Abstract Details

Title Bile Acid Metabolism is Altered in Multiple Sclerosis and Supplementation Leads to Amelioration of Neuroinflammation

Topic Multiple Sclerosis

Presentation(s) S55 - MS Basic Science (3:41 PM-3:52 PM)

Poster/Presentation
Number 002

Background

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.

Objective

To determine alterations in circulating bile acid (BA) metabolites in multiple sclerosis (MS) and determine the effects of a BA – tauroursodeoxycholic acid (TUDCA) on neuroinflammation.

Design/Methods

We enrolled discovery (50 healthy control [HC]/50 RRMS/50 PMS), validation (75 HC/50 RRMS/125 PMS) and pediatric (31 HC/31 MS) cohorts. 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 principal components curve derived from HCs.

We induced experimental autoimmune encephalomyelitis (EAE) in 7-8 week old C57/BL6 mice (immunization with MOG35-55). At onset of paralysis, we treated mice with oral TUDCA (500 mg/kg) or vehicle till day 28 post-immunization. We also examined effects of TUDCA on polarization of microglia (M1) and astrocytes (A1) in vitro.

Results

In the discovery cohort, MS patients 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=0.027) BA metabolism were higher in PMS compared to control. In pediatric MS, we again noted higher PDS scores for primary BA metabolism (p=0.015).

TUDCA treatment reduced EAE severity (p=0.01) and decreased demyelination, immune cell infiltration and astrocytosis. In vitro experiments revealed reduction in M1 polarization with TUDCA treatment. In astrocyte cultures with addition of factors (IL-1a, TNF-a, C1q) promoting A1 polarization, TUDCA treatment reduced expression of A1-specific gene transcripts.

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.

Authors/Disclosures
Pavan Bhargava, MD, FAAN (Johns Hopkins University) PRESENTER	The institution of Dr. Bhargava has received research support from EMD Serono. The institution of Dr. Bhargava has received research support from Amylyx pharmaceuticals. The institution of Dr. Bhargava has received research support from Genentech. The institution of Dr. Bhargava has received research support from GSK.
	No disclosure on file
Matthew Smith	Matthew Smith has nothing to disclose.
Bardia Nourbakhsh, MD (Johns Hopkins University)	The institution of Dr. Nourbakhsh has received research support from Genentech. The institution of Dr. Nourbakhsh has received research support from national MS Society . The institution of Dr. Nourbakhsh has received research support from Department of Defense. The institution of Dr. Nourbakhsh has received research support from NIH.
	No disclosure on file
	No disclosure on file
Emmanuelle Waubant, MD, PhD, FAAN (USCF MS Center)	The institution of Dr. Waubant has received research support from NIH. The institution of Dr. Waubant has received research support from NMSS. The institution of Dr. Waubant has received research support from PCORI. The institution of Dr. Waubant has received research support from Race to Erase MS. The institution of Dr. Waubant has received research support from Roche. The institution of Dr. Waubant has received research support from Department of Defense. Dr. Waubant has received publishing royalties from a publication relating to health care.
Ellen M. Mowry, MD, FAAN (Johns Hopkins University)	Dr. Mowry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BeCareLink, LLC. The institution of Dr. Mowry has received research support from Biogen. The institution of Dr. Mowry has received research support from Genentech. Dr. Mowry has received publishing royalties from a publication relating to health care.
Peter A. Calabresi, MD, FAAN (Johns Hopkins University)	Dr. Calabresi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Calabresi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Idorsia. An immediate family member of Dr. Calabresi has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MyMD. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Myelin Repair Foundation. The institution of Dr. Calabresi has received research support from Genentech. Dr. Calabresi has received publishing royalties from a publication relating to health care. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with NIH. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Grant reveiwer with Myelin Repair Foundation. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Speaker for CME with NYAS. Dr. Calabresi has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Academic CME.

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