Introduction: Irritable bowel syndrome (IBS) is a functional disorder which has been linked with abnormal serotonin functioning. It has a high psychiatric co-morbidity with depressive and anxiety disorders, conditions which result from a central serotonergic deficit. Tryptophan (TRP) forms the substrate for serotonin biosynthesis, but alternatively TRP can also be catabolised to kynurenine (KYN). Tryptophan catabolism along the kynurenine pathway is regulated by the enzyme indoleamine 2,3-dioxygenase (IDO), and therefore the ratio of kynurenine to tryptophan provides a measurement of IDO activity. The main inducer of IDO is the pro-inflammatory cytokine, interferon-gamma (IFN-γ). Aims: The primary aim of this study was to investigate tryptophan catabolism in IBS, and to relate such catabolism to immune activation and psychiatric co-morbidity. We hypothesised that there would be increased IFN-γ levels in IBS, and consequently, increased shunting of tryptophan along the kynurenine pathway at the expense of serotonin biosynthesis. Method: 42 female IBS subjects and 22 female healthy controls had plasma kynurenine and tryptophan concentrations measured using an HPLC method. Interferon-γ was assayed using an electro-chemiluminescence multiplex system imager. Co-morbid depressive and anxiety disorders were identified using a valid and reliable self-report tool, the Patient Health Questionnaire (PHQ), and the severity of IBS was assessed using a summary score of 4-point ordinal scales in accordance with a previously published method. Results: Of the 42 IBS subjects, 17 had severe IBS, 16 reported moderate symptoms and 9 reported mild IBS symptomatology. There was a significant positive correlation between IBS severity and Kyn/Trp ratio(r = 0.47, p=0.002). Those with severe IBS symptoms demonstrated increased tryptophan catabolism along the kynurenine pathway (i.e. increased Kyn/Trp ratio)compared to those with mildto-moderate IBS and healthy controls(p = 0.004); and those with severe IBS were over twice as likely to have depression or anxiety compared to those with less severe symptoms (RR = 2.2;95% C.I 1.2-3.9). No difference in IFN-γ levels was observed between the IBS patients and controls; however IFN-γ was positively correlated with Kyn:Trp ratio in the IBS group (r = 0.58, p = 0.005) and this was not seen in the controls (r = 0.05, p = 0.8). Conclusion: Our results indicate an increased sensitivity to IFN-γ in the regulation of tryptophan catabolism in IBS. This may predispose to the increased rate of Kyn production observed in severe IBS cases and to the high co-morbidity with depressive and anxiety disorders in this group.