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.
Highlights
multiple sclerosis (MS) is an incurable autoimmune disorder in which the immune system recognizes the myelin sheath surrounding neurons, instigating an inadvertent cascade of pathogenic inflammation within the central nervous system (CNS)
Tryptamine treated mice demonstrated a significant reduction in paralysis symptoms beginning from day 8 that persisted for the remaining duration of the study (Figure 1A)
The average weight of mice was measured throughout the time course of chronic progressive EAE and the data expressed as percent of starting body weight, clearly showed that while the vehicle-treated group started losing weight, especially on days 11–13, the tryptamine-treated mice showed a significant retention of weight when compared to the vehicle controls (Figure 1C)
Summary
MS is an incurable autoimmune disorder in which the immune system recognizes the myelin sheath surrounding neurons, instigating an inadvertent cascade of pathogenic inflammation within the central nervous system (CNS). The potential of the microbiome in inflammatory disorders serves as a doubleedged sword due to chronic intestinal dysbiosis being demonstrated to worsen and instigate inflammatory disorders (Lee et al, 2011; Li et al, 2018; Opazo et al, 2018; Saltzman et al, 2018; André et al, 2019) These previous studies have established that disparity in the microbial composition along barrier sites is directly involved with the clinical outcome of inflammatory disorders afflicting the host organism, and suggest further studies focused on the etiological role of the microbiome in inflammatory diseases in order to develop novel therapeutics and identify biomarkers for early detection
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