Bile acids as candidate therapies for multiple sclerosis: inverse signal analysis using the FDA adverse event reporting system and preclinical validation

BACKGROUND: Alterations in bile acid metabolism have been observed in individuals with multiple sclerosis (MS), yet the therapeutic implications of bile acid supplementation remain uncertain. METHODS: We conducted a two-stage study integrating pharmacovigilance analysis with preclinical validation to evaluate bile acid derivatives as candidate therapies for MS. A disproportionality analysis of the FDA Adverse Event Reporting System (FAERS; Q4/2003-Q2/2025) was performed to identify inverse associations between MS and bile acid preparations. The effects of ursodeoxycholic acid (UDCA) and obeticholic acid (6-ECDCA) were evaluated in a therapeutic experimental autoimmune encephalomyelitis (EAE) model, with treatment initiated after disease onset. RESULTS: Among 13,734,539 FAERS reports, 75,659 involved MS. Inverse associations were identified for UDCA (odds ratio [OR]: 0.197, 95% confidence interval [CI]: 0.117-0.333) and 6-ECDCA (OR: 0.128, 95% CI: 0.041-0.396). In the EAE model, UDCA was associated with lower clinical scores at the peak (day 18) and late phases (days 26-28), whereas 6-ECDCA showed only a non-significant trend toward improvement at day 28. CONCLUSION: This two-stage investigation highlights the potential utility of pharmacovigilance-guided approaches for identifying therapeutic candidates. Bile acid derivatives, particularly UDCA, are biologically plausible candidates meriting further investigation in the context of MS.