Trace aminergic regulation of gastrointestinal inflammation

Abstract

Gastrointestinal inflammatory disorders, including ulcerative colitis (UC), involve breakdown of the lining in the colon and hyper-activation of immune cells. Pathogenesis of UC remains poorly understood, though emerging evidence suggests that there is a dynamic interplay of environmental stimuli and stress to exacerbate symptomology in a genetically susceptible individual. Current therapeutic options for UC remain limited, and include dietary modifications, attempts at modifying the microbiome, immunosuppression, and in severe cases surgical removal of necrotic tissue. Despite the understanding of environmental stimuli in UC pathogenesis, there is a gap in knowledge in the field on how the gastrointestinal tract interacts with these stimuli. The work completed in this dissertation aimed to identify a trace amine receptor, Trace Amine Associated Receptor-1 (TAAR1), as a novel integrator of environmental stimuli (e.g. diet, microbiome) in the onset and progression of UC. Tyramine (TYR), a trace amine, is at high levels in foods that trigger bouts of UC, and levels of TYR are elevated in the fecal matter of UC patients. Here, I tested the hypothesis that TAAR1 in intestinal immune and epithelial cells can mediate the effects of TYR in the gastrointestinal tract (GIT), which causes exacerbation of UC. The data generated in this dissertation provides the first evidence that: 1) TYR levels in the GIT can propagate ulcerative colitis; 2) TYR can regulate tight junction mRNA and protein expression in epithelial cells; 3) TAAR1 activation by TYR can modulate the expression of pro-inflammatory cytokines from macrophages; and 4) TAAR1 is expressed in the GIT and the onset of dextran sulfate sodium induced colitis is attenuated in TAAR1-/- mice. Taken together, this thesis reveals a new mechanism that drives UC pathology and a new pharmacological target for combating UC.