Editorial: serotonin and irritable bowel syndrome – reconciling pharmacological effects with basic biology; authors' reply

Abstract

We thank Professor Quigley for his interest in our recent publication.1, 2 In that study, we investigated plasma concentrations of serotonin and its principal metabolite 5-HIAA for differences between IBS patients and healthy controls.1 Due to the prominent role of serotonin in both gut and brain function, different pharmacological therapies aimed at serotonergic targets, including 5HT3 antagonists, 5HT4 agonists and in particular SSRIs have traditionally been administered for IBS with a high variability in treatment efficacy. The Cochrane review from 2011 reports on a significant effect of SSRIs with regard to global improvement but not abdominal pain.3 In a recent meta-analysis, Ford et al. concluded that the relative risk of remaining symptomatic after therapy for SSRIs vs. placebo was 0.68 (95% CI = 0.51–0.91).4 On the other hand, Xie et al. recently showed that SSRIs have no benefit in alleviating symptoms or improving quality of life in IBS patients.5 The contradicting conclusions are probably based on differences in inclusion criteria and thereby in number of studies included in the meta-analyses. Furthermore, it has to be noted that comparing outcomes of trials in IBS patients remains difficult due to a large variety in the definition of study endpoints, as we have shown in a recent systematic review.6 In addition, it remains controversial whether a benefit from SSRI treatment arises from the treatment of co-existent psychopathologies,7 as Ladabaum et al. found no effect of citalopram in nondepressed IBS patients.8 The discrepancy in the evidence for efficacy of SSRIs could also be explained by the heterogeneity of the IBS population. Probably a more selective subgroup for serotonin-targeted therapy could be the solution. Patients could be selected based on psychological comorbidity,8, 9 but pre-treatment assessment of plasma and/or mucosal serotonin metabolism may aid patient selection in the future.1, 10 In this respect, measurement of plasma 5-HIAA appears attractive, as 5-HIAA is less sensitive to oxidative breakdown, compared with 5-HT, and therefore can be measured more reliably. It should however be noted that mere plasma measurements are probably unable to reflect the complexity of serotonergic biology in the gut and brain. Furthermore, Professor Quigley acknowledges the interesting differences in 5-HIAA concentrations between IBS-subtypes, particularly with respect to distinct low 5-HIAA concentrations in the IBS-M subtype in our study.1, 2 He also suggests that the shift of subtypes observed in IBS patients in longitudinal studies would speak against the hypothesis for a role of altered serotonin metabolism in IBS-M.2 Indeed about 50% of IBS patients tend to shift from one subtype to the other, mostly from IBS-M to IBS-D or IBS-C, or vice versa.11 However, this may not contradict our hypothesis. Serotonin is found to affect both gut motility and secretion.12 Therefore, one could speculate that the poorly understood changes in bowel pattern over time may be caused by changes in serotonin metabolism, reflected by plasma 5-HIAA concentrations. A study with a longitudinal design is needed to correlate plasma 5-HIAA concentrations with bowel pattern over time in IBS patients. Declaration of personal and funding interests: None.