# Causal Relationships Between Dietary Habits, Gut Microbiota, Metabolites, Serum Proteins and Laboratory Biomarkers in Kidney Stone Formation: A Mendelian Randomisation Study

## TL;DR

This study uses genetic data to explore how diet, gut microbes, and blood markers influence kidney stone formation, identifying key causal and indirect pathways.

## Contribution

The study identifies novel causal and mediated relationships between dietary habits and kidney stone formation through seven key biomarkers using Mendelian randomisation.

## Key findings

- Nine dietary factors, 11 gut microbiota types, and eight metabolites show direct causal links to kidney stone formation.
- Five dietary habits mediate kidney stone risk through seven biomarkers, with six showing facilitatory and three showing inhibitory effects.
- Mediation analysis reveals nine indirect pathways linking diet to kidney stones via laboratory biomarkers.

## Abstract

This study aimed to elucidate the causal interplay between dietary habits, gut microbiota composition, circulating metabolites, serum proteins, laboratory biomarkers and kidney stone formation, employing Mendelian randomisation (MR) to identify potential mediators. A rigorous two‐sample MR framework was employed to assess the causal associations between kidney stones and a spectrum of predisposing factors. This encompassed dietary patterns, gut microbiota profiles, circulating metabolic intermediates, serum proteins and laboratory test indicators. Significant associations were further analysed using mediation analysis to uncover indirect pathways. Initial significance was determined at p < 0.05, followed by the implementation of False Discovery Rate correction (FDR p < 0.05) to reduce the likelihood of false positives due to multiple comparisons. Direct causal relationships were established between kidney stones and 9 dietary factors (including fruit, alcohol, coffee intake), 11 gut microbiota types, 8 metabolites, 12 plasma proteins and 8 laboratory indicators (CRE, EGFR, CA, UAHDL, APOA, CYS and URNA). Notably, nine mediation pathways were discovered. These pathways reveal the indirect effects of dietary habits on kidney stone formation mediated through laboratory biomarkers. Specifically, five dietary habits—alcohol, coffee, fruit, champagne/white wine and dried fruit consumption—were shown to mediate through seven key factors: APOA, CA, CYS, EGFR, HDL, UA and URNA. Six of these mediations were positive, indicating facilitatory roles, while three exhibited negative mediation, suggestive of competitive inhibition in the diet‐kidney stone causal pathway. This MR study underscored the causal links between dietary habits, gut microbiota composition, circulating metabolites, serum proteins, laboratory biomarkers and kidney stone development, shedding light on potential mediators including seven laboratory biomarkers.