Association Between Gut Microbiota and Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study in a Chinese Population

TL;DR

This study finds a potential causal link between gut microbiota and chronic kidney disease in a Chinese population, with a specific focus on the genus Alistipes and the serum protein FBLN1.

Contribution

The study provides novel Mendelian randomization evidence for a causal relationship between gut microbiota and CKD in a Chinese population.

Findings

Genus Alistipes was associated with increased CKD risk in the JKB cohort.

Bifidobacterium catenulatum–Bifidobacterium pseudocatenulatum complex was linked to CKD risk in a BUN meta-GWAS.

FBLN1 mediates 26.7% of the effect of Alistipes on CKD risk.

Abstract

Background: Population differences in gut microbiota composition and related metabolites may influence their potential causal relationship with chronic kidney disease (CKD); however, this relationship remains poorly understood in the Chinese population. Materials and Methods: We conducted a two-sample Mendelian randomization (MR) study using summary statistics of 500 gut microbial features (9 phyla, 3 classes, 14 orders, 32 families, 95 genera, 248 species, and 99 gut metabolic modules (GMMs)) from the 4D-SZ (from Shenzhen, China) discovery cohort (n = 1539). CKD summary statistics were obtained from the China Kadoorie Biobank (CKB) (489 cases and 75,531 controls). Associations between gut microbiota and CKD were evaluated via inverse variance weighted, MR-Egger, weighted median, and MR-PRESSO. To validate our findings, we replicated the analyses in two independent East Asian CKD GWAS datasets: the Biobank of Japan (BBJ) dataset (2117 cases and 174,345 controls) and the J-Kidney-Biobank (JKB) dataset (382 cases and 3471 controls). We further validated the results via a meta-GWAS of BUN and eGFR in Biobank Japan (BBJ) and the Taiwan Biobank (TWB). Additionally, we analyzed 304 serum proteins from the Guangzhou Nutrition and Health Study (GNHS) and conducted mediation MR analyses to explore potential mediators. Result: At the locus-wide significance threshold, we identified 18 gut microbiome features associated with CKD onset in the China Kadoorie Biobank (CKB). Genus Alistipes (OR 1.02, 95% CI 1.00–1.03, p = 0.03) was associated with incident CKD risk in the JKB cohort. Species Bifidobacterium catenulatum–Bifidobacterium pseudocatenulatum complex (OR 1.0074, 95% CI 1.0070–1.0142, p = 0.01) was associated with incident CKD risk in a meta-GWAS of BUN. Sensitivity analyses, including Cochran’s Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots, yielded consistent results. Mediation analysis revealed that 26.7% (95% CI: 0.006–0.6700, p = 0.04) of the effect of Alistipes on CKD risk was mediated through the serum protein FBLN1. Conclusions: Our study provides Mendelian randomization-based evidence supporting a potential causal relationship between gut microbiota and CKD, highlighting the potential mediating role of FBLN1 in the association between genus Alistipes and CKD. Further studies are needed to explore whether and how genus Alistipes and FBLN1 contribute to CKD development.

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