Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation
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
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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Research Article Metabolism Neuroscience

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

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 4

The cell-surface bile acid receptor GPBAR1 is detected in demyelinating lesions in PMS brains.

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The cell-surface bile acid receptor GPBAR1 is detected in demyelinating ...
(A) Immunohistochemistry for PLP and CD68 identified an active and a mixed active/inactive MS WML, with GPBAR1+ cells detected within both of these lesions. Comparison of GPBAR1 staining (red) in an active lesion (B), a mixed active/inactive lesion (C), and control brain (D) revealed increased staining in MS lesions compared with control white matter. Double immunostaining for PLP (green) and GPBAR1 (red) shows the presence of GPBAR1+ cells (E) and vessels (F) in areas of demyelination. (G–I) Double immunostaining using GFAP (green) and GPBAR1 (red) demonstrates GPBAR1 staining in GFAP+ astrocytes in MS lesions. (J–L) Double immunostaining with CD68 (green) and GPBAR1 (red) demonstrates GPBAR1 staining in CD68+ macrophages in MS lesions. (M) Comparison of PLP and GPBAR1 gene expression in MS WML and NAWM revealed decreased PLP expression within the lesions with increased expression of GPBAR1, similar to findings noted on immunohistochemistry (n = 4 in each group). Scale bars: 200 μm (A); 100 μm (B–F); 20 μm (G–I). *P < 0.05, by 2-tailed Mann-Whitney U test. Data in M represent the mean ± SEM.