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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.
Authors
Miguel Verbitsky, Pavan Khosla, Daniel Bivona, Atlas Khan, Yask Gupta, Heekuk Park, Tian H. Shen, Aryan Ghotra, Katherine Xu, Iman A. Ghavami, Priya Krithivasan, Jeremiah Martino, Tanya Sezin, Tze Y. Lim, Victoria Kolupaeva, Nita A. Limdi, Yuan Luo, Hakon Hakonarson, Simone Sanna-Cherchi, Krzysztof Kiryluk, Cathy L. Mendelsohn, Anne-Catrin Uhlemann, Jonathan Barasch, Ali G. Gharavi
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