Kim Ji Eun, Nam Hoonsik, Park Ji In, Cho Hyunjeong, Lee Jangwook, Kim Hyo-Eun, Kim Dong Ki, Joo Kwon Wook, Kim Yon Su, Kim Bong-Soo, Park Sunghyouk, Lee Hajeong
Department of Internal Medicine, Korea University Guro Hospital, Seoul, South Korea.
College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, South Korea.
Microbiol Spectr. 2023 Mar 6;11(2):e0234422. doi: 10.1128/spectrum.02344-22.
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 analyses were performed on stool samples from 15 patients with DMN 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 (higher 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 of 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 the eGFR and proteinuria, in differentiating the DMN group from the control group. Metabolic pathway gene analysis of BCAAs 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. 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 for DMN. Whole metagenomic sequencing uncovered specific members of the gut microbiota associated with DMN. The gene families derived from the discovered species are involved in the metabolic pathways of methionine and branched-chain amino acids. Metabolomic analysis using stool samples showed increased methionine and branched-chain amino acids in DMN. These integrative omics results provide evidence of the gut microbiota-associated pathophysiology of DMN, which can be further studied for disease-modulating effects via prebiotics or probiotics.
糖尿病肾病（DMN）是糖尿病的一种严重并发症，也是一个主要的健康问题。尽管导致糖尿病肾病的糖尿病（DM）病理生理学尚不确定，但最近的证据表明肠道微生物群参与其中。本研究旨在通过综合临床、分类学、基因组学和代谢组学分析来确定糖尿病肾病中肠道微生物种类、基因和代谢物之间的关系。对15例糖尿病肾病患者和22例健康对照者的粪便样本进行了全宏基因组鸟枪法测序和核磁共振代谢组学分析。在调整年龄、性别、体重指数和估计肾小球滤过率（eGFR）后，确定有6种细菌在糖尿病肾病患者中显著升高。多变量分析发现糖尿病肾病组和对照组之间有216个微生物基因和6种代谢物存在差异（糖尿病肾病组缬氨酸、异亮氨酸、蛋氨酸、戊酸和苯乙酸水平较高，对照组乙酸水平较高）。使用随机森林模型对所有这些参数和临床数据进行综合分析表明，在区分糖尿病肾病组和对照组时，蛋氨酸和支链氨基酸（BCAAs）是仅次于eGFR和蛋白尿的最显著特征。对BCAAs和蛋氨酸的代谢途径基因分析还显示，参与这些代谢物生物合成的许多基因在糖尿病肾病组中含量较高的6种细菌中升高。肠道微生物群的分类学、遗传学和代谢特征之间的相关性提示将扩大我们对肠道微生物群参与糖尿病肾病发病机制的理解，并可能为糖尿病肾病提供潜在的治疗靶点。全宏基因组测序揭示了与糖尿病肾病相关的肠道微生物群的特定成员。从发现的物种中衍生的基因家族参与蛋氨酸和支链氨基酸的代谢途径。使用粪便样本的代谢组学分析显示糖尿病肾病中蛋氨酸和支链氨基酸增加。这些综合组学结果为糖尿病肾病的肠道微生物群相关病理生理学提供了证据，可通过益生元或益生菌对其疾病调节作用进行进一步研究。
