Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling

Abstract

Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)-the receptor of GUDCA-alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of <i>Clostridium bolteae</i>, which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with <i>C. bolteae</i> and Food and Drug Administration-approved UDCA alleviated osteoarthritis through the gut FXR-joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota-GUDCA-intestinal FXR-GLP-1-joint pathway offers a potential strategy for osteoarthritis treatment.