Genetic evidence is provided that gut microbiota influence CKD risk partially through circulating metabolites, highlighting the gut microbiota–metabolite–CKD axis as a potential therapeutic target.
Abstract
Chronic kidney disease (CKD) is a major global health concern with a multifactorial pathogenesis. Emerging evidence suggests that the gut microbiota and its metabolic products contribute to CKD development. However, robust evidence supporting metabolites as causal mediators in this pathway remains limited. We aimed to investigate causal relationships and mediating effects linking gut microbiota, circulating metabolites, and CKD.
Two-sample Mendelian randomization (MR) analyses were conducted using summary statistics from large-scale genome-wide association studies (GWAS) on gut microbiota, plasma metabolites, and CKD-related outcomes. Independent single-nucleotide polymorphisms strongly associated with each exposure were selected as instrumental variables. The inverse-variance weighted method served as the primary analysis, complemented by four additional MR approaches. Heterogeneity and pleiotropy were assessed using Cochran’s Q test, the MR-Egger intercept, and MR-PRESSO. Mediation analysis quantified the proportion of microbiota–CKD effects mediated by specific metabolites.
MR analyses identified causal associations among multiple gut microbial pathways, circulating metabolites, and CKD-related traits. Mediation analysis revealed that argininate partially mediated the effect of the microbial pathway PWY-6629 on the urinary albumin-to-creatinine ratio (UACR), accounting for 22% of the total effect. A one–standard-deviation increase in genetically predicted PWY-6629 activity was associated with a 1.3% increase in UACR, mediated through a 7.9% reduction in argininate levels. Conversely, higher genetically predicted argininate levels were associated with a 3.7% reduction in UACR.
This study provides genetic evidence that gut microbiota influence CKD risk partially through circulating metabolites, highlighting the gut microbiota–metabolite–CKD axis as a potential therapeutic target.
Abstract Observational studies have indicated that the gut microbiota is associated with diabetic kidney disease (DKD). However, it remains unclear whether disturbances in the gut microbiota causally contribute to DKD. This study aimed to investigate the causal relationships between the gut microbiota and DKD and explore peripheral immune cell traits as potential mediators. Summary statistics were extracted from genome-wide association studies of the Dutch Microbiome Project (N = 7,738), SUMMIT Consortium (N = 10,875), and GWAS summary statistics for immune cell traits (N = 3,757). We used a two-sample two-step mediation Mendelian randomization analysis to investigate genetic causality between immune cell traits and the phenotypes of DKD, causal effect of gut microbiota/microbiota metabolism pathways on DKD, and mediation effects of immune cell traits. In total, seven immune cell traits and five taxa were causally associated with the DKD phenotypes after multiple testing corrections. We performed mediation analysis on gut microbiota and immune cell traits that passed the Bonferroni correction, and identified five mediation relationships. For instance, mediation analysis indicated that Pseudoflavonifractor capillosus had adverse effects on chronic kidney disease in type 2 diabetes by downregulating CD25 expression in CD4+ regulatory T cells (proportion mediated = 19.8%, p = 0.035). These results indicate that the gut microbiota has causal effects on DKD and that immune cell traits exert a mediation effect to some extent.
Han Yan, H. Pang, Lingxiang Xie et al.· Renal Failure· 0 citations
INTRODUCTION
Coronary Atherosclerosis (CAS) is a complex disease influenced by host genes, the gut microbiota, and circulating metabolites. Causal relationships and mediating effects among these factors have not yet been clarified.
METHODS
A two-sample Mendelian Randomization (MR) study was conducted using genomewide association study data from FinnGen, OpenGWAS, and Canadian Longitudinal Study on Aging. A total of 473 genetic instruments for gut microbial traits and 1,400 for plasma metabolites were selected. We applied bidirectional Mendelian randomization, sensitivity tests, and two-step mediation analysis to assess causal effects and identify metabolic mediators.
RESULTS
18 gut microbiota taxa and 36 metabolites that are associated with coronary atherosclerosis. Protective taxa included Genus Roseibacillus and Genus Negativibacillus; Genus Geobacter C and Species Lawsonibacter sp000492175 were identified as risk. Inversely, bile acid derivatives, such as deoxycholic acid 12-sulfate, were negatively correlated, whereas guanidinoacetate was positively correlated. Mediation analysis found glutamine degradant, sphingomyelin, and 3β-hydroxy-5-cholestenoate as partially mediated by the microbial effect, with mediation proportions ranging from -30.1% to 15.8%.
