Perturbed gut microbiome and fecal and serum metabolomes are associated with chronic kidney disease severity

Abstract

Background Chronic kidney disease (CKD) is a severe public health problem associated with a disordered gut microbiome. However, the functional alterations of microbiota and their cross talk with metabolism pathways based on disease severity remain unclear. Results We performed metagenomics and untargeted metabolomics in a cohort of 68 patients with CKD of differing severities and 20 healthy controls to characterize the complex interplay between the gut microbiome and fecal and serum metabolites during CKD progression. We identified 26 microbial species that significantly changed in patients with CKD; 18 species changed as the disease progressed, and eight species changed only in a specific CKD group. These distinct changes in gut microbiota were accompanied by functional alterations in arginine and proline, arachidonic acid, and glutathione metabolism and ubiquinone and other terpenoid-quinone biosynthesis pathways during CKD progression. Further metabolomic analyses revealed that the distributions of toxic and pro-oxidant metabolites from these four essential metabolic pathways varied in the feces and serum as CKD progressed. Furthermore, we observed a complex co-occurrence between CKD severity-related bacteria and the characterized metabolites from the four essential metabolic pathways. Notably, Ruminococcus bromii, fecal hydroquinone, and serum creatinine were identified as the main contributors to the integrated network, indicating their key roles in CKD progression. Moreover, a noninvasive model including R. bromii and fecal hydroquinone, L-cystine, and 12-keto-tetrahydro-LTB4 levels classified the CKD severity (area under the curve [AUC]: > 0.9) and had better performance than the serum creatinine level for mild CKD (AUC: 0.972 vs. 0.896). Conclusions Perturbed CKD severity-related gut microbiota may contribute to unbalanced toxic and pro-oxidant metabolism in the gut and host, accelerating CKD progression, which may be an early diagnostic and therapeutic target for CKD.

Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study

“…A two-dimensional orthogonal partial least-squares discriminant analysis (OPLS-DA) plot was used to present the difference in metabolic profile between the controls and the UGI cancer group. First, in the training set, differential metabolites were identified based on the Wilcoxon test P < 0.05 and the variable importance in projection (VIP) > 1 calculated through PLS-DA. − Then, models consisting of metabolites, HLI and PRS, were constructed based on logistic regression. In particular, we evaluated the impact of lifestyle and genetic risk on the discriminative value of metabolite models.…”

Bibliometric Analysis of the Relationship between Gut Microbiota and Chronic Kidney Disease from 2001–2022

“…Based on the information obtained, 758 publications cited inflammation, metabolic dysregulation, obstruction, and other systemic diseases, ultimately leading to renal fibrosis. [14,28] Renal fibrosis causes irreversible kidney damage, accelerating CKD progression. [26,29] Recent evidence [30][31][32][33] has identified gut microbiota as a regulatory factor in the development of CKD.…”

Gut Microbiota and Neonatal Acute Kidney Injury

“…proline, arachidonic acid, glutathione metabolism as well as ubiquinone and other terpene-benzoquinone biosynthesis pathways, which may lead to toxic and prooxidative metabolic imbalances in the host, thus accelerating the progression of chronic kidney disease (CKD) 10 . Genus enterorhabdus and genus butyricicoccus are protective and risk factors for IgA nephropathy, respectively 11 , and Actinobacteria may be associated with the development and prognosis of IgA nephropathy 12 .…”

“…For example, gut dysbiosis induces several metabolic changes such as arginine and proline, arachidonic acid, glutathione metabolism as well as ubiquinone and other terpene-benzoquinone biosynthesis pathways, which may lead to toxic and pro-oxidative metabolic imbalances in the host, thus accelerating the progression of chronic kidney disease (CKD). 10 Genera Enterorhabdus and Butyricicoccus are protective and risk factors for IgA nephropathy, respectively, 11 and Actinobacteria may be associated with the development and prognosis of IgA nephropathy. 12 Additionally, changes in the diversity and composition of the gut microbiota caused by the expansion of genera Escherichia, Citrobacter, and Klebsiella, and the depletion of Roseburia may be closely related to diabetic kidney diseases (DKDs).…”