Tryptamine Attenuates Experimental Multiple Sclerosis Through Activation of Aryl Hydrocarbon Receptor
Abstract
Tryptamine is a naturally occurring monoamine alkaloid that functions as an agonist of the aryl hydrocarbon receptor (AHR). It is produced in large amounts through the breakdown of the essential amino acid tryptophan by commensal microorganisms in the gastrointestinal (GI) tract of warm-blooded organisms. Previous studies have shown that microbiota-derived AHR ligands are powerful regulators of neuroinflammation, further emphasizing the role of the gut-brain axis in the complex development of multiple sclerosis (MS).
In this study, we investigated whether tryptamine could alleviate symptoms of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that tryptamine treatment significantly reduced clinical signs of paralysis in EAE mice, decreased the infiltration of CD4+ T cells, Th17 cells, and RORĪ³T cells into the central nervous system (CNS), while increasing the population of FoxP3+ regulatory T cells (Tregs).
To determine whether tryptamine acts through AHR, myelin oligodendrocyte glycoprotein (MOG)-sensitized T cells were collected from either wild-type mice or Lck-Cre AHR^flox/flox mice, which lack AHR expression specifically in T cells. These cells were cultured with tryptamine and transferred into wild-type mice to induce passive EAE. Notably, tryptamine-treated cells from wild-type mice resulted in reduced paralysis and less neuroinflammation, whereas tryptamine-treated cells from Lck-Cre AHR^flox/flox mice induced severe paralysis and heightened neuroinflammation.
Additionally, tryptamine treatment led to alterations in the gut microbiota and promoted the production of butyrate. Collectively, these findings demonstrate for the first time that tryptamine administration mitigates EAE by WH-4-023 activating AHR and suppressing neuroinflammation.