SRP125915 PRJNA420573 Osteoarthritis induced by destabilization of the medial meniscus is reduced in germ-free mice Objective: To determine the contribution of the gut microbiota to the development of injury-induced osteoarthritis (OA).Design: OA was induced using the destabilized medial meniscus (DMM) model in 20 germ-free (GF) C57BL/6 male mice housed in a gnotobiotic facility and 23 strain-matched specific pathogen free (SPF) mice in 2 age groups -13.5 weeks avg age at DMM (17 SPF and 15 GF) and 43 weeks avg age at DMM (6 SPF and 5 GF). OA severity was measured using scores for articular cartilage structure (ACS), loss of SafO staining, osteophyte size, and synovial hyperplasia. Microbiome analysis by 16S rRNA amplicon sequencing was performed on stool samples and LPS and LPS binding protein were measured in plasma.Results: The maximum ACS score per joint (both age groups) was 28% lower (p =0.036) in GF mice while the SafO sum score of all sections evaluated per joint was decreased by 31% (p=0.009). The results were more significant when only the younger mice were included in the analysis. Young GF mice also had significant reductions in osteophyte size (36%, p= 0.0119) and LBP (26%, p=0.007) but not synovial scores or LPS. Overall Operational Taxonomic Units (OTU) reads for GF mice were very low when compared to the SPF controls. Differences in relative abundance of a number of OTUs were noted between SPF mice with high vs. low maximum ACS scores.Conclusions: These results suggest factors related to the gut microbiota promote the development of OA after joint injury.