Obesity is a risk factor for osteoarthritis (OA), the greatest cause of disability in the US. The impact of obesity on OA is driven by systemic in ammation, and increased systemic in ammation is now understood to be caused by gut microbiome dysbiosis. Oligofructose, a nondigestible prebiotic ber, can restore a lean gut microbial community pro le in the context of obesity, suggesting a potentially novel approach to treat the OA of obesity. Here, we report that — compared with the lean murine gut — obesity is associated with loss of bene cial Bi dobacteria, while key proin ammatory species gain in abundance. A downstream systemic in ammatory signature culminates with macrophage migration to the synovium and accelerated knee OA. Oligofructose supplementation restores the lean gut microbiome in obese mice, in part, by supporting key commensal micro ora, particularly Bi dobacterium pseudolongum. This is associated with reduced in ammation in the colon, circulation, and knee and protection from OA. This observation of a gut microbiome–OA connection sets the stage for discovery of potentially new OA therapeutics involving strategic manipulation of speci c microbial species inhabiting the intestinal space.