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Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation
Pavan Bhargava, … , Emmanuelle Waubant, Peter A. Calabresi
Pavan Bhargava, … , Emmanuelle Waubant, Peter A. Calabresi
Published March 17, 2020
Citation Information: J Clin Invest. 2020;130(7):3467-3482. https://doi.org/10.1172/JCI129401.
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Research Article Metabolism Neuroscience Article has an altmetric score of 25

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

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Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein–coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Authors

Pavan Bhargava, Matthew D. Smith, Leah Mische, Emily Harrington, Kathryn C. Fitzgerald, Kyle Martin, Sol Kim, Arthur Anthony Reyes, Jaime Gonzalez-Cardona, Christina Volsko, Ajai Tripathi, Sonal Singh, Kesava Varanasi, Hannah-Noelle Lord, Keya Meyers, Michelle Taylor, Marjan Gharagozloo, Elias S. Sotirchos, Bardia Nourbakhsh, Ranjan Dutta, Ellen M. Mowry, Emmanuelle Waubant, Peter A. Calabresi

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Figure 7

Therapeutic effect of TUDCA supplementation in EAE is dependent on GPBAR1.

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Therapeutic effect of TUDCA supplementation in EAE is dependent on GPBAR...
Nine- to 11-week-old female WT or GPBAR1-KO C57/BL6 mice were subcutaneously immunized with MOG35–55 and CFA in addition to intraperitoneal injection of PTX on day 0 and day 2. Mice were then monitored for signs of EAE, and at disease onset, the mice were randomized to oral gavage with either 500 mg/kg TUDCA or vehicle until day 28 after immunization. (A) Behavioral scores showed that TUDCA treatment resulted in reduced severity of EAE in WT mice. (B) No significant difference was noted in EAE severity between the 2 treatment groups in GPBAR1-KO mice. Individual data points are shown along with the mean ± SEM. Data were derived from 2 independent experiments. ***P < 0.001, by Mann-Whitney U test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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