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Bile acid metabolism is altered in MS and supplementation leads to amelioration of neuroinflammation
ECTRIMS Online Library. Bhargava P. Oct 12, 2018; 232054
Pavan Bhargava
Pavan Bhargava
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Abstract: 301

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Biomarkers

Introduction: Bile acids (BA) are cholesterol metabolites that have several functions, including direct effects on immune and glial cells. Whether BA metabolism is affected in MS is not known.
Objectives: To determine alterations in circulating BA metabolites in MS and determine the effects of a BA, tauroursodeoxycholic acid (TUDCA), on neuroinflammation.
Methods: We enrolled discovery (50 healthy controls [HC], 50 RRMS, 50 PMS), validation (75 HC, 50 RRMS, 125 PMS) and pediatric cohorts (31 HC, 31 MS). We utilized global (discovery and pediatric) or targeted (validation) metabolomics analyses to measure BA metabolites. We calculated pathway deregulation scores (PDS) - distance of an individual from a principal components curve derived from HCs. We used linear regression to compare PDS and BA levels between groups adjusting for age and sex.
We induced experimental autoimmune encephalomyelitis (EAE) in 7-8 week old C57/BL6 mice (with MOG35-55). At onset of paralysis, we treated mice with oral TUDCA (500 mg/kg) or vehicle till day 28 post-immunization. We compared behavioral scores and pathological outcomes (demyelination and immune cell infiltration) between groups and examined the effect of TUDCA on microglial polarization (M1/M2) and the development of neurotoxic (A1) astrocytes in vitro.
Results: MS patients in the discovery cohort had lower levels of multiple BAs compared to HC. PDS scores were higher in RRMS for secondary BA metabolism (p=0.002), while PMS had abnormalities in both primary and secondary BA metabolism (p< 0.002 for both). In the validation cohort, PDS scores for primary (p< 0.001) and secondary (p=0.04) BA metabolism were higher in PMS compared to HC. In pediatric MS, we again noted higher PDS scores for primary BA metabolism (p=0.015).
In EAE, severity was reduced in the TUDCA group (p< 0.05) with a corresponding decrease in demyelination and immune cell infiltration. In vitro, M1 polarization was reduced (reduced NOS2 gene expression and nitrite production) with TUDCA treatment versus vehicle. In astrocyte cultures with added factors (IL-1a, TNF-a, C1q) promoting A1 polarization, we noted reduced expression of A1-specific gene transcripts with TUDCA compared to vehicle.
Conclusions: BA metabolism was altered in both adult and pediatric MS. BA supplementation ameliorated EAE, and in vitro treatment prevented pro-inflammatory polarization of microglia and astrocytes. Targeting BA metabolism may yield new therapeutic avenues for MS.
Disclosure: Dr. Bhargava: is supported by a Young Investigator Award from the Race to Erase MS, a Career Transition Award from the National MS Society and the John F Kurtzke Clinician Scientist Development award from the American Academy of Neurology.
Ms. Mische: nothing to disclose.
Mr. Smith: nothing to disclose.
Dr. Nourbakhsh: has received research support from PCORI and National MS Society.
Mr. Reyes: nothing to disclose.
Mr. Martin: nothing to disclose.
Dr. Waubant: nothing to disclose.
Dr. Mowry: has received research support from Biogen and Sanofi Genzyme for investigator-initiated studies and is site PI of studies funded by Biogen and Sun Pharma. She receives free medication for a clinical trial of which she is PI from Teva Neuroscience. She receives royalties for editorial duties from UpToDate. Her research is additionally funded by PCORI, the Department of Defense, and the National MS Society.
Dr. Calabresi: has received research support from Biogen, Novartis, Annexon, MedImmune and Sanofi Genzyme, and is on the Scientific Advisory Board for Disarm Therapeutics and Biogen.

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