Tryptamine Attenuates Experimental Multiple Sclerosis Through Activation of Aryl Hydrocarbon Receptor

Abstract

Tryptamine is a naturally occurring monoamine alkaloid which has been shown to act as an aryl hydrocarbon receptor (AHR) agonist. It is produced in large quantities from the catabolism of the essential amino acid tryptophan by commensal microorganisms within the gastrointestinal (GI) tract of homeothermic organisms. Previous studies have established microbiota derived AHR ligands as potent regulators of neuroinflammation, further defining the role the gut-brain axis plays in the complex etiology in multiple sclerosis (MS) progression. In the current study, we tested the ability of tryptamine to ameliorate symptoms of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We found that tryptamine administration attenuated clinical signs of paralysis in EAE mice, decreased the number of infiltrating CD4+ T cells in the CNS, Th17 cells, and RORγ T cells while increasing FoxP3+Tregs. To test if tryptamine acts through AHR, myelin oligodendrocyte glycoprotein (MOG)-sensitized T cells from wild-type or Lck-Cre AHRflox/flox mice that lacked AHR expression in T cells, and cultured with tryptamine, were transferred into wild-type mice to induce passive EAE. It was noted that in these experiments, while cells from wild-type mice treated with tryptamine caused marked decrease in paralysis and attenuated neuroinflammation in passive EAE, similar cells from Lck-Cre AHRflox/flox mice treated with tryptamine, induced significant paralysis symptoms and heightened neuroinflammation. Tryptamine treatment also caused alterations in the gut microbiota and promoted butyrate production. Together, the current study demonstrates for the first time that tryptamine administration attenuates EAE by activating AHR and suppressing neuroinflammation.

The Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome by Downregulating miRNA that Target Inflammatory Pathways

“…The detection of the cytokines was performed using ELISA MAX standards kits from Biolegend. The staining of cells for dual markers was performed as described in our previous publications (Al-Ghezi et al, 2019;Becker et al, 2020;Dopkins et al, 2020;Mohammed et al, 2020b). In brief, MNCs and spleen cells were treated with Fc Block reagent (BD Pharmingen, San Diego, CA) followed by staining cells with various antibodies by incubation at 4°C for 20-30 min.…”

Phytochemicals From Vicia faba Beans as Ligands of the Aryl Hydrocarbon Receptor to Regulate Autoimmune Diseases

“…The calculated binding energies for stizolamine, vicine, convicine, L-cystine, wyerone acid, jasmonic acid, tuberonic acid, and wyerone epoxide against the AhR are provided for the first time. In the case of the products of biotransformation, except for tryptamine (98), m-tyramine (99), equol (100), baicalein (101), and taxifolin (102), the rest of the molecules lack reports addressing this subject. For comparative purposes, Table 1 shows our calculated binding affinities for all molecules along with a reference of its biotransformation.…”

“…Regarding the metabolic fate of the selected compounds, the AhR-binding ability of tryptamine (98), an L-tryptophan microbiome derivative (84) was calculated as −5.95 kcal/mol. Hence, it is also consistent with the literature and highlights the reliability of the implemented method.…”

Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases

“…It is interesting to note that microbiota-derived AhR ligands can also serve as potent regulators of neuroinflammation, further characterizing the role for AhR in the gut-brain axis in suppressing MS progression. For example, a recent study suggested that tryptamine administration attenuates EAE by activating AhR and suppressing neuroinflammation [ 129 ]. Tryptamine treatment also caused alterations in the gut microbiota and promoted butyrate production [ 129 ].…”

“…For example, a recent study suggested that tryptamine administration attenuates EAE by activating AhR and suppressing neuroinflammation [ 129 ]. Tryptamine treatment also caused alterations in the gut microbiota and promoted butyrate production [ 129 ]. Tryptophan metabolites produced by the intestinal microbiota along with type I interferons activate AhR in astrocytes and lead to suppression of inflammation [ 180 ].…”