Metabolomics Analysis Identifies Abnormal Bile Acid Metabolism in Multiple Sclerosis
MS patients have abnormalities in multiple metabolic pathways that can be identified by metabolomics. Bile acids (BA) have several functions, including direct modulation of myeloid cells in the peripheral immune system and microglia in the CNS through specific receptors expressed on these cells. Recent studies have shown promising results of BA treatment in various neurodegenerative conditions. Whether BA metabolism is affected in MS has not been well studied.
To use global (untargeted) and targeted metabolomics to determine differences in plasma levels of primary and secondary BA metabolites in patients with progressive MS (PMS) and relapsing remitting MS (RRMS), as compared to healthy controls (HC).
We enrolled two cohorts for this study – a discovery cohort including 150 participants (50 HC, 50 RRMS, 50 PMS) and a validation cohort including 250 participants (75 HC, 50 RRMS, 125 PMS). Plasma from participants in the discovery cohort underwent global metabolomics analysis, which identified a total of over 600 metabolites of which 25 are involved in BA metabolism. Plasma from the validation cohort underwent targeted measurement of 15 primary and secondary BAs to confirm the results obtained from untargeted analyses. We calculated pathway deregulation scores (PDS) – a representation of the distance of each individual from a principal components curve derived from HCs (higher scores denote greater abnormality). We used linear regression to compare PDS and individual BA levels between groups adjusting for age and sex.
In the discovery cohort, we noted lower levels of multiple primary and secondary BAs in the MS cohort compared to HCs. Comparison of PDS scores revealed higher scores in the RRMS group for secondary BA metabolism (p=0.002) with PMS group demonstrating abnormalities for both primary and secondary BA metabolism (p<0.002 for both) as compared to HC.
In the validation cohort, PDS scores for primary (p<0.001) and secondary (p=0.04) BA metabolism were higher in the PMS group compared to controls. In particular, reductions in multiple glycine and taurine conjugated BAs were noted in the PMS group. Levels of multiple different BAs were negatively correlated with MS disease duration after adjustment for age and sex.
BA metabolism is altered in MS and is negatively correlated with disease duration. These results identify a potential role of BA metabolism in MS and may help develop targeted therapies.