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Gut Microbial Genes and Metabolism for Methionine and Branched-Chain Amino Acids in Diabetic Nephropathy

ABSTRACT:

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. Whole metagenome shotgun sequencing and nuclear magnetic resonance metabolomic analysis were performed on stool samples from 15 patients with DMNs and 22 healthy controls. 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 6 metabolites (valine, isoleucine, methionine, valerate and phenylacetate levels in the DMN group and higher acetate levels in the control group) 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 the control group. Metabolic pathway gene analysis of BCAA and methionine also revealed that many genes involved in the biosynthesis of these metabolites were elevated in the 6 species that were more abundant in the DMN group. 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.

Linked cross omic data sets:

Raw sequencing data associated with this study are available in the European Nucleotide Archive (ENA): accession number PRJEB57320.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR) -

PROVIDER: MTBLS6331 | MetaboLights | 2023-03-01

REPOSITORIES: MetaboLights

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Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.

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Gut Microbial Genes and Metabolism for Methionine and Branched-Chain Amino Acids in Diabetic Nephropathy

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