Background: Bile acids (BAs) have emerged as important mediators in neuroinflammation and neurodegeneration, important features of multiple sclerosis (MS). This study aimed to examine serum BA levels in newly diagnosed people with MS (pwMS) and explore their association with disability worsening.

Methods: The study included 907 pwMS and 907 matched controls from the Swedish population-based EIMS cohort, with clinical follow-up data from the Swedish MS Registry. Serum BA levels were analyzed using liquid chromatography-high-resolution mass spectrometry. Differential expression analysis was used to study differences in BAs between pwMS and controls. Cox proportional-hazard models were used to assess associations between BA concentrations and confirmed disability worsening (CDW) and the risk of reaching EDSS milestones 4.0 and 6.0.

Results: PwMS had lower concentrations of the primary conjugated BA, glycochenodeoxycholic acid (GCDCA, log2 FC - 0.29, p = 0.009) compared to controls. In relapsing-remitting MS compared to controls, lower concentrations of primary conjugated BAs (log2 FC - 0.30, p = 8.40E - 5), secondary conjugated BAs (log2 FC - 0.18, p = 0.007), and total BAs (log2 FC - 0.22, p = 2.99E - 4) were found. Sex-specific differences were also found, with male pwMS showing more substantial BA alterations. Elevated total BA levels were associated with increased risk for CDW (HR 1.22, 95% CI 1.08-1.39), driven mainly by primary conjugated (HR 1.19, 95% CI 1.06-1.33) and secondary conjugated BAs (HR 1.21, 95% CI 1.08-1.39).

Conclusions: This study identified alterations in serum BA profiles in pwMS compared to controls, with strong associations between conjugated BAs and the risk of disability worsening. These findings underscore the potential role of BAs in MS pathogenesis and disability worsening, suggesting they may be promising targets for future therapeutic interventions. Further research is warranted to clarify the underlying mechanisms of these associations.