Genetic evidence supporting the causal role of gut microbiota in chronic kidney disease and chronic systemic inflammation in CKD: a bilateral two-sample Mendelian randomization study

Abstract

BackgroundThe association of gut microbiota (GM) and chronic kidney disease (CKD), and the relevancy of GM and chronic systemic inflammation in CKD, were revealed on the basis of researches on gut–kidney axis in previous studies. However, their causal relationships are still unclear.ObjectiveTo uncover the causal relationships between GM and CKD, as well as all known GM from eligible statistics and chronic systemic inflammation in CKD, we performed two-sample Mendelian randomization (MR) analysis.Materials and methodsWe acquired the latest and most comprehensive summary statistics of genome-wide association study (GWAS) from the published materials of GWAS involving GM, CKD, estimated glomerular filtration rate (eGFR), c-reactive protein (CRP) and urine albumin creatine ratio (UACR). Subsequently, two-sample MR analysis using the inverse-variance weighted (IVW) method was used to determine the causality of exposure and outcome. Based on it, additional analysis and sensitivity analysis verified the significant results, and the possibility of reverse causality was also assessed by reverse MR analysis during this study.ResultsAt the locus-wide significance threshold, IVW method and additional analysis suggested that the protective factors for CKD included family Lachnospiraceae (P=0.049), genus Eubacterium eligens group (P=0.002), genus Intestinimonas (P=0.009), genus Streptococcu (P=0.003) and order Desulfovibrionales (P=0.001). Simultaneously, results showed that genus LachnospiraceaeUCG010 (P=0.029) was a risk factor for CKD. Higher abundance of genus Desulfovibrio (P=0.048) was correlated with higher eGFR; higher abundance of genus Parasutterella (P=0.018) was correlated with higher UACR; higher abundance of class Negativicutes (P=0.003), genus Eisenbergiella (P=0.021), order Selenomonadales (P=0.003) were correlated with higher CRP levels; higher abundance of class Mollicutes (0.024), family Prevotellaceae (P=0.030), phylum Tenericutes (P=0.024) were correlated with lower levels of CRP. No significant pleiotropy or heterogeneity was found in the results of sensitivity analysis, and no significant causality was found in reverse MR analysis.ConclusionThis study highlighted associations within gut-kidney axis, and the causal relationships between GM and CKD, as well as GM and chronic systemic inflammation in CKD were also revealed. Meanwhile, we expanded specific causal gut microbiota through comprehensive searches. With further studies for causal gut microbiota, they may have the potential to be new biomarkers for targeted prevention of CKD and chronic systemic inflammation in CKD.

Causal relationship between gut microbiota and chronic renal failure: a two-sample Mendelian randomization study

“…Previous studies on the gut microbiome and CKD have primarily utilized animal models ( Vaziri et al, 2013 ), with observations often showing inconsistencies. While there have been reports on the causal relationship between the gut microbiome and CKD ( Li et al, 2023 ; Ren et al, 2023 ), significant variations in the richness and evenness (α-diversity) of bacterial species across different CKD stages have been observed ( Wu et al, 2020 ). CRF represents a more severe stage of kidney pathology.…”

Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis

“…Lower p -value thresholds (e.g., < 5.0E−08) are commonly employed to ensure robustness of associations, reduce heterogeneity, and enhance the accuracy of the research. However, such stringent criteria might also exclude potentially meaningful associations ( Bottigliengo et al, 2022 ; Chen et al, 2023 ; Liu et al, 2023 ; Ren et al, 2023 ). Our analysis indicated that some associations, previously insignificant, became significant when the p -value threshold was relaxed, underscoring the importance and complexity of p -value selection in research on the relationship between inflammatory proteins and ALS.…”

Genetic evidence strengthens the bidirectional connection between gut microbiota and Shigella infection: insights from a two-sample Mendelian randomization study

“…Consequently, we employed MR analysis, providing a robust framework to systematically investigate the causal relationship between Shigella infection and the gut microbiota. Ren et al, 2023). CRP has been previously recognized as a marker of Shigella infection activity (Khan et al, 1995).…”