Objectives/Goals: Osteoarthritis (OA) is a multifactorial disease where sustained gut inflammation is a continued source of inflammatory mediators driving degenerative processes in joints. The goal was to use spontaneous equine model to compare fecal and leukocyte microbiome and correlation to transcriptome in OA. Methods/Study Population: Seventy-six horses (31 OA, 45 controls) were enrolled by population-based sampling. Feces and peripheral blood mononuclear cells (PBMC) were collected. Horses were determined to have OA by clinical and radiographic evidence. Horses were excluded if they received medications or joint injections within two months. Fecal and circulating leukocyte bacterial microbial 16s-seq was performed. Bulk RNAseq of PBMC was performed by the Illumina platform. Gene expression data were mapped to the equine genome, and differential expression analysis was performed with DESeq2. Qiime2 was used for microbial analysis. Enrichment analysis was performed with a cluster profiler. Correlation analyses were performed between the datasets. Results/Anticipated Results: Beta and alpha microbial diversity differed in feces and PBMC of OA vs. healthy horses. Horses with OA had an increased Firmicutes to Bacteroidetes ratio compared with controls. The fecal microbiome of OA horses had significantly higher amounts of Firmicutes Oribacterium (q Discussion/Significance of Impact: These data suggest that altered microbiome and PBMC gene expression are associated with naturally occurring OA in the translational equine model. While Oribacterium has been detected in humans with rheumatoid arthritis, its role in OA warrants further proteomic and metabolomic profiling.