Research breakthrough opens potential ‘new therapeutic avenue for MS patients’
US scientists say they have reached “a new frontier” in targeting the chronic inflammation behind multiple sclerosis (MS).
Researchers from the University of Virginia School of Medicine (UVA) were able to block the activity of an important T-cell receptor in an animal model of MS – leading to beneficial changes to the gut microbiome and recovery in experimental mice.
While the importance of the microbiome in MS has long been established, the UVA findings give us “a better understanding of the cross-talk” between the microbiome and the immune system.
The results also raise the prospect of “a new therapeutic avenue for MS patients”: a novel microbiome-centric clinical approach that could mediate the overactive immune response behind MS and other autoimmune diseases.
The focus of the UVA study was on the role of the aryl hydrocarbon receptor (AHR) – a homeostatic regulator in T-cells that is activated by non-pathogenic exogenous ligands such indoles, kynurenines, and other chemicals present in barrier tissues such as the intestine.
The UVA researchers immunised cohoused Cd4creAhrfl/fl and littermate control Ahrfl/fl mouse strains with myelin oligodendrocyte glycoprotein to induce experimental autoimmune encephalomyelitis (or EAE, an MS animal model). By studying mice whose AHR was deleted from their CD4+ T-cells and silencing AHR activity, they hoped to learn more about the role of AHR in autoimmunity.
Instead, they discovered that AHR had a previously unknown function as a regulator of the gut microenvironment – with AHR deficiency in T-cells leading to an increase in bile acids and short-chain fatty acids that induced T-cell apoptosis and led mice to recover from EAE.
“We have demonstrated that deleting Ahr from CD4+ T cells increases recovery in EAE in a microbiome-dependent manner,” the UVA report states.
“While AHR deficiency did not grossly alter the composition of the microbiome, it significantly impacted the production of microbiome-mediated metabolites.
“In particular, AHR deficiency in T cells led to an increase in bile acids and a subset of short-chain fatty acids that ultimately impacted T cell viability.”
“At the mechanistic level,” the report continues, “our data suggest that specific metabolites elevated in the cecum of Cd4creAhrfl/fl mice reduce T cell fitness and viability.”
“In particular, the cecal environment of Cd4creAhrfl/fl animals is characterized by high levels of isovaleric acid and taurocholic acid, which induce T cell apoptosis in vitro, suggesting a potential mechanism for EAE recovery.”
The UVA group claims the research is “the first demonstration… of a role for AHR in T lymphocytes as a regulator of the microbiome activity that ultimately influences the outcome of CNS autoimmunity.”
They also believe that it builds “a foundation for further work” that could ultimately lead to new clinical treatments for MS and related disorders.
"We are approaching the search for multiple sclerosis therapeutics from a new direction,” said the study’s lead author, Andrea Merchak.
“This receptor can easily be targeted with medications, so we may have found a more reliable route to promote a healthy gut microbiome.
“Ultimately, fine-tuning the immune response using the microbiome could save patients from dealing with the harsh side effects of immunosuppressant drugs.”
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