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

Yunzi Liu,Yik W Loh,Julian Singer,Huiling Wu,Weiping Zhu,Weiming Wang,Laurence Macia,Charles R Mackay,Yan J Li,Steven J Chadban

doi:10.3389/fcell.2021.648639

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.

Highlights

Acute kidney injury (AKI) occurs in approximately 10–15% of hospitalized patients (Al-Jaghbeer et al, 2018), with substantial impacts on morbidity, mortality and cost
high fiber (HF) fed mice were protected from FA-induced acute kidney injury (AKI), displaying significantly lower SCr (5.7 ± 3.0 vs 69.3 ± 54.2 μmol/L, P < 0.01) and BUN (11.7 ± 5.5 vs 50.1 ± 27.2 mmol/L, P < 0.001) compared to those fed normal chow (NC) at day 2, with no difference compared to non-folic-acid nephropathy (FAN) controls (Figures 1A,B)
We examined the expression of innate immune receptors (TLR2 and TLR4), inflammasome components (NLRP3 and ASC) and downstream inflammatory molecules in the kidney at day 2 post FA-injection by real-time PCR. mRNA expression of TLR2 and TLR4, inflammasome components (NLRP3 and ASC) and downstream pro-inflammatory cytokines (IL6 and TNFα) and chemokines (CCL2 and CXCL2) were significantly upregulated in the kidneys of NC-fed mice at day 2 compared to non-FAN controls

Summary

Introduction

Acute kidney injury (AKI) occurs in approximately 10–15% of hospitalized patients (Al-Jaghbeer et al, 2018), with substantial impacts on morbidity, mortality and cost. A variety of pathogenic stimuli in AKI converge on a common cascade of injuryinduced events, initiating innate immune responses via damageassociated molecular patterns (DAMPs) which activate Toll like receptors (TLRs) and the NLRP3 inflammasome, forming a vicious cycle of cell death and inflammation driven by proinflammatory cytokines, chemokines, and inflammatory cells (Rabb et al, 2016). Characterized initially by an exacerbated innate inflammatory response causing endothelial dysfunction, altered microcirculation, and tubular injury, innate immune cell-derived cytokines facilitate engagement and activation of adaptive immunity. In addition to being the main energy source for colonocytes, SCFAs mediate a range of extra-intestinal effects and have the capability to regulate host physiological functions and impact development of immune and inflammatory responses both locally and at distant sites after entering the circulation via active transport mediated by monocarboxylate transporters (Stumpff, 2018). SCFAs exert their effects through binding to metabolite-sensing G-protein-coupled receptors (GPR41, GPR43, and GPR109A) (Tan et al, 2014) or epigenetically via histone deacetylase (HDAC) modulation (Tan et al, 2014)

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