Research progress of gut microbiome and diabetic nephropathy

Abstract

Diabetic nephropathy is an important complication of diabetic microvascular injury, and it is also an important cause of end-stage renal disease. Its high prevalence and disability rate significantly impacts patients' quality of life while imposing substantial social and economic burdens. Gut microbiota affects host metabolism, multiple organ functions, and regulates host health throughout the life cycle. With the rapid development of technology, researchers have found that gut microbiota is closely related to the progression of diabetic kidney disease. This review explores the role of gut microbiome in diabetic nephropathy summarizing proposed mechanisms of progression and focusing on microbial metabolites, intestinal barrier disruption, inflammation, filtration barrier damage and renal fibrosis. This review also examines the mechanism and limitations of current treatments, including drugs, fecal microbiota transplantation, and lifestyle changes, offering new perspectives on prevention and treatment.

Keywords: diabetic nephropathy; enteric-renal axis; gut microbiota; inflammation; probiotics; short-chain fatty acids.

Figure 1

Gut-kidney axis. The increase of outer membrane vesicles (OMV) produced by Gram-negative bacteria, OMV contains abundant lipopolysaccharide (LPS), which reduces the intestinal tight junction related proteins occludin and zonula occludens-1 (ZO-1), and damages intestinal barrier. These are transferred to the renal tubulointers space through blood circulation, leading to enhancced expression of inflammatory factors such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1 and IL-6 in renal tubular epithelial cells through the Caspase-11 pathway. LPS binds to Toll-like receptor (TLR)4, up-regulates the expression of TLR4 and nucleotide-binding oligomeric domain-like receptor protein (NLRP)3 and promotes renal fibrosis. Enterogenous endotoxin damage of intestinal epithelial cells, the damage of glomerular filtration barrier, lead to increased proteinuria.

Figure 2

Multiple drug treatments that interfere with the gut microbiota. Prebiotics inhibites Toll-like receptor/nuclear factor kappa-B (TLR/NF-κB) signaling pathway and phosphatidylinositol-3-kinase-protein Kinase B (PI3K-AKT) pathway. They reduce the production of pro-inflammatory factors, and repaired the tight junction between intestinal epithelium. Methanolic extract of Moutan Cortex (MC) reduces Inhibitor-κBα (I-κBα) phosphorylation and NF-κB activation in macrophages by inhibiting lipopolysaccharide (LPS), thereby inhibiting inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2) expression, and decreasing concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. MC polysaccharides can reshape the intestinal flora to produce more short-chain fatty acids (SCFA) in diabetic kidney disease (DKD) rat model, and reduce serum inflammatory factors and alleviate kidney injury in the process.