Gut microbial genes and metabolism for methionine and branched-chain amino acids in diabetic nephropathy
Aims/hypothesis: Diabetic mellitus nephropathy (DMN) is a serious complication of diabetes and a major health concern. Although the pathophysiology of diabetes mellitus (DM) leading to DMN is uncertain, recent evidence suggests the involvement of the gut microbiome. This study aimed to determine the relationships among gut microbial species, genes, and metabolites in DMN through an integrated clinical, taxonomic, genomic, and metabolomic analysis.  Methods: Whole metagenome shotgun sequencing and nuclear magnetic resonance metabolomic analysis were performed on stool samples from 15 patients with DMNs and 22 healthy controls.  Results: Six bacterial species were identified to be significantly elevated in the DMN patients after adjusting for age, sex, body mass index, and estimated glomerular filtration rate (eGFR). Multivariate analysis found 216 microbial genes and six metabolites (valine, isoleucine, methionine, valerate, and phenylacetate: higher in DMN; acetate: higher in control) that were differentially present between the DMN and control groups. Integrated analysis of all these parameters and clinical data, using the random forest model, showed that methionine and branched-chain amino acids (BCAAs) were among the most significant features, next to eGFR and proteinuria, in differentiating DMN from control groups. Metabolic pathway gene analysis of BCAA and methionine also revealed that many genes involved in the biosynthesis of these metabolites were elevated in the six species that were more abundant in the DMN group.  Conclusions/interpretation: The suggested correlation among taxonomic, genetic, and metabolic features of the gut microbiome would expand our understanding of gut microbial involvement in the pathogenesis of DMN and may provide potential therapeutic targets of DMN.