The gluten-free diet is the only treatment available for gluten-related disorders, such as celiac disease, an autoimmune reaction to gluten, or non-celiac gluten or wheat sensitivity, a symptomatic reaction to wheat or gluten. However, gluten may not be the only culprit, and patients on a gluten-free diet have been suggested to symptomatically improve through the placebo effect, alterations in immune activity, and alterations in gut microbiota composition. It is unclear which of these mechanisms underlie symptoms in gluten-related disorders and well-designed clinical studies are needed to better understand them. This thesis aims to understand the mechanisms and symptomatic responses by which wheat and gluten affect individuals with gluten-related disorders. I hypothesize that patients with gluten-related disorders have increased psychological symptoms and immune reactivity which may be modulated by the gut microbiota. To test this, I conducted a clinical crossover trial to investigate whether whole wheat or gluten triggered symptoms versus gluten-free control, or nocebo, in irritable bowel syndrome patients adopting a gluten-free diet. Participants reacted similarly to each intervention, suggesting a strong 'nocebo effect' to be the main trigger of their symptoms. However, several participants did not comply to the protocol, muddying the results. Subsequent follow-up visits after disclosing personalized study results found no changes in participant beliefs, behaviours, and symptoms, and most remained on a gluten-free diet. Next, a systematic review of 65 observational studies found an elevated risk of IBD in celiac disease and vice versa. Finally, a systematic review of 6 RCTs found limited evidence that probiotics are safe and possibly therapeutic for ameliorating symptoms in celiac disease. Overall, the work presented in this thesis critically assesses the mechanisms by which gluten and wheat trigger symptoms in gluten-related disorders and highlights the importance of rigorous clinical trial design to control for psychological factors and patient compliance. / Thesis / Doctor of Philosophy (PhD) / Gluten, a wheat protein, is commonly associated with the autoimmune condition celiac disease, symptomatic worsening from gluten or wheat in non-celiac gluten/wheat sensitivity, and irritable bowel syndrome. This thesis strove to understand how gluten and other wheat proteins impact symptoms via psychological, immune, and/or bacteria-mediated pathways in gluten-related disorders. A clinical trial tested the effects of whole wheat, gluten, and gluten-free control on symptoms in irritable bowel syndrome patients on a gluten-free diet. We found no differences between interventions but discovered widespread diet non-compliance and that patient fears triggered symptoms. Informing patients of whether wheat, gluten, or gluten-free control triggered their symptoms did not change their dietary beliefs or behaviours. Additionally, two systematic reviews found a relationship between celiac disease and inflammatory bowel disease, and a possible therapeutic effect of probiotics in celiac patients. Our findings provided insights into the content and quality of the clinical evidence for gluten-related disorders.