Kynurenine Pathway Metabolites as Novel Translational Biological Markers of Irritable Bowel Syndrome: Relationship to Gastrointestinal Function, Cognition and Co-morbid Depression

This study is based on the hypothesis that the disruption of this brain-gut axis in irritable bowel syndrome (IBS) is a consequence of increased degradation of tryptophan along the kynurenine pathway. The investigators aim to fully characterize this putative metabolic abnormality and determine its impact on both gastrointestinal (GI) and central nervous system (CNS) signaling by examining the relationship between individual pathway metabolites, GI symptoms and cognitive processing in IBS patients

An increased degradation of tryptophan along the kynurenine pathway has been reported in both depression and IBS (Clarke et al 2009a; Fitzgerald et al 2008; Myint et al 2007). Although such studies have suggested an alteration in the production of quinolinic acid as a consequence of this disruption, actual levels of this NMDA receptor agonist remain to be measured and are essential to the full characterization of pathway disruption. The relevance of this strategy is confirmed by studies that have implicated peripheral quinolinic acid measures as surrogate marker of disease activity in juvenile idiopathic inflammatory myopathies (Rider et al 2002). Moreover it has been demonstrated that increasing plasma levels of this neurotoxic metabolite can influence CNS processes (Yan et al 2005) and that an increased peripheral production of kynurenine can increase central quinolinic acid concentrations (Raison et al 2009a). A correlation between alterations in the kynurenine pathway, GI disturbances and cognitive outcomes remains to be fully defined. In this study, the investigators propose to obtain a complete profile of plasma kynurenine pathway metabolites in IBS patients with and without comorbid depression. Temporal instability in symptom profile is a hallmark of IBS and represents a considerable obstacle to biomarker discovery (Clarke et al 2009b). The preliminary data generated here will potentially be used as the basis for future grant applications that will propose a longitudinal study of these putative biomarker candidates.

BACKGROUND/SIGNIFICANCE

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder accounting for up to 20% of cases presenting at gastroenterologist clinics in the western world with an unexplained female predominance (Ersryd et al 2007). Although the typical symptoms are commonly experienced in the general population, the abdominal pain and disturbances in defecatory function experienced by IBS sufferers are on a scale that positions the disorder as one of the leading causes of work absenteeism and presenteeism in western societies. Clearly the burden it places on the individual sufferer and society as a whole is substantial and is further compounded by its draining of healthcare resources (Clarke et al 2009b).

Despite the widespread prevalence of the disorder is it still poorly understood and is largely characterized by the lack of a reliable validated biological marker. This is reflected in the reliance on symptom based diagnostic criteria in conjunction with the exclusion of other gastrointestinal disorders (Drossman 2006). Further complications arise in the form of the psychiatric comorbidity so frequently observed among the IBS population (Spiller 2004). It is perhaps unsurprising then that treatment options are inadequate and advances in our understanding of the disorder are urgently required to address the unmet medical needs of its sufferers.