Fiber Derived Microbial Metabolites Prevent Acute Kidney Injury Through G-Protein Coupled Receptors and HDAC Inhibition

Abstract

Short-chain fatty acids (SCFA) derived from gut microbial fermentation of fiber have been shown to exert anti-inflammatory and immune-modulatory properties in acute kidney injury (AKI). However the direct mechanistic link between SCFAs, diet and the gut microbiome is yet to be established. Using the murine model of folic-acid nephropathy (FAN), we examined the effect of dietary fiber on development of AKI (day 2) and subsequent chronic kidney disease (CKD) (day 28). FAN was induced in wild-type and knockout mice lacking G protein–coupled receptors GPR41, GPR43, or GPR109A. Mice were randomized to high-fiber or normal-chow diets, or SCFAs in drinking water. We used 16S rRNA sequencing to assess the gut microbiome and 1H-NMR spectroscopy for metabolic profiles. Mice fed high-fiber were partially protected against development of AKI and subsequent CKD, exhibiting better kidney function throughout, less tubular injury at day 2 and less interstitial fibrosis and chronic inflammation at day 28 vs controls. Fiber modified the gut microbiome and alleviated dysbiosis induced by AKI, promoting expansion of SCFA-producing bacteria Bifidobacterium and Prevotella, which increased fecal and serum SCFA concentrations. SCFA treatment achieved similar protection, but not in the absence of GPR41 or GPR109A. Histone deacetylase activity (HDAC) was inhibited in kidneys of high-fiber fed mice. We conclude that dietary manipulation of the gut microbiome protects against AKI and subsequent CKD, mediated by HDAC inhibition and activation of GPR41 and GPR109A by SCFAs. This study highlights the potential of the gut microbiome as a modifiable target in the prevention of AKI.

Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

“…In a murine model of cisplatin-induced AKI, significant fatty acid oxidation dysfunction and extensive lipid deposition in the mice with AKI were found (9). In addition, histone deacetylase activity (HDAC) was inhibited in kidneys of high-fiber fed mice, and dietary manipulation of the gut microbiome could protect against AKI and subsequent CKD, mediated by HDAC inhibition and activation of two G proteincoupled receptors GPR41 and GPR109A by Short-chain fatty acids (10). Arachidonic acid can be converted into prostaglandin E 2 by the cascade catalysis of cyclooxygenase (COX)-1 and -2 and prostaglandin E synthase (PGES).…”

Quantitative Increase in Short-Chain Fatty Acids, Especially Butyrate Protects Kidney from Ischemia/Reperfusion Injury

“… 22 Dietary manipulation of the gut microbiome protects against AKI, mediated by HDAC inhibition and SCFAs. 23 Yamamura et al 24 founded serum SCFAs were positively associated with fecal SCFAs even after adjusting for age and sex. Furthermore, fecal acetate was likely to be positively associated with serum acetate.…”

Gut Microbiota Mediates the Protective Effects of Traditional Chinese Medicine Formula Qiong-Yu-Gao against Cisplatin-Induced Acute Kidney Injury

“…Gut microbiota-derived metabolites are key mediators between the microbiota and the kidney ( 34 ). SCFAs, the products of bacterial fermentation from dietary fibers, are recognized as signaling molecules which could affect the renal physiology or even ameliorate kidney injury by acting as HDAC inhibitors ( 35 – 38 ). For example, acetic acid was shown to ameliorate sepsis-induced AKI via attenuation of HDAC activity ( 36 ).…”