SUN-040 MANIPULATING THE GUT MICROBIOME BY DIETARY FIBRE TO PREVENT FOLIC ACID INDUCED KIDNEY DISEASE

Abstract

Gut dysbiosis has been associated with inflammation and mortality in chronic kidney disease. Bacterial fermentation of dietary fibre produces short-chain fatty acids (SCFAs) that regulate inflammation and immunity. Here we evaluated the effect of dietary fibre or SCFA supplementation on development of AKI and subsequent fibrosis in a murine model of folic acid nephropathy (FAN). FAN was induced in C57BL/6 (WT) and GRP43-/- mice by intraperitoneal folic acid injection. Mice were fed a high fibre (HF) diet, normal chow (NF), or supplemented with oral SCFAs (150mM sodium acetate (SA), 150mM propionate (SP), or 100mM butyrate (SB) in drinking water). Diets and SCFA treatment commenced 2 weeks prior to injection and continued throughout the duration of all experiments. Samples were collected on day 2 and 28 after FAN induction. Gut microbiota composition was assessed by 16S rRNA sequencing of faecal DNA. Metabolic profiling of serum and faeces was performed using 1H NMR spectroscopy. HF diet protected against FAN, with improvement of renal function and histological parameters versus NF diet, as evidenced by lower serum creatinine (day2: 5.7±3.0 vs 69.3±54.2; day28: 6.6±2.2 vs 12.3±4.4, P<0.0001), reduced tubular injury (P<0.05) and less cellular infiltration at days 2 and 28. FAN caused intestinal dysbiosis, while gut microbiota balance was restored by HF diet with increased relative abundance of phylum Actinobacteria at the expense of Firmicutes, and expansion of SCFA producing Bifidobacterium (p<0.0001) and Prevotella (p<0.0005) genera compared to FAN controls on NF diet. This change in microbial ecology correlated with a significant increase in faecal SCFAs (p<0.0005) and serum acetate (1.00±0.18vs0.53±0.15, p<0.0001) relative to NF fed controls. Supplementation with SCFAs in FAN achieved similar degrees of protection from loss of renal function (P<0.0001) and histological injury at days 2 and 28, and interstitial fibrosis at day 28. mRNA expression of the innate immune receptor (TLR2), proinflammatory cytokines (IL-6, TNFα) and chemokine (MIP2) at day 2 and 28, and fibrotic genes (TGFb, MMP2 & MMP9 ) at day 28 were downregulated in HF diet and SCFA mice compared with NF diet. SA supplementation was equally effective in GPR43+/+ and GPR43-/- FAN mice. Kidney tissue histone deacetylase (HDAC) activity was inhibited in HF FAN mice (P<0.01) at day 2, with significantly reduced mRNA expression of HDAC4 (P<0.005) and HDAC10 (P<0.01) compared to NF FAN mice. HF diet prevented development of folic acid induced acute and chronic kidney injury through enrichment of SCFA producing gut bacteria and increased SCFA production that inhibited HDAC activity. The protective effects of dietary modulation of the gut microbiota identify this as a simple, potentially translatable therapy for AKI and CKD.