Perturbations of the Gut Microbiome and Metabolome in Children with Calcium Oxalate Kidney Stone Disease

Abstract

Background: The relationship between the composition and function of gut microbial communities and early-onset calcium oxalate kidney stone disease is unknown.

Methods: We conducted a case-control study of 88 individuals aged 4-18 years, which included 44 individuals with kidney stones containing ≥50% calcium oxalate and 44 controls matched for age, sex, and race. Shotgun metagenomic sequencing and untargeted metabolomics were performed on stool samples.

Results: Participants who were kidney stone formers had a significantly less diverse gut microbiome compared with controls. Among bacterial taxa with a prevalence >0.1%, 31 taxa were less abundant among individuals with nephrolithiasis. These included seven taxa that produce butyrate and three taxa that degrade oxalate. The lower abundance of these bacteria was reflected in decreased abundance of the gene encoding butyryl-coA dehydrogenase (P=0.02). The relative abundance of these bacteria was correlated with the levels of 18 fecal metabolites, and levels of these metabolites differed in individuals with kidney stones compared with controls. The oxalate-degrading bacterial taxa identified as decreased in those who were kidney stone formers were components of a larger abundance correlation network that included Eggerthella lenta and several Lactobacillus species. The microbial (α) diversity was associated with age of stone onset, first decreasing and then increasing with age. For the individuals who were stone formers, we found the lowest α diversity among individuals who first formed stones at age 9-14 years, whereas controls displayed no age-related differences in diversity.

Conclusions: Loss of gut bacteria, particularly loss of those that produce butyrate and degrade oxalate, associates with perturbations of the metabolome that may be upstream determinants of early-onset calcium oxalate kidney stone disease.

Keywords: intestine; kidney stones; metabolism; pediatric nephrology.

Figure 1.

The relative abundance of 32 bacterial taxa and the abundance of the bacterial gene butyryl-CoA dehydrogenase were lower among participants with kidney stone disease. (A) Taxa identified as differentially abundant in those with kidney stones compared with controls. Butyrate-producing and oxalate-degrading species are marked to the right of the plot. Relative abundance of bacterial genes for (B) butyrate production and (C) oxalate degradation. IQR, interquartile range.

Figure 2.

The fecal metabolome is distinct in participants with kidney stone disease. (A) PCA of untargeted fecal metabolite survey. (B) LDA distinguishes those with kidney stones from controls with 77% accuracy. (C) Metabolites increased (right) and decreased (left) in those who form kidney stones. (D) Correlation of metabolite concentration and bacterial abundance. Stars indicate significant correlations, after controlling for study group. PC, principal component.

Figure 3.

Oxalate-degrading bacterial taxa identified as decreased among kidney stone formers were components of a larger correlation network. (A) Correlation network of oxalate-degrading bacteria observed in the study. Taxa are connected if the absolute correlation was >0.5. Node size corresponds to mean taxon abundance. (B) Abundance of oxalate-degrading species.

Figure 4.

The lowest diversity of the gut microbiome was found among individuals who first formed kidney stones between 9 and 14 years of age. (A) Species richness and Shannon diversity of bacterial communities in participants with kidney stones and controls. (B) Quadratic fits of diversity versus age of stone formation. (C) Candidate taxa associated with age-dependent diversity profile in those who form kidney stones.