The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) remains the leading cause of the end-stage renal disease and is a major burden on the healthcare system. The current understanding of the mechanisms responsible for the progression of DKD recognizes the involvement of oxidative stress, low-grade inflammation, and fibrosis. Several circulating metabolites that are the end products of the fermentation process, released by the gut microbiota, are known to be associated with systemic immune-inflammatory responses and kidney injury. This phenomenon has been recognized as the "gut-kidney axis." Butyrate is produced predominantly by gut microbiota fermentation of dietary fiber and undigested carbohydrates. In addition to its important role as a fuel for colonic epithelial cells, butyrate has been demonstrated to ameliorate obesity, diabetes, and kidney diseases via G-protein coupled receptors (GPCRs). It also acts as an epigenetic regulator by inhibiting histone deacetylase (HDAC), up-regulation of miRNAs, or induction of the histone butyrylation and autophagy processes. This review aims to outline the existing literature on the treatment of DKD by butyrate in animal models and cell culture experiments, and to explore the protective effects of butyrate on DKD and the underlying molecular mechanism.

Keywords: butyrate; diabetic kidney disease; epigenetics; immune; inflammation.

Figure 1

Origin, Production, Transport, Effects, and Mechanism of Butyrate. Butyrate is produced from dietary fiber by bacterial fermentation through two metabolic pathways: (1) butyryl-CoA is transformed to butyrate via butyrate kinase and (2) the CoA moiety of butyryl-CoA is transferred to butyrate and acetyl-CoA via butyryl-CoA: acetate CoA-transferase. The two most important butyrate-producing bacteria are Faecalibacterium prausnitzii and Eubacterium rectale/Roseburia spp. Butyrate is absorbed by colonic epithelial cells as energy sources mainly through MCTs and SMCTs. About three of the de-orphanized GPCRs (GPR41, GPR43, and GPR109A) have been identified as butyrate receptors in the human intestinal mucosa, renal intrinsic cells, immune cells, pancreatic β cells, and adipose tissues. Butyrate act as epigenetic regulators by the inhibition of HDAC, the upregulation of miRNAs, or induction of the histone butyrylation and autophagy. Although controversial, most studies believe that exogenous or endogenous butyrate improves inhibits oxidative stress, and ameliorates diabetic inflammation. GPCRs, G-protein coupled receptors; MCTs, monocarboxylate transporters; SMCTs, sodium-coupled monocarboxylate transporters; CoA, coenzyme A; HDAC, histone deacetylase; miRNAs, microRNAs.

Figure 2

Overview of the molecular mechanism of butyrate in the prevention and treatment of DKD. The pathological process of DKD involves persistent HG-induced oxidative stress, immune system disorders, and inflammation (red arrows). Endogenous or exogenous butyrate (green arrows) inhibits the activity of HDAC, opens the structure of chromatin, and facilitates the expression of the Nrf2 gene, which may enter the nucleus and upregulate the downstream targets HO1 and NQO1 and then inhibits oxidative stress and inflammation in DKD. Meanwhile, GPR43 and GPR109A are important receptors of butyrate for renal protection, and the interaction between β-arrestin-2 and I-κBα is induced by butyrate via GPR43, suggesting that butyrate-mediated GPR43-β-arrestin-2 signaling may be a novel and promising target for DKD (green arrows). Moreover, it has been found that butyrate reverses HG-induced the downregulation of miR-7a-5p and inhibits the expression of P311, followed by the inhabitation of the kidney fibrosis of DKD (green arrows) and activated autophagy via the AMPK/mTOR pathway to delay the DKD progression. Notably, butyl-CoA, a metabolite of butyrate, is the substrate of histone butyrylation modification, irrespective of whether butyrate or sodium butyrate improves DKD renal injury through histone butyrylation pathway or the cross-talk of the histone post-translational modifications has not been reported. Nrf2, Nuclear factor erythroid 2-related factor 2; HO1, heme oxygenase 1; NQO1, NAD(P)H dehydrogenase quinone 1; HDAC, histone deacetylase; HAT, histone acetyltransferase; UTR, untranslated region; NF-κB, nuclear factor kappa B; Kbu, histone lysine butyrylation; Kac, histone lysine acetylation; ACSS2, acetyl-CoA synthetase 2; p300, a histone acetylation transferase that mediates butyrylation; P311, an RNA-binding protein, which could stimulate fibrosis; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin.