A low-protein diet supplemented with an α-ketoacid-diet modulates intestinal flora and urinary metabolism in diabetic nephropathy mice.

BACKGROUND/

OBJECTIVES

Diabetic nephropathy (DN) is one of the most frequent and serious complications of diabetes mellitus. A low-protein diet supplemented with an α-ketoacid diet (LPD-KA) is a crucial intervention for individuals with chronic kidney disease. Nevertheless, the effects and mechanism of LPD-KA in DN remain unclear.

MATERIALS/

METHODS

Db/db mice were randomly assigned into three groups: normal protein diet (NPD), low-protein diet (LPD), and LPD-KA groups, with db/m mice fed with NPD as the Control (Cont) group. PAS and Masson staining were performed after detecting the weight, blood glucose, and renal biochemical indicators. 16S rRNA sequencing and Urine metabolomics were conducted.

RESULTS

LPD-KA for DN mice improved the renal tissue damage and fibrosis, with lower body and kidney weights, blood glucose, urinary glucose, serum creatinine, blood urea nitrogen, urinary albumin/creatinine ratio, 24-h urine microalbumin, and glycosylated hemoglobin A1c levels. Compared to the NPD group, LPD-KA increased relative abundance of Firmicutes/Bacteroides, f_Lachnospiraceae, g_Akkermansia, g_Clostridium, g_Staphylococcus, g_Enterococcus, and f_Enterococcaceae. Moreover, LPD-KA altered urinary metabolomics, including up-regulation of nephroprotective differentially expressed metabolites (DEMs) L-histidinol and gluconolactone, and down-regulation of nephrotoxic DEMs 2-ketobutyric acid, dihydrocortisol, citramalic acid, and L-erythrulose, which were enriched in the protein digestion and absorption and tyrosine metabolism pathway. Spearman's correlation analysis revealed strong correlation between the crucial genus flora (Lactobacillus, Akkermansia, Bacteroides, Adlercreutzia, Rikenella, and Clostridium) and the above metabolites.

CONCLUSION

LPD-KA modulated the intestinal flora and urinary metabolism to attenuate DN progression, with Lactobacillus, Akkermansia, Bacteroides, L-histidinol, gluconolactone, 2-ketobutyric acid, and dihydrocortisol as potential biomarkers, providing new insights into the clinical application of LPD-KA for DN treatment.