Dimitrios C Ladakis, Kimystian L Harrison, Matthew D Smith, Krista Solem, Sachin Gadani, Larissa Jank, Soonmyung Hwang, Farzaneh Farhadi, Blake E Dewey, Kathryn C Fitzgerald, Elias S Sotirchos, Shiv Saidha, Peter A Calabresi, Pavan Bhargava
{"title":"胆汁酸代谢物可预测多发性硬化症的进展，对进展期疾病补充胆汁酸是安全的。","authors":"Dimitrios C Ladakis, Kimystian L Harrison, Matthew D Smith, Krista Solem, Sachin Gadani, Larissa Jank, Soonmyung Hwang, Farzaneh Farhadi, Blake E Dewey, Kathryn C Fitzgerald, Elias S Sotirchos, Shiv Saidha, Peter A Calabresi, Pavan Bhargava","doi":"10.1016/j.medj.2024.09.011","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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<sup>+</sup> and Th1/17 cells decreased, while CD4<sup>+</sup> 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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>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.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.\",\"authors\":\"Dimitrios C Ladakis, Kimystian L Harrison, Matthew D Smith, Krista Solem, Sachin Gadani, Larissa Jank, Soonmyung Hwang, Farzaneh Farhadi, Blake E Dewey, Kathryn C Fitzgerald, Elias S Sotirchos, Shiv Saidha, Peter A Calabresi, Pavan Bhargava\",\"doi\":\"10.1016/j.medj.2024.09.011\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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<sup>+</sup> and Th1/17 cells decreased, while CD4<sup>+</sup> 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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Funding: </strong>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.</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2024.09.011\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.09.011","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.
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.
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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