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Abstract: TH-PO902

Targeting the Gut-Kidney Axis Through Dietary Modification in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Li, Yan J., University of Sydney, Sydney, New South Wales, Australia
  • Chen, Xiaochen, University of Sydney, Sydney, New South Wales, Australia
  • Loh, Yik Wen, University of Sydney, Sydney, New South Wales, Australia
  • Tan, Jian, University of Sydney, Sydney, New South Wales, Australia
  • Macia, Laurence, University of Sydney, Sydney, New South Wales, Australia
  • Chadban, Steven J., University of Sydney, Sydney, New South Wales, Australia
  • Wu, Huiling, University of Sydney, Sydney, New South Wales, Australia
Background

Dietary fibre has been associated with decreased inflammation and mortality in CKD, with short-chain fatty acids (SCFA) derived from gut microbial fermentation of fibre proposed to mediate this effect. Here we explored the impact of dietary fibre content on the development of experimental diabetic nephropathy (DN).

Methods

Diabetes was induced using streptozotocin (STZ) in wild-type (WT) B6 and GPR43-/- mice. Diabetic mice were randomized to 4 diets; resistant starch (RS), high fibre (HF), zero fibre (ZF), control diet (NF), or supplemented with oral SCFAs (acetate 150mM, proprionate 100mM, butyrate 50mM). Gut microbiota composition was assessed by 16S rRNA sequencing of faecal DNA.

Results

All STZ treated mice developed diabetes and remained similarly hyperglycaemic. HF and RS fed mice were protected from DN, with reduced albuminuria (p<0.01), glomerular hypertrophy (p<0.0001), interstitial fibrosis (p<0.0001) and podocyte injury (p<0.05) at 12 weeks compared to those on NF and ZF. Diet markedly altered gut microbial composition by weighted UniFrac, with cluster separation of diabetic mice according to diet (ANOSIM p=0.0001, R=0.93). HF and RS feeding increased relative abundance of phylum Bacteroidetes at the expense of Firmicutes and expanded the SCFA producing Prevotella (p<0.001) and Bifidobacterium (p<0.001) genera compared to controls. This change in microbial ecology correlated with a significant increase in faecal SCFAs and serum acetate. Supplementation with SCFAs in diabetic mice achieved similar degrees of protection from albuminuria and histological injury. Acetate reduced expression of pro-inflammatory cytokine (IL6, IFNγ), chemokine (CCL2, CXCL10) and fibrosis (fibronectin, TGFβ1) genes in diabetic kidneys compared to controls (p<0.05). Diabetic mice deficient in GPR43, a receptor for SCFAs, were unresponsive to acetate supplements with no reduction in albuminuria compared to WT diabetic mice at 12 weeks.

Conclusion

Dietary fibre protects against DN through modulation of the gut microbiota, enrichment of SCFA producing bacteria and increased SCFA production. Similar protection achieved by SCFA supplement and absence of protection in GPR43-/- mice identify SCFAs as likely mediators of this effect. Dietary interventions targeting the gut microbiota warrant further investigation as a novel reno-protective therapy in DN.