# Evaluation of the gut-kidney axis in kidney stone disease

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $732,932

## Abstract

PROJECT SUMMARY
Kidney stone disease is highly prevalent, increasingly common, and associated with considerable morbidity.
However, 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 new treatments for kidney
stone prevention. However, most prior studies of the gut microbiome in this population 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.
In this proposal, we build on our recent discoveries of the role of diet, antibiotics, the gut microbiome, and the
metabolome in kidney stone disease. We leverage an interdisciplinary team that is uniquely poised to define the
human gut-kidney axis in kidney stone disease by combining expertise in using nutritional profiling, mediation
analyses of high-dimensional microbiome and metabolomic data, and large data analytics. The proposed
research tests the central hypothesis that diet and antibiotics contribute to nephrolithiasis by perturbing the gut-
kidney axis through alterations of the gut microbiome. In doing so, the proposed studies will identify metabolic
pathways in the gut-kidney axis that could be targets for novel therapeutics to prevent kidney stones. In Aim 1,
we will identify perturbations of the microbiome and metabolome in kidney stone disease. We will assess diet
and collect stool and urine from 300 participants ≥4 years old without recent antibiotic exposure (150 with calcium
kidney stones and 150 matched controls), oversampling younger participants. We will sequence the gut
microbiome using shotgun metagenomics and measure downstream metabolites using untargeted
metabolomics of stool and urine, targeted short-chain fatty acid metabolomics of stool, and 24-hour urine
chemistries. Using novel mediation models, we will define the direct and indirect effect of diet on the gut
microbiome and intestinal and urinary metabolites and its contribution to kidney stones. In Aim 2, we will, for the
first time, determine the relationship between oral antibiotic exposure and urine chemistries in kidney stone
disease. We will link 24-hour urine chemistry results with pharmaceutical claims and clinical data of individuals
in the HealthCore database, which includes >48 million individuals. 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. We will then perform a cohort study to identify how oral antibiotics alter urine
chemistri...

## Key facts

- **NIH application ID:** 9957071
- **Project number:** 5R01DK122156-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michelle Denburg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $732,932
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957071

## Citation

> US National Institutes of Health, RePORTER application 9957071, Evaluation of the gut-kidney axis in kidney stone disease (5R01DK122156-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957071. Licensed CC0.

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