases, thereby affecting gene transcription, and also signals through the metabolite-sensing G protein receptor (GPR)109a. We produced an mAb to mouse GPR109a and found high expression on podocytes in the kidney. Wild-type and Gpr109a(-/-) mice were induced to develop nephropathy by a single injection of Adriamycin and treated with sodium butyrate or high butyrate-releasing high-amylose maize starch diet. Butyrate improved proteinuria by preserving podocyte at glomerular basement membrane and attenuated glomerulosclerosis and tissue inflammation. This protective phenotype was associated with increased podocyte-related proteins and a normalized pattern of acetylation and methylation at promoter sites of genes essential for podocyte function. We found that GPR109a is expressed by podocytes, and the use of Gpr109a(-/-) mice showed that the protective effects of butyrate depended on GPR109a expression. A prebiotic diet that releases high amounts of butyrate also proved highly effective for protection against kidney disease. Butyrate and GPR109a play a role in the pathogenesis of kidney disease and provide one of the important molecular connections between diet, the gut microbiota, and kidney disease. (AU)

• FAPESP's process: 14/13135-4 - The role of metabolite-sensing receptors- (GPR41, GPR43 and GPR109A) and epigenetic pathways for the progression of nephropathy
• Grantee: Raphael Jose Ferreira Felizardo
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/15205-4 - Role of short chain fatty acids on experimental focal and segmental glomerulosclerosis
• Grantee: Raphael Jose Ferreira Felizardo
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/50410-8 - Effects of short-chain fatty acids produced by probiotic bacteria in the prophylaxis and treatment of allergic airway inflammation
• Grantee: Caroline Marcantonio Ferreira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants