Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling.
Summary
This study defines a gut–joint axis in which decreased GUDCA and intestinal FXR signaling modulate osteoarthritis via GLP-1. In mice, inhibiting intestinal FXR alleviated osteoarthritis through GLP-1, and GLP-1 receptor activation mitigated disease while blockade attenuated benefits. Human cohorts showed altered bile acid metabolism consistent with the mechanism.
Key Findings
- Osteoarthritis cohorts showed reduced glycoursodeoxycholic acid (GUDCA) and altered microbial bile acid metabolism.
- Suppressing intestinal FXR alleviated osteoarthritis in mice via intestine-secreted GLP-1.
- GLP-1 receptor activation mitigated osteoarthritis, whereas GLP-1 receptor blockade attenuated benefits.
Clinical Implications
GLP-1 receptor agonists may offer disease-modifying potential in osteoarthritis; modulation of intestinal FXR or bile acid composition could become therapeutic targets pending clinical trials.
Why It Matters
It uncovers a mechanistic link between intestinal FXR, GLP-1 signaling, and osteoarthritis, suggesting repurposing GLP-1 receptor agonists and targeting gut bile acid pathways for joint disease.
Limitations
- Human data are observational and do not establish clinical efficacy of interventions.
- Translational generalizability from mice to human osteoarthritis remains to be proven.
Future Directions
Conduct randomized clinical trials of GLP-1 receptor agonists in osteoarthritis; test intestinal FXR modulators and bile acid interventions; define microbiome drivers of GUDCA changes.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- III - Human observational cohorts coupled with mechanistic animal experiments suggest causal pathways but no clinical trial evidence.
- Study Design
- OTHER