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

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 1

Bile acid metabolism is altered in MS.

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Bile acid metabolism is altered in MS. (A) Overview of bile acid metabol...
(A) Overview of bile acid metabolism. (B) Heatmap of mean standardized bile acid metabolite concentrations derived from untargeted metabolomic profiling in the discovery cohort consisting of patients with RRMS (n = 56), patients with PMS (n = 52), and HCs (n = 50). Multiple bile acid metabolites in both primary and secondary bile acid metabolism pathways were lower in the MS groups compared with controls. Asterisks denote significant differences compared with HCs based on multivariate linear regression models adjusted for age, sex, and race (P < 0.05). (C) Box plots of pathway deregulation scores for primary bile acid metabolism in the discovery cohort demonstrated significant abnormality in the PMS group compared with controls. For all box plots, the center line indicates the median, the box indicates the 25th and 75th percentiles, the whiskers indicate 1.5 × IQR, and the dots indicate outliers. (D) Box plots of pathway deregulation scores for secondary bile acid metabolism in the discovery cohort show significant abnormality in the RRMS and PMS groups compared with the control group. P values for C and D were derived from multivariate linear regression models adjusted for age, sex, and race. (E) Heatmap of mean standardized bile acid metabolite concentrations derived from targeted metabolomic profiling in the validation cohort consisting of patients with RRMS (n = 50), patients with PMS (n = 125), and HCs (n = 75). Multiple bile acid metabolites in both primary and secondary bile acid metabolism pathways were lower in the MS groups compared with the control group. Asterisks denote significant differences as in B. (F) Box plots of pathway deregulation scores for primary bile acid metabolism in the validation cohort demonstrate significant abnormality in the PMS group compared with controls. (G) Box plots of pathway deregulation scores for secondary bile acid metabolism in the validation cohort show significant abnormality in the PMS group compared with controls. P values in F and G were derived as in C and D. (H) An increase in the DCA (sum of all DCA metabolites) to CA (sum of all CA metabolites) metabolite ratio was noted in the PMS group compared with the control group. The ratios of DCA to individual conjugated CA metabolites were also higher in the PMS group (I and J). (K) The ratio of the sum of UDCA and LCA metabolites to the sum of CDCA metabolites was higher in the PMS group compared with the control group. Data in H–K represent the mean ± SEM, and P values were determined using a linear regression model.