Sodium butyrate ameliorates insulin resistance and renal failure in CKD rats by modulating intestinal permeability and mucin expression

Abstract

Background The associated increase in the lipopolysaccharide (LPS) levels and uremic toxins in chronic kidney disease (CKD) has shifted the way we focus on intestinal microbiota. This study shows that a disruption of the intestinal barrier in CKD promotes leakage of LPS from the gut, subsequently decreasing insulin sensitivity. Butyrate treatment improved the intestinal barrier function by increasing colonic mucin and tight junction (TJ) proteins. This modulation further ameliorated metabolic functions such as insulin intolerance and improved renal function. Methods Renal failure was induced by 5/6th nephrectomy (Nx) in rats. A group of Nx and control rats received sodium butyrate in drinking water. The Nx groups were compared with sham-operated controls. Results The Nx rats had significant increases in serum creatinine, urea and proteinuria. These animals had impaired glucose and insulin tolerance and increased gluconeogenesis, which corresponded with decreased glucagon-like peptide-1 (GLP-1) secretion. The Nx animals suffered significant loss of intestinal TJ proteins, colonic mucin and mucin 2 protein. This was associated with a significant increase in circulating LPS, suggesting a leaky gut phenomenon. 5′adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, known to modulate epithelial TJs and glucose metabolism, was significantly reduced in the intestine of the Nx group. Anti-inflammatory cytokine, interleukin 10, anti-bacterial peptide and cathelicidin-related antimicrobial peptide were also lowered in the Nx cohort. Butyrate treatment increased AMPK phosphorylation, improved renal function and controlled hyperglycemia. Conclusions Butyrate improves AMPK phosphorylation, increases GLP-1 secretion and promotes colonic mucin and TJ proteins, which strengthen the gut wall. This decreases LPS leakage and inflammation. Taken together, butyrate improves metabolic parameters such as insulin resistance and markers of renal failure in CKD animals.

Gut Microbiota as Diagnostic Tools for Mirroring Disease Progression and Circulating Nephrotoxin Levels in Chronic Kidney Disease: Discovery and Validation Study

“…Overall, our findings demonstrate a link of gut-metabolite-kidney axis to the pathogenesis of renal impairment and highlight specific gut microorganisms as useful biomarker for early diagnosis and prognosis monitoring of CKD. Short-chain fatty acids (SCFAs), produced by gut microbiota-mediated fermentation [41], have been shown to be nephroprotective [42,43]. In 5 core CKD-associated genera identified to be inversely correlated with the disease course (Figure 4), Roseburia and Pseudobutyrivibrio are butyrate-producing bacteria [44], while Dialister spp.…”

Constipation in chronic kidney disease: it is time to reconsider

“…Decreased mucin secretion and the lower viscosity of gastric secretions have been reported in non-CKD patients with constipation, which may delay colon transit due to diminished lubrication [69]. It is important to note that the decreased secretion of mucin has also been observed in CKD rats, and this was increased by the administration of butyrates [70].…”

The Controversial Role of Human Gut Lachnospiraceae

“…Dyslipidemia due to elevation of cholesterol and triglycerides that increasing the levels of Acetyl-CoA in obese patient and metabolic disturbance [69]. [73]. Activation of GPR109A and inhibition of AKT and nuclear factor-κB p65 signaling pathways in IBD in mice [74].…”