Oral Butyrate Reduces Progression of Kidney Damage in a Diabetic Kidney Disease Mouse Model

Background: Patients with diabetic kidney disease (DKD) display an altered gut microbiome composition when compared to healthy subjects, with a lower prevalence of short chain fatty acids (SCFAs)-producing bacteria. Such reduction might exacerbate DKD, since SCFAs, including butyrate, are associated with health benefits. For this reason, we hypothesized that oral butyrate supplementation reduces DKD progression in mice. Methods: For this study, L-NAME dissolved in drinking water was administered to diabetic BKS db/db male mice (80/mg/kg/day) for 4 weeks to accelerate DKD progression. Together with L-NAME, mice also received either standard diet or food with 5% sodium butyrate (n=10 per group), starting at the same time. In this period, blood pressure, glomerular filtration rate (GFR), besides total body water, glycemia and albuminuria were monitored during follow up period. After 4 weeks, animals were sacrificed whereupon blood samples and organs were collected. Results: In animals fed with regular diet, L-NAME caused a reduction in GFR of 17% at 3 weeks, when compared to baseline. In contrast, mice treated with butyrate did not show any decline in GFR. Furthermore, mice on standard diet showed a significant increase in albuminuria when compared to baseline (p=0.03), which was not the case for the mice that received butyrate (p=0.5). Such difference in kidney function might explain the difference in total body water, which was higher in mice fed with regular diet (p=0.03). Interestingly, glycemia and blood pressure were comparable between groups, suggesting that other mechanisms underlie the effect of butyrate on kidney function. Analysis of kidney biopsies revealed smaller glomeruli (p=0.03) and less mesangial expansion (p=0.0082) in mice treated with butyrate, as well as less fibrosis in the medulla (p=0,04), when compared to mice fed with standard diet. This is also supported by a reduction in Collagen I mRNA expression extracted from whole kidney homogenate (p=0.08). Conclusion: Our results show that oral sodium butyrate supplementation diminishes DKD progression by protecting against mesangial expansion and fibrosis. Future microbiome sequencing from feces and caecum content, together with metabolomic analysis on plasma samples, will help to further understand the effect of butyrate on DKD.