Therapeutic Targets For MS Found In The Gut
By Deborah Borfitz
March 2, 2023 | Neuroscientists at the University of Virginia (UVA) have succeeded in alleviating the harmful inflammation of multiple sclerosis (MS) in a mouse model of the disease by modulating the gut microbiome to disable a key immune regulator known as aryl hydrocarbon receptor (AHR). That’s a well-known and “easily druggable target” that multiple drugs now in clinical trials are attempting to block, says Andrea Merchak, a UVA doctoral candidate in neuroscience.
Another therapeutic possibility is to instead look downstream to “modulate the bile acids that are part of the normal physiology of all humans... [which] should be relatively safe and straightforward to do,” she adds. One of those, taurocholic acid, was identified as the most efficient driver of apoptosis—an important form of programmed cell death—and thus a potential avenue for treating MS in a newly published study in PLOS Biology (DOI: 10.1371/journal.pbio.3002000).
Several academic groups have discovered other candidate bile acids, so the next step is to find the one that most efficiently reduces immune cell activity to impede the harmful, chronic inflammation seen in MS and similar autoimmune disorders, says Merchak. Perhaps some combination of those bile acids will heighten the therapeutic effect for patients.
MS is a T cell-driven autoimmune disease affecting 2.3 million people worldwide and patients at present rely on immunosuppressant drugs that come with a lot of unpleasant and dangerous side effects, she notes. Since there is no cure, treatments focus on helping them manage their symptoms, control flareups, and slow progression of the disease.
The ‘Nitty-Gritty’
Merchak works in the lab of Alban Gaultier, Ph.D., associate professor at the UVA School of Medicine and its Center for Brain Immunology and Glia. The output has previously focused primarily on the use of myelin-forming oligodendrocyte progenitor cells to repair some of the damage done when patients’ immune system mistakenly attacks their body.
That the latest project looked earlier in the diseases process, before the damage occurred, was a “happy accident” occasioned by Gaultier’s lab specializing in MS and the introduction of toolsets for looking at the microbiome by a previous graduate student, explains Merchak. Scientists across the field are now well aware that environmental exposures through the gut can influence how the immune system forms and responds later in life.
The effects of these exposures seem to be specific to individuals, she adds. “We are just starting to dig into the nitty-gritty to understand the specific interactions that are occurring” and the implications in certain cells and diseases.
In the latest paper, Merchak looked at a specific type of immune cell—the type 17 T helper cell—which has been associated with many different autoimmune disorders, including rheumatoid arthritis and psoriasis as well as multiple sclerosis. “By understanding these basic mechanisms, we are going to be able to more fully appreciate how some of these disorders are related in their origins and... we might be able to find similar solutions,” she says.
Merchak’s work received the support of UVA’s TransUniversity Microbiome Initiative (TUMI), which serves as the central hub for the university’s cutting-edge microbiome research. TUMI helps researchers across different specialties collaborate and share their expertise because UVA, like most universities, does not have a microbiome department.
TUMI also provides expensive and technical tools to UVA researchers, notably mouse colonies who either have known bacterial consortia in their guts, are completely germ-free, or have been humanized with the gut microbiome from human patients, says Merchak. The study reported in PLOS Biology predominantly required bioinformatics support, but TUMI assistance was needed for 16S sequencing on the microbiomes and metabolomic analysis.
