Urobiota analysis and genome-wide association study in pediatric recurrent urinary tract infections and vesicoureteral reflux

TL;DR

This study explores how genetic factors and urinary microbiota are linked in children with urinary tract infections and vesicoureteral reflux.

Contribution

The first characterization of host genetic influences on the pediatric urobiota in UTI and VUR.

Findings

Four urobiota community types were identified, associated with VUR, age, and toilet training.

Genome-wide significant associations were found with bacterial abundances near genes like CXCL12, ABCC1, and ROBO1.

Cxcl12 was induced in mice after uropathogenic infection, linking UTI, VUR, and cardiovascular phenotypes.

Abstract

Urinary tract infections (UTIs) are the most common severe bacterial infections in young children, often associated with vesicoureteral reflux (VUR). To explore host genetic-microbiota interactions and their clinical implications, we analyzed the urinary microbiota (urobiota) and conducted genome-wide association studies for bacterial abundance traits in pediatric patients with UTI and VUR from the Randomized Intervention for Children with Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation cohorts. We identified 4 urobiota community types based on relative abundance, characterized by the genera Enterococcus, Prevotella, Pseudomonas, and Escherichia/Shigella, and their associations with VUR, age, and toilet training. Children with VUR exhibited decreased microbial diversity and increased abundance of genera that included opportunistic pathogens, suggesting a disrupted urobiota. We detected genome-wide significant genetic associations with urinary bacterial relative abundances, in or near candidate genes including CXCL12, ABCC1, and ROBO1, which are implicated in urinary tract development and response to infection. We showed that Cxcl12 was induced 12 hours after uropathogenic bacterial infection in mouse bladder. The association with CXCL12 suggests a genetic link between UTI, VUR, and cardiovascular phenotypes later in life. These findings provide the first characterization to our knowledge of host genetic influences on the pediatric urobiota in UTI and VUR, offering insights into the interplay between disease, host genetics, and the urobiota composition.

Genetic variations influence bacterial composition of urine in children with recurrent urinary infections and vesicoureteral reflux.

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