Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort

Gerard Clarke, Peter Fitzgerald, John F Cryan, Eugene M Cassidy, Eamonn M Quigley, Timothy G Dinan, Gerard Clarke, Peter Fitzgerald, John F Cryan, Eugene M Cassidy, Eamonn M Quigley, Timothy G Dinan

Abstract

Background: Irritable bowel syndrome (IBS) is a common disorder that affects 10-15% of the population. Although characterised by a lack of reliable biological markers, the disease state is increasingly viewed as a disorder of the brain-gut axis. In particular, accumulating evidence points to the involvement of both the central and peripheral serotonergic systems in disease symptomatology. Furthermore, altered tryptophan metabolism and indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many stress-related disorders. The kynurenine pathway of tryptophan degradation may serve to link these findings to the low level immune activation recently described in IBS. In this study, we investigated tryptophan degradation in a male IBS cohort (n = 10) and control subjects (n = 26).

Methods: Plasma samples were obtained from patients and healthy controls. Tryptophan and its metabolites were measured by high performance liquid chromatography (HPLC) and neopterin, a sensitive marker of immune activation, was measured using a commercially available ELISA assay.

Results: Both kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls. Neopterin was also increased in the IBS subjects and the concentration of the neuroprotective metabolite kynurenic acid was decreased, as was the kynurenic acid:kynurenine ratio.

Conclusion: These findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls. This study provides novel evidence for an immune-mediated degradation of tryptophan in a male IBS population and identifies the kynurenine pathway as a potential source of biomarkers in this debilitating condition.

Figures

Figure 1
Figure 1
A/B: (A) Plasma kynurenine Levels (μmol/L) in healthy controls and male IBS patients and (B) Kynurenine:tryptophan ratio in healthy controls and male IBS patients.
Figure 2
Figure 2
A/B: (A) Plasma kynurenic acid levels (μmol/L) in healthy controls and male IBS patients and (B) Kynurenic acid:kynurenine ratio in healthy controls and male IBS patients.
Figure 3
Figure 3
A/B: (A) Plasma neopterin levels (nmol/L) in healthy controls and male IBS patients.(B)Correlation between neopterin levels and the kyn:tryp ratio (Pearson product-moment correlation, *p < 0.05, r = 0.7055).

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