Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang

Jicheng Li,Hongxin Fu,Yu Pang,Jiuyao Zhou,Qiuhe Chen,Honglian Li,Yuan Zhou,Ruirui Lu,Yiwen Cao,Junbiao Wu,Bihao Liu,Guoxing Fang

doi:10.3389/fphar.2020.606689

Abstract

Immunoglobulin A nephropathy (IgAN), an autoimmune renal disease with complicated pathogenesis, is one of the principal reasons for end-stage renal disease in the clinic. Evidence has linked apparent alterations in the components of the microbiome and metabolome to renal disease in rats. However, thus far, there is insufficient evidence that supports the potential relationship between gut microbiome, circulating metabolites, and IgAN. This study was designed to probe the effects of IgAN on intestinal microecology and metabolic phenotypes and to understand the possible underlying mechanisms. Fecal and serum samples were collected from IgAN rats. Composition of the gut microbiota and biochemical changes in the metabolites was analyzed using 16S rDNA sequencing and untargeted metabolomics. The IgAN rats exhibited renal insufficiency and increased concentration of 24-h urine protein, in addition to deposition of IgA and IgG immune complexes in the kidney tissues. There was a disturbance in the balance of gut microbiota in IgAN rats, which was remarkably associated with renal damage. Marked changes in microbial structure and function were accompanied by apparent alterations in 1,403 serum metabolites, associated with the disorder of energy, carbohydrate, and nucleotide metabolisms. Administration of Zhen Wu Tang ameliorated microbial dysbiosis and attenuated the renal damage. Besides, treatment with Zhen Wu Tang modulated the metabolic phenotype perturbation in case of gut microbiota dysbiosis in IgAN rats. In conclusion, these findings provided a comprehensive understanding of the potential relationship between the intestinal microbiota and metabolic phenotypes in rats with IgAN. Elucidation of the intestinal microbiota composition and metabolic signature alterations could identify predictive biomarkers for disease diagnosis and progression, which might contribute to providing therapeutic strategies for IgAN.

Highlights

Immunoglobulin A nephropathy (IgAN), first proposed by Berger in 1968, is an autoimmune renal disease with multifactorial pathogenesis that has emerged as a crucial element in progression to end-stage renal disease (ESRD) (Berger and Hinglais, 1968; Lai et al, 2016)
Illumina MiSeq sequencing analysis was applied to identify the composition of gut flora in the fecal samples of rats. 1,309,828 effective tags were acquired after filtering the data quality, with an average number of 87,322 tags per sample (Supplementary Table S1). These sequences were assigned to 1,620 operational taxonomic units (OTUs) based on 97% sequence resemblance
The data in this study suggested that vital alterations in the gut microbial gene functions were associated with metabolism. 3,196 KEGG Orthology (KO) terms were determined using PICRUSt analysis, which were found to be associated with 21 significantly altered metabolic pathways in IgAN (Supplementary Table S4), such as adipocytokine signaling pathway, D-arginine and D-ornithine metabolism, flavone and flavonol biosynthesis, biotin metabolism, riboflavin metabolism, and caprolactam degradation

Summary

Introduction

Immunoglobulin A nephropathy (IgAN), first proposed by Berger in 1968, is an autoimmune renal disease with multifactorial pathogenesis that has emerged as a crucial element in progression to end-stage renal disease (ESRD) (Berger and Hinglais, 1968; Lai et al, 2016). As the most common type of glomerulonephritis, the diagnosis of IgAN hinges upon an important pathological manifestation characterized by excessive accumulation and deposition of IgA immune complexes in the mesangial zone, mesangial cell proliferation, and mesangial matrix dilation (Floege and Daha, 2018; Taylor et al, 2019). Urinary protein, caused by excessive deposition of IgA immune complexes, accompanied by macroscopic hematuria and hypertension, is the paramount manifestation of IgAN in the clinic.

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