Reno-Protective Effect of Low Protein Diet Supplemented With α-Ketoacid Through Gut Microbiota and Fecal Metabolism in 5/6 Nephrectomized Mice

BACKGROUND: Low protein supplemented with α-ketoacid diet (LKD) was recommended to be an essential intervention to delay the progression of chronic kidney disease (CKD) in patients who were not yet on dialysis. Aberrant gut microbiota and metabolism have been reported to be highly associated with CKD. However, the effect of LKD on gut microbiota and related fecal metabolism in CKD remains unclear. METHODS: Mice were fed with normal protein diet (NPD group), low protein diet (LPD group), and low protein diet supplemented with α-ketoacid (LKD group) after 5/6 nephrectomy. At the end of the study, blood, kidney tissues, and feces were collected for biochemical analyses, histological, 16S rRNA sequence of gut microbiome, and untargeted fecal metabolomic analyses. RESULTS: Both LKD and LPD alleviate renal failure and fibrosis, and inflammatory statement in 5/6 nephrectomized mice, especially the LKD. In terms of gut microbiome, LKD significantly improved the dysbiosis induced by 5/6Nx, representing increased α-diversity and decreased F/B ratio. Compared with NPD, LKD significantly increased the abundance of g_Parasutterella, s_Parabacteroides_sp_CT06, f_Erysipelotrichaceae, g_Akkermansia, g_Gordonibacter, g_Faecalitalea, and s_Mucispirillum_sp_69, and decreased s_Lachnospiraceae_bacterium_28-4 and g_Lachnoclostridium. Moreover, 5/6Nx and LKD significantly altered fecal metabolome. Then, multi-omics analysis revealed that specific metabolites involved in glycerophospholipid, purine, vitamin B6, sphingolipid, phenylalanine, tyrosine and tryptophan biosynthesis, and microbes associated with LKD were correlated with the amelioration of CKD. CONCLUSION: LKD had a better effect than LPD on delaying renal failure in 5/6 nephrectomy-induced CKD, which may be due to the regulation of affecting the gut microbiome and fecal metabolic profiles.