SUN-303 DIETARY MANIPULATION OF THE GUT MICROBIOTA REDUCES DIABETIC KIDNEY INJURY IN MICE

Abstract

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) globally. High dietary fibre intake has been associated with decreased inflammation and mortality in CKD. Short-chain fatty acids (SCFA) derived from gut microbial fermentation of dietary fibre are thought to regulate gut and systemic inflammation. Here we evaluated the effect of dietary modification, or supplementation with the three main SCFAs (acetate, propionate, butyrate) on the development of DN in a mouse model of streptozotocin (STZ) induced diabetes. Diabetes was induced using a low dose STZ protocol in C57BL/6 mice. Three weeks after STZ injection, diabetic mice were switched to a zero-fibre (ZF) or high-fibre (HF) diet, whilst control diabetic mice remained on the normal diet. For mechanistic studies, two-weeks after STZ, groups of diabetic mice received daily intra-peritoneal injections of either sodium acetate (SA), propionate (SP), butyrate (SB) 200mg/kg or saline for 2 weeks, then switched to oral SCFAs (SA 150mM, SP 100mM, SB 50mM, or pH and sodium-matched water) in their drinking water for the duration of the study. Blood, urine and kidneys were collected after 12 weeks. All STZ-treated mice developed diabetes within two weeks. Diet altered the gut microbiome in diabetic mice, with significant preservation of diversity evident in HF compared to ZF mice. As compared to ZF and normal diets, HF fed mice had higher faecal SCFA levels (>2-fold, p<0.05) and serum acetate concentrations (>3-fold, p<0.001). HF fed mice were protected from DN, with a reduction in albuminuria of 50% (p<0.01), reduced kidney to body weight ratio (1.33 vs 2.4, p<0.0001), glomerular hypertrophy (22±17.5 vs 35.5±15.3 (x104 μm3), p<0.0001), glomerular cellularity (24.9±1.7 vs 36.6±1.7, p<0.0001), interstitial fibrosis (p<0.0001) and podocyte injury (p<0.0001) compared to diabetic controls on normal or ZF diets. Treatment of diabetic mice with SA, SP or SB achieved similar degrees of protection to the HF-diet, with less glomerular hypertrophy (p<0.01), podocyte injury (p<0.05), interstitial fibrosis (p<0.001) and interstitial macrophage accumulation (p<0.01), as compared to diabetic controls. Albuminuria was also reduced by over 50% (p<0.05). mRNA expression of cytokines (IL6, TGF-β), chemokine (CCL2) and pro-fibrotic (fibronectin) genes in the kidney were attenuated in SA treated diabetic mice versus controls (p<0.05). Treatment with dietary fibre supplementation provides protection against development of DN through modulation of the gut microbiota with increased gastrointestinal release and systemic distribution of SCFAs. SCFA treatment was similarly protective, supporting SCFAs as a key mediator of the beneficial effects of the HF diet. Manipulation of the gastrointestinal microbiota through diet may be a novel strategy in prevention and management of diabetic nephropathy.