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

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Abstract

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.

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Acknowledgments

The Alimentary Pharmabiotic Centre is a Centre for Science and Technology (CSET) funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan. The authors and their work were supported by SFI (grant numbers SFI/12/RC/2273, 02/CE/B124 and 07/CE/B1368), Health Research Board (HRB) through Health Research Awards (grant no HRA_POR/2011/23; TGD, JFC and GC) and UCC Strategic Research Fund towards the purchase of CANTAB® software licenses.

Conflict of interest

The authors declare no conflict of interest.

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Author notes

  1. Eamonn M. M. Quigley

    Present address: Division of Gastroenterology & Hepatology, Methodist Hospital and Weill Cornell College of Medicine, Houston, TX, USA

Authors and Affiliations

  1. Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

    Paul J. Kennedy, Andrew P. Allen, Ann O’Neill, Eamonn M. M. Quigley, John F. Cryan, Timothy G. Dinan & Gerard Clarke

  2. Department of Psychiatry, University College Cork, Cork, Ireland

    Paul J. Kennedy, Andrew P. Allen, Timothy G. Dinan & Gerard Clarke

  3. Department of Medicine, University College Cork, Cork, Ireland

    Eamonn M. M. Quigley

  4. Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland

    John F. Cryan

  5. Department of Psychiatry/Alimentary Pharmabiotic Centre, 1.15 Biosciences Institute, University College Cork, Cork, Ireland

    Gerard Clarke

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Kennedy, P.J., Allen, A.P., O’Neill, A. et al. Acute tryptophan depletion reduces kynurenine levels: implications for treatment of impaired visuospatial memory performance in irritable bowel syndrome. Psychopharmacology 232, 1357–1371 (2015). https://doi.org/10.1007/s00213-014-3767-z

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