MS Linked to Alterations in Bile Acid Metabolism

Nancy A. Melville

October 31, 2018

ATLANTA — Adult and pediatric patients with multiple sclerosis (MS) have significant alterations in levels of bile acid metabolism compared with healthy individuals, new research suggests.

These results, combined with compelling preclinical findings from supplementation of a bile acid in mouse models with MS, have spurred research on potential new therapies, investigators report.

"We found that bile acid metabolism was altered in both adult and pediatric MS," Pavan Bhargava, MD, assistant professor of neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, said to attendees here at ANA 2018: 143rd Annual Meeting of the American Neurological Association.

This research is the first to explore bile acid metabolism in MS, Bhargava later told Medscape Medical News.

"The abnormalities we noted have not been previously described," he added. "The clinical significance of these abnormalities is still being worked out."

Adult Cohorts

Bile acids are cholesterol metabolites that have a key role in the absorption of lipid in the gut and are associated with bacterial species that are linked to the risk for development of MS, Bhargava explained. These bacterial species include Clostridium clusters XIVa and IV and Parabacteroides.

The acids are already being evaluated in other neurodegenerative diseases for their potential neuroprotective effects, the researchers note.

To evaluate circulating levels of primary and secondary bile acids in patients with MS, Bhargava and colleagues enrolled two adult cohorts at the Johns Hopkins Multiple Sclerosis Center.

In a discovery cohort, 52 patients acted as healthy controls, 56 patients had relapsing-remitting MS (RRMS), and 50 patients had progressive MS. Participants were assessed using a global metabolomics analysis of more than 600 metabolites, of which 25 are involved in bile acid metabolism.

Analysis of this cohort showed that, compared with the healthy control group, patients with MS had lower levels of multiple primary bile acids, which are produced in the liver, and secondary bile acids, which are modified in the gut.

Whereas the RRMS group had higher pathway deregulation scores (PDS), indicating greater abnormality for secondary bile acids (P = .002), those with progressive MS showed abnormalities in primary as well as secondary bile acid metabolism (P < .002 for both) compared with the healthy control persons.

In further evaluation of the effect in a validation cohort, 75 healthy control persons, 50 patients with RRMS, and 125 patients with progressive MS underwent a more targeted measurement of 15 primary and secondary bile acids.

Adults in the progressive MS group again had higher PDS scores for primary (P < .001) as well as secondary (P = .02) bile acid metabolism. Specifically, reductions were seen in multiple glycine and taurine conjugated bile acids.

Analyses in Children, Mice

In a pediatric cohort, 31 patients with MS and 31 healthy control persons were enrolled at the University of California, San Francisco, Pediatric Multiple Sclerosis Center.

In this younger group, those with MS had higher PDS scores in terms of primary bile acid metabolism (P = .01) and reductions in multiple primary bile acid metabolites that were similar to those seen in adults with MS.

The findings prompted the researchers to further investigate the role of supplementation of the bile acid tauroursodeoxycholic acid (TUDCA) in a mouse model with MS with experimental autoimmune encephalomyelitis (EAE), a common model for central nervous system neuroinflammation.

They found that 28 days after the mice were immunized, those treated with TUDCA had significantly greater reduction of EAE (P = .01).

The TUDCA-treated mice further showed reductions in EAE severity, with reduced demyelination, decreased macrophage/microglial infiltration, and decreased astrocytosis.

Further studies involving microglia that were isolated from mice showed TUDCA to have anti-inflammatory effects on microglia. The addition of TUDCA reduced NOS2 gene expression, as well as expression in IL-1alpha and TNF-alpha. These have been implicated in the production of neurotoxic reactive astrocytes, Bhargava said.

In addition, studies on astrocytes isolated from neonatal mice showed that TUDCA treatment blocked the upregulation of genes associated with the production of neurotoxic reactive astrocytes.

"Bile acid supplementation ameliorated EAE, and in vitro treatment prevented proinflammatory polarization of microglia and astrocytes," Bhargava reported.

Future Plans

The investigators are now moving ahead with further research in humans. They are testing the effect of supplementation of TUDCA in a group of patients with progressive MS in a phase 1 clinical trial.

"The aim of this placebo-controlled trial is to assess the safety and tolerability of TUDCA in MS. The secondary objectives are to assess the effects of TUDCA on circulating bile acid levels, the gut microbiome, and the immune system," Bhargava said.

In the trial of 60 individuals, TUDCA can be added to existing pharmacologic therapy or provided as a stand-alone treatment for patients who are not receiving a disease-modifying therapy, he added.

With regard to other neurodegenerative diseases, TUDCA is currently being tested in a trial of patients with ALS, and other research is underway, Bhargava reported.

"A drug that contains a combination of TUDCA and another molecule, phenylbutyrate, is also being tested in ALS and Alzheimer's disease," he said. "Recent studies in Alzheimer's have shown abnormalities in circulating bile acids, although these appear to be distinct from the pattern we observe in MS."

Dr Bhargava has reported no relevant financial relationships.

ANA 2018: 143rd Annual Meeting of the American Neurological Association. Abstract 563, presented October 21, 2018.

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