Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and affects nearly a million Americans. There is no cure, so treatments focus on helping patients manage their symptoms, control flare-ups, and slow the progression of the disease. Scientists have struggled to understand the causes of MS, but recent research suggests an important role for the gut microbiome. Now, University of Virginia Health System (UVA) neuroscientists report they have discovered a potential way to disrupt the chronic inflammation responsible for MS. Their findings may also benefit other autoimmune diseases.
Their work is published in the journal PLOS Biology in a paper titled, “The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation.”
Scientists have struggled to understand the causes of MS, but recent research suggests an important role for the gut microbiome. UVA’s new findings reinforce that an immune system controller found in “barrier tissues” such as the intestine plays a vital role in the disease.
“MS is a T cell-driven autoimmune disease that attacks the myelin of the CNS and currently has no cure,” wrote the researchers. “MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR’s precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness.”
“We are approaching the search for multiple sclerosis therapeutics from a new direction,” said Andrea Merchak, a doctoral candidate in neuroscience, and her colleagues in the lab of Alban Gaultier, PhD, of the University of Virginia School of Medicine’s department of neuroscience and its Center for Brain Immunology and Glia (BIG). “By modulating the microbiome [the collection of microorganisms that naturally live inside us], we are making inroads in understanding how the immune response can end up out of control in autoimmunity. We can use this information to find early interventions.”
Gaultier and his collaborators blocked the activity of the regulator, called aryl hydrocarbon receptor, in T cells and found that doing so had a significant effect on the production of bile acids and other metabolites in the microbiomes of lab mice. With this receptor out of commission, inflammation decreased and the mice recovered.
The findings pave the way for utilizing a similar approach to interrupt the harmful inflammation in people with MS, though further research is needed.
UVA’s new research points to future efforts to target the microbiome to reduce the inflammation responsible for MS and other autoimmune diseases.
“Due to the complexity of the gut flora, probiotics are difficult to use clinically. This receptor can easily be targeted with medications, so we may have found a more reliable route to promote a healthy gut microbiome,” Merchak said. “Ultimately, fine-tuning the immune response using the microbiome could save patients from dealing with the harsh side effects of immunosuppressant drugs.”
