Doctor of Philosophy
Microbiology and Immunology
Burton, Jeremy P.
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.
Summary for Lay Audience
Kidney stone disease affects approximately 10% of the population; it has been described as a pain worse than childbirth and its treatment is a financial drain to the health care system. Many people develop stones time and time again, but why this happens is not well known. This project aimed to determine if the microbiota, the bacteria that live within us, is a factor in this disease. We determined that the bacteria, and the products they make, in the gut and urinary tract of people with stone disease are different from healthy individuals in ways that may exacerbate stone formation. The majority of kidney stones are composed of calcium oxalate, and the gut bacteria in stone formers may be causing the increased levels of oxalate that we measured in the patient’s urine. Stone formers that are exposed to antibiotics more often also carried antibiotic-resistant bacteria within them, indicating previous antibiotic exposure damages the beneficial microbial ecosystem. When we investigated medical devices (ureteral stents) that are used in stone patients which can become infected with bacteria, antibiotic use did not prevent the presence of harmful bacteria on the devices, or in the bladder. We also found that the stent microbiota was different if the patient had diabetes, IBS/IBS, and other comorbidities. These factors should be considered in future stone patients that require ureteral stents and we believe the standard of care of antibiotics needs to be modified. Using a model of stone disease in fruit flies, we determined that beneficial bacteria could protect against stone formation, and that harmful bacteria in the urinary tract may be making stone disease worse. Future research could lead to the development of effective probiotics against kidney stones. Overall, we have found that bacteria are intimately involved in stone formation — some harmful bacteria present in stone formers encourage stone formation, while beneficial bacteria in healthy people are protective. This condition is increasing in prevalence, and we need better solutions to prevent it — this work illustrates that bacteria may be the key to future kidney stone treatment.
Al, Kaitlin F., "Characterizing the Role of the Microbiome in Kidney Stone Disease" (2020). Electronic Thesis and Dissertation Repository. 7122.
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