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

Raphael J. F. Felizardo, Danilo C. de Almeida, Rafael L. Pereira, Ingrid K. M. Watanabe, Nayara T. S. Doimo, Willian R. Ribeiro, Marcos A. Cenedeze, Meire I. Hiyane, Mariane T. Amano, Tárcio T. Braga, Caroline M. Ferreira, Raphael B. Parmigiani, Vinicius Andrade-Oliveira, Rildo A. Volpini, Marco Aurélio R. Vinolo, Eliana Mariño, Remy Robert, Charles R. Mackay, Niels O. S. Camara

Research output: Contribution to journalArticleResearchpeer-review

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.?Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade-Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.
Original languageEnglish
Number of pages15
JournalFASEB Journal
Volume33
DOIs
Publication statusAccepted/In press - Nov 2019

Keywords

  • glomerulopathy
  • podocyte
  • ADR nephropathy
  • SCFA

Cite this

Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., ... Camara, N. O. S. (Accepted/In press). Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. FASEB Journal, 33. https://doi.org/10.1096/fj.201901080R
Felizardo, Raphael J. F. ; de Almeida, Danilo C. ; Pereira, Rafael L. ; Watanabe, Ingrid K. M. ; Doimo, Nayara T. S. ; Ribeiro, Willian R. ; Cenedeze, Marcos A. ; Hiyane, Meire I. ; Amano, Mariane T. ; Braga, Tárcio T. ; Ferreira, Caroline M. ; Parmigiani, Raphael B. ; Andrade-Oliveira, Vinicius ; Volpini, Rildo A. ; Vinolo, Marco Aurélio R. ; Mariño, Eliana ; Robert, Remy ; Mackay, Charles R. ; Camara, Niels O. S. / Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. In: FASEB Journal. 2019 ; Vol. 33.
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title = "Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms",
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.?Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade-Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mari{\~n}o, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.",
keywords = "glomerulopathy, podocyte, ADR nephropathy, SCFA",
author = "Felizardo, {Raphael J. F.} and {de Almeida}, {Danilo C.} and Pereira, {Rafael L.} and Watanabe, {Ingrid K. M.} and Doimo, {Nayara T. S.} and Ribeiro, {Willian R.} and Cenedeze, {Marcos A.} and Hiyane, {Meire I.} and Amano, {Mariane T.} and Braga, {T{\'a}rcio T.} and Ferreira, {Caroline M.} and Parmigiani, {Raphael B.} and Vinicius Andrade-Oliveira and Volpini, {Rildo A.} and Vinolo, {Marco Aur{\'e}lio R.} and Eliana Mari{\~n}o and Remy Robert and Mackay, {Charles R.} and Camara, {Niels O. S.}",
year = "2019",
month = "11",
doi = "10.1096/fj.201901080R",
language = "English",
volume = "33",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "Federation of American Society for Experimental Biology",

}

Felizardo, RJF, de Almeida, DC, Pereira, RL, Watanabe, IKM, Doimo, NTS, Ribeiro, WR, Cenedeze, MA, Hiyane, MI, Amano, MT, Braga, TT, Ferreira, CM, Parmigiani, RB, Andrade-Oliveira, V, Volpini, RA, Vinolo, MAR, Mariño, E, Robert, R, Mackay, CR & Camara, NOS 2019, 'Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms', FASEB Journal, vol. 33. https://doi.org/10.1096/fj.201901080R

Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. / Felizardo, Raphael J. F.; de Almeida, Danilo C.; Pereira, Rafael L.; Watanabe, Ingrid K. M.; Doimo, Nayara T. S.; Ribeiro, Willian R.; Cenedeze, Marcos A.; Hiyane, Meire I.; Amano, Mariane T.; Braga, Tárcio T.; Ferreira, Caroline M.; Parmigiani, Raphael B.; Andrade-Oliveira, Vinicius; Volpini, Rildo A.; Vinolo, Marco Aurélio R.; Mariño, Eliana; Robert, Remy; Mackay, Charles R.; Camara, Niels O. S.

In: FASEB Journal, Vol. 33, 11.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms

AU - Felizardo, Raphael J. F.

AU - de Almeida, Danilo C.

AU - Pereira, Rafael L.

AU - Watanabe, Ingrid K. M.

AU - Doimo, Nayara T. S.

AU - Ribeiro, Willian R.

AU - Cenedeze, Marcos A.

AU - Hiyane, Meire I.

AU - Amano, Mariane T.

AU - Braga, Tárcio T.

AU - Ferreira, Caroline M.

AU - Parmigiani, Raphael B.

AU - Andrade-Oliveira, Vinicius

AU - Volpini, Rildo A.

AU - Vinolo, Marco Aurélio R.

AU - Mariño, Eliana

AU - Robert, Remy

AU - Mackay, Charles R.

AU - Camara, Niels O. S.

PY - 2019/11

Y1 - 2019/11

N2 - 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.?Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade-Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.

AB - 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.?Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade-Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.

KW - glomerulopathy

KW - podocyte

KW - ADR nephropathy

KW - SCFA

U2 - 10.1096/fj.201901080R

DO - 10.1096/fj.201901080R

M3 - Article

VL - 33

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

ER -