Osteoarthritis is a common degenerative condition of the joints that is usually attributed to “wear and tear” and is managed by treating the symptoms. By performing metabolomic studies in hundreds of patients from independent clinical cohorts, Yang et al. identified specific differences in bile acids between people who did or did not have osteoarthritis (see the Perspective by Liu), identified the underlying signaling mechanism, and also linked the differences in bile acids to specific species among the intestinal microbiota. Using a mouse model of osteoarthritis, the authors demonstrated the effectiveness of repurposing a clinically approved drug that targets bile acid metabolism. Moreover, human patients using this drug for other reasons had a lower risk of requiring a knee replacement for osteoarthritis, providing further support for potential clinical translation. —Yevgeniya Nusinovich The gut microbiota has emerged as a critical regulator of host health by producing a diverse range of microbial metabolites to affect physiological and pathophysiological processes ( 1– 3). These metabolites can affect innate and adaptive immune systems ( 4, 5) and regulate key metabolic pathways in the hosts ( 6, 7). Although previous research has demonstrated the functional roles of microbial metabolites in systematic immune and metabolic disorders, few studies have explored whether metabolites play a role in conditions with localized effects, such as joint diseases.