Bile Acids Metabolites as Predictors of long-term Multiple Sclerosis Progression
Marianna Cortese1, Kjetil Bjornevik1, Clary B. Clish3, Gilles Edan4, Mark Freedman5, Hans-Peter Hartung6, Xavier Montalban7, Rupert Sandbrink6,8,9, Ernst-Wilhelm Radue10,11, Frederik Barkhof12,13, Eva-Maria Wicklein14, Ludwig Kappos11, Kassandra Munger1, Alberto Ascherio1,2,15
1Department of Nutrition, 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, 3Metabolomics Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, 4CHU Hôpital Pontchaillou, 5Department of Medicine, University of Ottawa, 6Department of Neurology, Medical Faculty, Heinrich-Heine University, 7Multiple Sclerosis Center of Catalonia (Cemcat), Vall Hebron University Hospital-Multiple Sclerosis Centre of Catalonia, 8Vico Therapeutics B.V., 9Cellerys AG, 10Medical Image Analysis Center, 11Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Head, Spine and Neuromedicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, 12Image Analysis Center, 13Amsterdam University Medical Centers, 14Bayer AG, 15Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Objective:
To examine the association of serum levels of bile acid metabolites with multiple sclerosis (MS) progression.
Background:

Bile acids have been suggested to be dysregulated in MS and have neuroprotective properties in vitro and in vivo. It is unknown whether serum levels of bile acid metabolites in early MS predict long-term disease progression.

Design/Methods:

In this prospective study, we measured primary and secondary bile acids in blood samples collected at baseline among the 468 participants in the BENEFIT clinical trial enrolled at the time of their clinically isolated syndrome. We used linear regression to examine the relationship of the bile acid metabolites with change in clinical disability (EDSS, MSFC) and radiological progression markers (T1-hypointense lesion volume, brain volume loss) to year 5. Bile acid concentrations were measured by liquid chromatography-mass spectrometry and were log transformed and standardized by sex. Models were adjusted for age, sex, initial treatment allocation, steroid treatment, multifocal symptoms, number of T2-lesions, and body mass index, and further for mean 25-hydroxyvitamin D and cigarette smoking as measured by repeated serum cotinine levels within the first 2 years from CIS. Investigations of other disease course markers and machine learning analyses are ongoing.

Results:

Higher levels of several primary and secondary bile acids were associated (p<0.05) with less deterioration in clinical disability as measured by EDSS (cholic acid, hyodeoxycholic acid) and MSFC (glycoursodeoxycholic acid, chenodeoxycholic acid glycine conjugate, lithocholic acid glycine conjugate). Bile acids were not associated with radiological progression markers. Adjusting the multivariable models further for vitamin D and smoking did not change the results.

Conclusions:

Preliminary results of this metabolomic study suggest a bile acid dysregulation in early MS that may predict clinical MS progression 5 years after the first clinical episode.