DISCUSSION
These findings provide genetic evidence for the involvement of the gut microbiota in the development of coronary atherosclerosis, which may occur through metabolic pathways. Beneficial microbial taxa may be preferentially sustained by amino acid metabolism and anti-inflammatory mediators, whereas pathogenic taxa tend to proliferate under conditions characterized by lipid and sterol metabolic dysregulation.
CONCLUSION
This study emphasizes the potential central axis of gut microbiota-plasma metabolites-CAS and identifies microbial and plasma metabolite candidates that may serve as targets for early prevention and intervention of CAS. These findings provide new insights into the molecular mechanisms underlying the interactions between gut microbiota and plasma metabolites in the development and progression of C.
The human oral and gut microbiota are the 4 largest microbial communities in the body and play crucial roles in maintaining homeostasis and influencing disease. Observational studies have suggested links between these microbiota and bone neoplasm-related phenotypes, but establishing causality has been challenging due to confounding factors and reverse causality. We conducted a bidirectional, 2-sample Mendelian randomization (MR) study to investigate evidence consistent with a potential causal association between the saliva and gut microbiota and various bone neoplasm-related phenotypes. Genetic instruments for saliva and gut microbiota were sourced from large genome-wide association studies. Inverse variance weighted was the primary MR method, supplemented by 4 other MR techniques. Sensitivity analyses, including MR-Egger regression, were performed to assess pleiotropy and heterogeneity. In the forward MR analysis,
Veillonella parvula
from the saliva microbiota was associated with a decreased risk of bone and connective tissue neoplasms (β: −0.236, 95% CI: [−0.275, −0.197],
P
= 8.20E−33). MR analyses identified genetically predicted associations between several microbial taxa and bone neoplasm-related phenotypes. Reverse MR analyses showed that genetic liability to bone neoplasm-related phenotypes was associated with variation in the composition of the oral (e.g.,
Order Bacteroidales
,
Rothia mucilaginosa
) and gut microbiota (e.g.,
Class Methanobacteria
,
Genus Eubacterium oxidoreducens group
). Sensitivity analyses confirmed the robustness of these findings, as no statistical evidence of substantial heterogeneity or directional horizontal pleiotropy was detected. This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes. Our findings identify several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes. However, these genetically informed associations require further mechanistic, experimental, and prospective clinical validation before clinical application.
BACKGROUND
IgA nephropathy (IgAN) is an immune-inflammatory glomerulonephritis mediated by both genetic and environmental factors. Recent research indicates a close association between gut microbiota dysbiosis and IgAN development. Additionally, circulating inflammatory proteins also play a significant role in the progression of IgAN. However, the causal relationship among gut microbiota, circulating inflammatory proteins, and IgAN remains unclear.
METHODS
This study utilized publicly available Genome-Wide Association Study (GWAS) data for Mendelian randomization (MR) analysis to investigate the causal relationship among gut microbiota, circulating inflammatory proteins, and IgAN, as well as to examine the mediating role of circulating inflammatory proteins in the association between gut microbiota and IgAN. The primary analytical method employed in this study was Inverse Variance Weighted (IVW) analysis with specific attention given to Bayesian Weighted MR results and supported by MR-Egger regression, Weighted Median Model (WME), median model, and Simple Model (SM) approaches. Several sensitivity analyses were performed to evaluate the robustness of MR analysis findings.
RESULTS
(1) MR analysis of gut microbiota and IgAN indicates negative associations between g_Roseburia, g_Faecalibacterium, s_Odoribacter_splanchnicus, and s_Roseburia_unclassified with IgAN risk, while positive associations exist between s_Paraprevotella_unclassified and s_Lachnospiraceae_bacterium_7_1_58FAA with IgAN risk. (2) Circulating inflammatory proteins to IgAN in MR analysis showed that IL-10RA was negatively correlated with the risk of IgAN, while TSGP-CD5, FGF23, LIF, and TGF-α levels were positively correlated with the risk of IgAN. (3) Mediation analysis suggests that TGF-α serves as a mediator between s_Odoribacter_splanchnicus and the causality of IgAN. (4) The results of the reverse MR analysis suggest no significant causal effect of IgAN on gut flora and circulating inflammatory proteins. Sensitivity analyses consistently support the reliability of the study results.
CONCLUSION
Our research findings, obtained through genetic methods, substantiate the causal link between gut microbiota, circulating inflammatory proteins, and IgAN. The identification of biomarkers offers novel insights into the potential mechanisms underlying IgAN, which can be advantageous for early diagnosis and the development of more effective treatment strategies.
Pengpeng Dong, Xiao-Yu Li, Xue Feng et al.· International Urology and Ne...· 0 citations