The Impact of Short Chain Fatty Acids on Calcium Regulatory Pathways in Kidney Stone Formers

About This Grant

Project Summary/Abstract Urolithiasis (urinary stone disease) is a rapidly escalating public health crisis worldwide. The prevalence of kidney stones has more than doubled over the past 40 years, yet minimal new strategies for disease prevention have become available for decades. Calcium oxalate (CaOx) is one of the most common types of urolith, but this mineral composition requires expensive methods of physical removal. Following stone removal procedures, recurrence rates are as high as 50% in 5 years, highlighting an urgent need for novel, effective, and accessible stone prevention strategies. Disturbances in calcium balance constitute the most common metabolic abnormality underlying CaOx stone formation, yet the causes of these imbalances are often not identified. Recent discoveries suggest that the microbiome and microbial metabolites may influence stone formation. For instance, patients with CaOx urolithiasis exhibit deficiencies in short chain fatty acids (SCFAs), a class of metabolites produced in the gut following microbial fermentation of dietary and prebiotic fibers. In rodent models of urolithiasis, SCFA supplementation markedly reduces CaOx renal crystallization, potentially by lowering urinary oxalate and exerting anti-inflammatory effects in the kidneys. However, the relationship between SCFAs and calcium homeostasis in the context of CaOx urolithiasis remains poorly understood. This gap in knowledge is especially important given the high prevalence of idiopathic calcium disturbances in CaOx stone formers. In this study, we will use a multi-omics approach to delineate the interplay between the microbiome, SCFAs, calcium regulation, and stone risk in a natural canine model of CaOx urolithiasis. Dogs are a particularly powerful translational model for studying CaOx stone formation, as dogs form CaOx stones commonly and share several risk factors and features of disease pathology with humans. This includes parallels in calcium disturbances, microbiome abnormalities, and lower abundances of SCFA-producing bacteria. First, we will perform a prospective, case-control study to define interactions between SCFAs and individual calcium regulatory pathways in dogs with and without CaOx urolithiasis. This will bridge major gaps in our understanding of the microbiome and its role in stone pathogenesis. Second, we will examine how these pathways can be manipulated using prebiotic fibers to enrich SCFA production. This will provide practical insight into an inexpensive and accessible dietary supplement as a potential new stone prevention strategy. Third, we will determine how specific microbial and metabolic features predict stone recurrence. This will help us identify potential risk factors for stone recurrence that can be used to guide patient monitoring. We have assembled a powerful multidisciplinary mentoring team that is uniquely suited to guide this project. Data from this work will also lay the foundation for a future R01 funding application. With the resources and protected time provided through this award, I will advance my professional training and create a clear path towards independence as a translational microbiome and urological researcher.