Acute tryptophan depletion reduces kynurenine levels: Implications for treatment of impaired visuospatial memory performance in irritable bowel syndrome

Rationale: A visuospatial episodic memory impairment has recently been identified in irritable bowel syndrome. Increased tryptophan metabolism along the kynurenine pathway has also been reported in irritable bowel syndrome, which may play a role in altered cognitive performance as peripheral kynurenine can cross the blood brain barrier and lead to the production of neuroactive metabolites, which modulate glutamatergic and cholinergic signalling, key neurotransmitter systems involved in cognitive function. Objectives: Utilising the acute tryptophan depletion (ATD) protocol, the aim of this study was to examine if manipulating peripheral levels of tryptophan regulates cognitive performance in irritable bowel syndrome and also to determine for the first time if the ATD protocol alters kynurenine supply to the central nervous system. Methods: In this double-blind, placebo-controlled, crossover design study, nine female patients with irritable bowel syndrome and 14 matched female healthy controls participant completed a range of tests from the CANTAB^® following ATD and placebo. Plasma tryptophan and kynurenine, self-report measures of gastrointestinal symptoms, mood and arousal were determined pre- and post-treatment on each study day. Results: Following placebo (p∈=∈0.016) but not ATD (p∈>∈0.05), patients with irritable bowel syndrome exhibited impaired visuospatial memory performance (Paired Associates Learning (PAL) test). In addition, ATD significantly decreased (p∈<∈0.001) and placebo significantly increased (p∈<∈0.001) plasma kynurenine levels in both groups. Conclusions: Manipulating peripheral tryptophan and kynurenine levels using ATD modulates hippocampal-mediated cognitive performance in irritable bowel syndrome but not healthy controls. These data may have important implications for reducing cognitive impairment in irritable bowel syndrome.