Microbiome-Metabolomics Analysis Reveals the Protection Mechanism of α-Ketoacid on Adenine-Induced Chronic Kidney Disease in Rats.

Yenan Mo,Chuan Zou,Chunlan Ji,Zhaoyu Lu,Yuchi Wu,Xusheng Liu,Lei Zhang,Huang Sun,Wenjia Geng,Lixin Wang

doi:10.3389/fphar.2021.657827

Abstract

Objectives: As nitrogen-free precursors of corresponding essential amino, α-ketoacid have been widely prescribed to end-stage renal disease patients together with a low protein diet However, the impact of α-ketoacid on intestinal microbiota in chronic kidney disease (CKD) individuals is unknown. The study aims at investigating the variation in the intestinal microbiota and metabolic profile in response to α-ketoacid treatment in an adenine-induced CKD rat model. Design: Rats in the treatment groups were given solution of compound α-ketoacid tablets. At the end of the study, blood, feces, colon tissues and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses. Results: α-Ketoacid treatment reduced serum creatinine, blood urea nitrogen and 24 h urine protein, and alleviated tubular atrophy, glomerulosclerosis and interstitial fibrosis in adenine-induced CKD rats. Moreover, α-ketoacid significantly improved intestinal barrier and increased the abundance of Methanobrevibacter, Akkermansia, Blautia and Anaerositipes while reduced the abundance of Anaerovorax and Coprococcus_3 at the genus level. In addition, our results also demonstrated that α-ketoacid significantly reduced the concentrations of indoxyl sulfate, betaine, choline and cholesterol. Spearman’s correlation analysis revealed that the abundance of Coprococcus_3 was positively correlated with serum level of betaine, trimethylamine N-oxide, indoxyl sulfate, cholic acid and deoxycholic acid. Conclusion: α-Ketoacid has a reno-protective effect against adenine-induced CKD, which may be mediated regulation of serum metabolic profiles via affecting intestinal microbial community.

Highlights

Chronic kidney disease (CKD) is an emerging epidemic that contributes to high incidences of morbidity and mortality (Collaboration, 2020)
Α-Ketoacid have been widely prescribed to end-stage kidney disease (ESKD) patients together with a low protein diet (LPD) (Mitch, 2000; Bernhard et al, 2001), which has been indicated by guidelines to be a fundamental tool to delay CKD progressions (Group, 2013)
Integrating serum untargeted metabolomics and sequencing of gut microbiota was used to investigate the response to α-ketoacid treatment in adenine-induced CKD rats. we revealed that several feature gut microbiota and metabolic pathways were highly associated with the beneficial outcomes of CKD

Summary

Introduction

Chronic kidney disease (CKD) is an emerging epidemic that contributes to high incidences of morbidity and mortality (Collaboration, 2020). Α-Ketoacid have been widely prescribed to ESKD patients together with a low protein diet (LPD) (Mitch, 2000; Bernhard et al, 2001), which has been indicated by guidelines to be a fundamental tool to delay CKD progressions (Group, 2013). Besides increasing body weight and muscle body mass, α-ketoacid showed many protective effect on CKD individuals, including reducing proteinuria and histological damage of kidney (Gao et al, 2010), reducing phosphate and parathyroid hormone levels (Garneata et al, 2016; Di Iorio et al, 2018), and declining diastolic blood pressure (Di Iorio et al, 2018) when supplemented with protein restriction in CKD patients and nephrectomy animals. The impact of intestinal function and intestinal microbiota with the presence of α-ketoacid is unknown

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Conclusion