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., 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. FASEB J. 33, 11894–11908 (2019). http://www.fasebj.org

Specific alterations in gut microbiota in patients with chronic kidney disease: an updated systematic review

“…Uropathogenic Escherichia coli, the leading pathogen of urinary tract infections (UTIs) or hemolytic uremic syndrome, contributes to kidney injury through alphahemolysin or Shiga toxin [51], and a 1% relative gut abundance of Escherichia is an independent risk factor for Escherichia bacteriuria and UTI [52]. Depletion of the genera Prevotella, Roseburia, Faecalibacterium, and Coprococcus may result in less production of butyrate [22] which is known to have renal protection effects [53]. Genus Bifidobacterium was depleted in CKD patients, and supplementing Bifidobacterium longum reduced serum creatinine, urea nitrogen, and PCS in CKD models [54].…”

Dietary resistant starch preserved through mild extrusion of grain alters fecal microbiome metabolism of dietary macronutrients while increasing immunoglobulin A in the cat

“…There was a greater effect as time progressed perhaps indicating adaptation to RS consumption. On a molar basis, RS is a particularly efficient precursor of butyrate production [ 59 ] and has been shown to ameliorate proteinuria in a mouse model of CKD [ 60 ], aspects that may be beneficial to diabetic cats, which have a paucity of butyrate-producing bacteria in their microbiome [ 61 ]. Increased fecal butyrate in the HRS diet group indicates the potential for dietary RS to exert a benefit in cats.…”

Gut Microbiota as Important Mediator Between Diet and DNA Methylation and Histone Modifications in the Host

“…In fact, a diet rich in acetate and butyrate protected mice against T1D and this SCFA-induced protection happened via changes in gut/immune regulation, expanding T reg cells and reducing pathogenic B cells, CD4+, and CD8+ T cells [107]. Butyrate impairs progression of nephropathy through, at least in part, protective effects on podocytes mediated by DNA methylation and Histone Deacetylases (HDACs) -dependent mechanisms, involving genes essential for podocyte function, as well as activation of GPR109a [108]. Donohoe et al demonstrated that, in gnotobiotic mice colonized with wild-type or mutant strains of butyrate-producing Butyrivibrio fibrisolvens, a fiber-rich diet induced strong tumor-suppressive effects in a microbiota-and butyrate-dependent manner.…”