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

Significance Statement Although antibiotics have been associated with an increased risk of kidney stones, particularly early in life, perturbations of the gut microbiome and metabolome in early-onset nephrolithiasis have not been investigated. Using shotgun metagenomic sequencing and untargeted metabolomics of stool samples in a study of 44 children with kidney stones and 44 controls matched for age, sex, and race, the authors found that 31 bacterial taxa—including seven butyrate-producing taxa and three that degrade oxalate—were less abundant among children with calcium oxalate stones. Levels of 18 metabolites differed between cases and controls and correlated with the fecal bacteria that were less abundant among children with nephrolithiasis. Such disruptions in the gut microbiome and metabolome may thus be determinants of early-onset disease and may explain the association between antibiotics and nephrolithiasis. 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.