Cross-sectional analyses of metabolites across biological samples mediating dietary acid load and chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a major public health burden, with dietary acid load (DAL) and gut microbiota playing crucial roles. As DAL can affect the host metabolome, potentially via the gut microbiota, we cross-sectionally investigated the interplay between DAL, host metabolome, gut microbiota, and early-stage CKD (TwinsUK, n = 1,453). DAL was positively associated with CKD stage G1-G2 (Beta (95% confidence interval) = 0.34 (0.007; 0.7), p = 0.046). After adjusting for covariates and multiple testing, we identified 15 serum, 14 urine, 8 stool, and 7 saliva metabolites, primarily lipids and amino acids, associated with both DAL and CKD progression. Of these, 8 serum, 2 urine, and one stool metabolites were found to mediate the DAL-CKD association. Furthermore, the stool metabolite 5-methylhexanoate (i7:0) correlated with 26 gut microbial species. Our findings emphasize the gut microbiota's therapeutic potential in countering DAL's impact on CKD through the host metabolome. Interventional and longitudinal studies are needed to establish causality.

Keywords: Biological sciences; Health sciences; Internal medicine; Medical specialty; Medicine; Metabolomics; Natural sciences; Nephrology; Systems biology.

Graphical abstract

Figure 1

Flow chart of the study design

Figure 2

Metabolites associated with CKD and acid intake Metabolites identified through random forest machine learning that pass multivariable regression analysis (p < 0.05, FDR corrected [Benjamini & Hochberg]) and are associated with CKD (red) and acid intake (blue) in (A) serum, (B) urine, (C) stool, and (D) saliva. All analyses were corrected for age, sex, and BMI.

Figure 3

Mediation analysis between DAL and CKD stage G1-G2 Mediation analysis of the association between DAL and CKD stage G1-G2, using metabolite of interest as potential mediator in (A) serum,(B) urine, and (C) stool. Path coefficients are illustrated beside each path and variance accounted for (VAF) score is denoted below the mediator. All associations are statistically significant (p < 0.05). (D) Spearman correlation between mediating metabolites across biological samples (∗p < 0.05; ∗∗p < 0.01 and ∗∗∗p < 0.001). All analyses are corrected for age, sex, and BMI. Abbreviations: DAL, dietary acid load; CKD, chronic kidney disease; VAF, variance accounted for.

Figure 4

Gut microbiota, CKD and DAL Effect of (A) CKD and (B) DAL on Shannon alpha diversity (ns = non-significant) and (C) gut microbiota species identified to significantly (p < 0.05; FDR corrected [Benjamini & Hochberg]) associate with the stool metabolite 5-methylhexanoate (i7:0) in the discovery cohort. All analyses are corrected for age, sex, and BMI.