TY - JOUR
T1 - Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease
AU - Ladakis, Dimitrios C.
AU - Harrison, Kimystian L.
AU - Smith, Matthew
AU - Solem, Krista
AU - Gadani, Sachin
AU - Jank, Larissa
AU - Hwang, Soonmyung
AU - Farhadi, Farzaneh
AU - Dewey, Blake
AU - Fitzgerald, Kate
AU - Sotirchos, Elias S.
AU - Saidha, Shiv
AU - Calabresi, Peter
AU - Bhargava, Pavan
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - bile acids
KW - multiple sclerosis
KW - Translation to patients
KW - TUDCA
UR - http://www.scopus.com/inward/record.url?scp=85207744605&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85207744605&partnerID=8YFLogxK
U2 - 10.1016/j.medj.2024.09.011
DO - 10.1016/j.medj.2024.09.011
M3 - Article
C2 - 39447576
AN - SCOPUS:85207744605
SN - 2666-6359
JO - Med
JF - Med
ER -