The cumulative incidence of kidney stone disease in the United States has doubled over 15 years, and its prevalence is now equivalent to that of diabetes. This dramatic and unexplained rise in incidence has disproportionately affected children and young women. More than the episodic occurrence of debilitating stone events, nephrolithiasis is a disorder of mineral metabolism with considerable associated morbidity, including increased risk for chronic kidney disease, fracture, hypertension, and cardiovascular disease. Despite its increasing prevalence, high morbidity, and annual costs of $10 billion, no new treatments to prevent kidney stones have been introduced in the last 30 years. Understanding how dysbiosis of the gut microbiome contributes to nephrolithiasis could lead to novel treatments for kidney stone prevention. However, most prior studies of the gut microbiome focused on Oxalobacter formigenes without considering the role of the entire gut microbiome in the gut-kidney axis, which is the complex interplay between the intestinal and urinary tracts in human health and disease. A critical barrier to developing new treatments for stone prevention is a lack of understanding of how perturbations of the gut microbiome and downstream changes in metabolites in the intestinal and urinary tracts contribute to kidney stone disease. Discovery of unique microbial communities and their associated metabolites could lead to the identification of therapeutic targets for kidney stone prevention.
The long-term goal of this project is to identify metabolic pathways in the gut-kidney axis that could be targets for novel therapeutics to prevent kidney stones. Our group investigates how diet and antibiotics alter the gut-kidney axis in humans using nutritional profiling, mediation analyses of high-dimensional microbiome and metabolomic data, and large data analytics. We demonstrated that insufficient zinc intake, which decreases gut microbiome diversity, is associated with an increased risk of calcium stones in adolescents. Our pilot data show that butyrate-producing and oxalate-degrading taxa are less abundant in individuals with calcium stones (N = 44) versus controls. Butyrate is a short-chain fatty acid (SCFA) that maintains the gut mucosal barrier and regulates expression of SLC26 oxalate transporters in the intestine. Loss of bacteria that produce butyrate and degrade oxalate may act synergistically to increase intestinal absorption and urinary excretion of oxalate. At a population level, we were also the first group to demonstrate that exposure to certain oral antibiotics (fluoroquinolones, sulfas, cephalosporins, nitrofurantoin, and broad-spectrum penicillins) is a risk factor for kidney stones. The risk was greatest for those exposed at younger ages, which is consistent with reports that antibiotic exposures at younger ages produce more profound alterations of host macronutrient metabolism than those later in life. Collectively, these findings have informed our central hypothesis that diet and antibiotics contribute to nephrolithiasis by perturbing the gut-kidney axis through alterations of the gut microbiome.
In Aim 1, we will define the impact of diet on the gut microbiome and intestinal and urinary metabolites in stone disease. In Aim 2, we will determine, for the first time, how antibiotics alter urine chemistries. Aim 1: To identify perturbations of the microbiome and metabolome in kidney stone disease. We will assess diet and collect stool and urine from 300 children (≥4 years old) and adults without antibiotic exposure in the last 3 months (150 with calcium kidney stones and 150 matched controls). In Aim 1a, we will sequence the gut microbiome using shotgun metagenomics. In Aim 1b, we will measure downstream metabolites using untargeted metabolomics of stool and urine, targeted SCFA metabolomics of stool, and 24-hour urine chemistries. We hypothesize that lower abundance of metabolites in stool that affect intestinal absorption of oxalate (e.g. butyrate) mediate diet-related changes of the gut microbiome in patients with kidney stones. The results of this Aim will reveal intermediary metabolites that may contribute to kidney stones. Aim 2: To define the link between oral antibiotic exposure and urine chemistries in kidney stone disease. We will leverage the HealthCore database of >48 million individuals with medical and pharmacy coverage and link pharmaceutical claims and clinical data with 24-hour urine chemistry results. In Aim 2a, we will conduct a nested case-control study to determine the relationship between the dose and duration of antibiotic exposure and kidney stones and to identify sub-groups at greatest risk. In Aim 2b, we will conduct a cohort study to identify how oral antibiotics alter urine chemistries among 228,665 individuals 4-65 years of age. We hypothesize that greater exposure to fluoroquinolones, sulfas, cephalosporins, nitrofurantoin, and broad-spectrum penicillins increase stone risk by increasing urine oxalate. The results of this Aim will identify urine chemistries through which antibiotics may contribute to kidney stones.
Impact: Our proposal was built on our recent discoveries of the role of diet, antibiotics, the gut microbiome, and the metabolome in kidney stone disease.Our unique study design and interdisciplinary team will define the human gut-kidney axis in nephrolithiasis by leveraging our expertise in kidney stones, pharmacoepidemiology, large data linkage, the microbiome and metabolome, and mediation analyses of high-dimensional data. These results will identify metabolites that contribute to kidney stones following perturbation of the gut microbiome and provide key insights for future studies of primary and secondary stone prevention.