Gut microbiota-derived short-chain fatty acids and kidney diseases

Abstract

Gut microbiota and its metabolites play pivotal roles in host physiology and pathology. Short-chain fatty acids (SCFAs), as a group of metabolites, exert positive regulatory effects on energy metabolism, hormone secretion, immune inflammation, hypertension, and cancer. The functions of SCFAs are related to their activation of transmembrane G protein-coupled receptors and their inhibition of histone acetylation. Though controversial, growing evidence suggests that SCFAs, which regulate inflammation, oxidative stress, and fibrosis, have been involved in kidney disease through the activation of the gut-kidney axis; however, the molecular relationship among gut microbiota-derived metabolites, signaling pathways, and kidney disease remains to be elucidated. This review will provide an overview of the physiology and functions of SCFAs in kidney disease.

Keywords: gut microbiome; gut–kidney axis; kidney diseases; short-chain fatty acids.

Figure 1

Short-chain fatty acids to host appetite and metabolism control. Short-chain fatty acids (SCFAs) produced via microbiota fermentation of non-digestible dietary fibers or endogenous substrates can be used as fuel for colonocytes and stimulate intestinal gluconeogenesis, which improves glucose tolerance. Moreover, SCFAs can stimulate enteroendocrine L cells to release anorexigenic hormones PYY and GLP-1. These hormones promote satiety and suppress appetite which may promote weight loss. GLP-1 increases the production of insulin and decreases the production of glucagon in the pancreas, which then increases the uptake of glucose in muscle and adipose tissues. SCFAs can also decrease fatty acid synthesis and promote fatty acid oxidation in the liver. In adipose tissue, SCFAs can increase adipogenesis and inhibit lipolysis, thereby decreasing free fatty acids. Meanwhile, SCFAs can promote the secretion of leptin that suppresses appetite. Abbreviations: GLP-1, glucagon-like peptide 1; GPCRs, G protein-coupled receptors; HDAC, histone acetylation; PYY, peptide YY.

Figure 2

Regulation of short-chain fatty acids to host inflammation and immune. SCFAs can stimulate intestinal epithelial cells to release Muc2, which enhance the gut barrier function and heighten the response to pathogens and commensal bacteria. Moreover, SCFAs can reduce the recruitment of neutrophils under certain condition, with an increase in the levels of TGF-β, IL-10 and a decrease in the levels of IL-6, IL-1β, NO, and TNF-α to inhibit inflammation. Meanwhile, SCFAs promote T-cell production of IL-10 and Treg to prevent inflammatory responses. On the other hand, SCFAs act on DCs to limit the expression of T cell-activating molecules such as MHC II molecules and costimulatory molecules, leading to the generation of tolerogenic T cells rather than inflammatory T cells. The tolerogenic effect of SCFAs on DCs can lower inflammatory responses. However, the direct effect of SCFAs on T cells enhances the generation of Th1 and Th17 cells to boost immunity to fight pathogens, which means that activation of SCFAs for immune cells and epithelial cells may increase inflammatory responses, if not properly regulated. Abbreviations: DCs, dendritic cells; FAs, short-chain fatty acids; GPCRs, G protein-coupled receptors; HDAC, histone acetylation; NO, nitrous oxide; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.

Figure 3

Regulation of short-chain fatty acids to improve kidney function SCFAs can decrease the disruption of epithelial tight junction. After getting absorbed in blood, SCFAs can suppress oxidation stress by increasing superoxide dismutase, catalase, and reduced glutathione, and by decreasing nitric oxide (NO) and reactive oxygen species (ROS), which can lead to the decline of renal fibrosis and amelioration of tubular damage. In addition, SCFAs can also inhibit apoptosis by promoting autophagy and suppressing inflammation by regulating immune system, thereby decreasing serum creatine as well as blood urea nitrogen to improve renal function. Regulation of SCFAs on blood pressure and plasma glucose may help to ameliorate renal function in chronic kidney diseases. However, SCFAs can also increase Th17 and Th1 cells to promote acetate- or C2-induced renal disease (C2RD) under certain condition, as the negative outcomes of SCFAs on kidney. Abbreviation: SCFAs, short-chain fatty acids.