Multiple sclerosis (MS) patients have lower than usual levels of molecules called bile acids circulating in their blood, a study found. These molecules, produced in the liver to aid fat absorption in the gut, also appear to block inflammation and nerve cell damage in the brain.
Oral treatment with tauroursodeoxycholic acid (TUDCA) — a bile acid now in a clinical trial for progressive MS, detailed below — reduced the number of immune cells infiltrating the brain and demyelination (the loss of myelin, the protective coat of nerve cells) in an animal model of MS, lessening overall disease severity, its researchers reported.
Their study, “Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation,” was published in the Journal of Clinical Investigation.
Bile acids, the products of cholesterol metabolism, mainly work in the gut to help absorb lipids (fats). But they may also exert a neuroprotective role by preventing inflammation.
Studies have shown that receptors for these molecules exist on many cells, including those in the brain and the immune system, and that activating these receptors lessens disease severity in animal models of MS.
Whether bile acid metabolism is problematic (abnormal) in MS patients remains unknown.
To address this, a team led by researchers at Johns Hopkins University investigated blood levels of bile acids in 107 MS patients — 56 with relapsing-remitting disease (RRMS) and 51 with progressive MS — and compared their levels to those of 52 healthy people serving as controls.
Levels of 25 metabolites related to bile acid metabolism were tested in all participants, including primary bile acid metabolites (synthesized in the liver), and secondary bile acid metabolites (later modified by enzymes in the gut).
Results showed lower levels of several primary bile acids in progressive MS patients compared to controls, and multiple secondary bile acids that were lower in both patient groups compared to healthy individuals.
These changes in bile acid metabolism remained significant after adjusting for factors like age, sex, and race. They were also confirmed in a larger group of MS patients (175 patients) and controls — but in this group, RRMS patients did not have significantly lower levels of secondary bile acids compared to the control group.
“Overall, the data from both metabolomics [the study of metabolites] approaches in the adult cohorts revealed alterations in bile acid metabolism in patients with MS, with greater abnormality noted in the PMS [progressive MS] group,” the researchers wrote.
Additional analysis showed that bile acid metabolism was not affected by the kind of treatment patients were receiving, and that those with pediatric-onset MS had similar alterations to their bile acid metabolism as did adult patients.
To understand if bile acid levels could affect patients’ brains, researchers next examined if their brain lesions had receptors associated with bile acid signaling.
They found two such receptors — FXR and GPBAR-1 — with more pronounced levels in lesions of white matter (brain regions composed mainly of nerve fibers) than were seen in healthy white matter.
The receptor GPBAR-1, in particular, was found in astrocytes and cells of the innate immune system — macrophages and myeloid cells — in brain lesions. Both these cells types play key roles in the inflammation and nerve cell degeneration seen in the brain of MS patients.
The team then treated astrocytes and brain immune cells (microglia) in the lab with TUDCA, an endogenous (originating within an organism) bile acid. Results confirmed the protective role of bile acids in MS, as TUDCA prevented astrocytes and microglia from doing damage, without affecting their viability as cells.
Treating mice with experimental autoimmune encephalomyelitis — a common animal model of MS — with TUDCA further supported evidence of bile acids as neuroprotective, with treated animals showing lesser demyelination and immune cell infiltration, and fewer toxic astrocytes. This easing in disease severity was mediated by the GPBAR-1 receptor, the investigators found.
“The results of this study expand our understanding of how alterations in the metabolome may affect aspects of MS disease [development] and potentially impact processes that mediate neurodegeneration in multiple neurological diseases,” they concluded.
“We also provide a paradigm for future studies to identify additional metabolic pathways that could be targeted to modify the course of MS,” the researchers added.
This team in now leading a Phase 1/2 clinical trial (NCT03423121) testing the safety and early efficacy of a daily oral TUDCA supplement versus placebo in progressive MS patients with low blood levels of bile acids. Funded by the National MS Society, the study is enrolling up to 60 adults with progressive disease at Johns Hopkins University.
Like many clinical trials, this study may be affected by the COVID-19 pandemic. Patients interested in taking part are often still encouraged to contact the site.
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