458 Defining the impact of short-chain fatty acids on the gut–urinary axis in a naturally occurring canine model of calcium oxalate urolithiasis

Objectives/Goals: Short-chain fatty acids (SCFAs) exert protective effects against calcium oxalate (CaOx) urinary stone formation in experimental rodent models, yet these effects are not understood in natural stone formers. This study will define the impact of SCFAs on stone risk factors along the gut–kidney axis in a natural canine model of CaOx stone disease. Methods/Study Population: A randomized, placebo-controlled, clinical trial will be performed using a crossover study design. Twenty dogs that are natural CaOx stone formers will be fed a standardized diet and randomized to receive either a daily prebiotic fiber (inulin) that stimulates SCFA production or a placebo. We will perform fecal shotgun metagenomics and SCFA quantification before and after each intervention (four timepoints) to identify how inulin and SCFAs enrich or deplete pathways relevant to stone formation within the gut microbiome. RT-qPCR will be performed to determine the effects of SCFAs on intestinal oxalate transporter gene expression (SLC26A3 and SLC26A6). At each timepoint, urinary shotgun metagenomics and quantification of urine biochemical profiles used to predict stone risk will also be performed. Results/Anticipated Results: We anticipate that prebiotic stimulation of SCFAs with inulin will reduce stone risk factors along the gut–urinary axis in a natural canine model of urinary stone disease. Specifically, we anticipate that prebiotic stimulation of SCFAs will 1) modify gut and urinary microbial communities to promote pathways considered protective against stone formation, 2) alter the expression of oxalate transporters (SLC26A3, SLC26A6) to reduce net oxalate absorption, and 3) reduce stone-promoting metabolites (e.g., oxalate) in the urine. Discussion/Significance of Impact: By defining the impact of prebiotic fibers and SCFAs on the gut–urinary axis in a natural animal model of CaOx urolithiasis, we will lay the foundation for novel nutritional strategies to prevent CaOx stone disease in both humans and animals.