Characterizing the Role of the Microbiome in Kidney Stone Disease
Abstract
The goal of this thesis was to increase understanding of the role of the human microbiome in kidney stone disease, from stone nidus formation through to surgical stone treatment, using a combination of in vitro, in vivo, and human clinical investigations.
We first optimized our methods of sample collection for the use of such protocols in clinical studies involving urinary and gut microbiota investigations. We developed a novel method of fecal sampling that is amenable to study participants, inexpensive, and results in reliable downstream sequencing results.
We then utilized this sampling methodology in clinical investigations into the microbiota of surgical kidney stone patients using a systems-level approach. We determined that there is a microbiota present in all kidney stone crystalline compositions, which was previously unknown. The urinary microbiome was distinct between stone formers and controls in both microbiota composition and based on targeted metabolomics. Stone formers had higher urinary oxalate concentrations and elevated relative abundance of inflammatory and uropathogenic microbes throughout the course of stone treatment. In the gut, stone formers had altered microbial community composition at both a taxonomic and functional level, with implications for uropathogen abundance and host oxalate homeostasis. We determined that the gut has a significant and multipronged contribution to kidney stone formation.
In a cohort of primarily nephrolithiasis-related urological patients, we further characterized the microbiota associated with ureteral stents, an almost ubiquitous component of surgical stone treatment. We determined that the stent microbiota is reproducible and patient specific, and not represented by the urinary microbiota. Patient factors and comorbidities drive the stent microbiota composition, and neither the microbial community nor degree of stent encrustation were altered by antibiotic use, indicating that perhaps antibiotic use in stent patients needs recalibration.
Finally, we investigated host-microbe interactions in stone formation using in vitro and in vivo models, specifically how uropathogens may contribute to stone formation and how probiotics may provide therapeutic benefit. We determined that both pathogenic and beneficial bacteria have the capability of shaping stone disease progression and should be considered in stone treatment.
Collectively, these studies have shed light on the contribution of microbes in this prevalent and morbid condition, and elucidated novel ways to harness the microbiome in nephrolithiasis management.