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Randomized Controlled Trial
. 2025 Mar 14;6(3):100522.
doi: 10.1016/j.medj.2024.09.011. Epub 2024 Oct 23.

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease

Dimitrios C Ladakis  1 , Kimystian L Harrison  1 , Matthew D Smith  1 , Krista Solem  1 , Sachin Gadani  1 , Larissa Jank  1 , Soonmyung Hwang  1 , Farzaneh Farhadi  1 , Blake E Dewey  1 , Kathryn C Fitzgerald  1 , Elias S Sotirchos  1 , Shiv Saidha  1 , Peter A Calabresi  1 , Pavan Bhargava  2
Affiliations
Randomized Controlled Trial

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease

Dimitrios C Ladakis et al. Med. .

Abstract

Background: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.

Methods: Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters.

Findings: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups.

Conclusions: Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

Funding: National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.

Keywords: TUDCA; Translation to patients; bile acids; clinical trial; multiple sclerosis; progressive MS.

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Conflict of interest statement

Declaration of interests E.S.S. has received consulting fees from Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam and speaking honoraria from Alexion, Viela Bio, and Biogen. S.S. has received consulting fees from Medical Logix for the development of continuing medical education programs in neurology and has served on scientific advisory boards for Biogen, Novartis, Genentech Corporation, TG Therapeutics, Clene Pharmaceuticals, and ReWind Therapeutics. He has performed consulting for Novartis, Genentech Corporation, JuneBrain LLC, Innocare Pharma, Kiniksa Pharmaceuticals, and Lapix Therapeutics. He is the principal investigator (PI) of investigator-initiated studies funded by Genentech Corporation, Biogen, and Novartis. He previously received support from the Race to Erase MS Foundation. He has received equity compensation for consulting from JuneBrain LLC and Lapix Therapeutics. He was also the site investigator of trials sponsored by MedDay Pharmaceuticals and Clene Pharmaceuticals and is the site investigator of trials sponsored by Novartis and Lapix Therapeutics. P.A.C. has received funding from MRF for this work and is the PI on a grant from Genentech to Johns Hopkins University (JHU). He has received consulting fees from Lilly, Idorsia, and Novartis. P.B. has received grant funding to JHU from Amylyx Pharmaceuticals, Genentech Corporation, EMD-Serono, and GSK.

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