Abnormalities in serotonin (5-HT) signaling have been implicated in IBS pathogenesis. When induced by luminal chemical and mechanical signals, enterochromaffin (EC) cells release 5-HT, which stimulates 5-HT3 and 5-HT4 receptors on primary afferent neurons, which feed into peristaltic and secretomotor reflexes, regulating intestinal motility and secretion.1 In patients with diarrhea-predominant IBS (IBS-D), platelet-depleted postprandial plasma 5-HT concentrations are higher compared to patients with constipation (IBS-C) and healthy controls,2-5 while IBS-C patients have a mitigated postprandial rise in plasma 5-HT compared to controls.3,6 Plasma 5-HT is almost exclusively derived from gut EC cells secreting 5-HT, which is not taken up by platelets and overflows into the circulation.1 Plasma 5-HT levels also positively correlate with gut motility under both fasting and fed conditions7 suggesting that they parallel the mucosal bioavailability of 5-HT in the intestine. Together, these findings suggest that differences in mucosal 5-HT levels are involved in the clinical bowel habit phenotype in IBS. This concept is indirectly supported by the beneficial effects of 5-HT4 receptor agonists in IBS-C and 5-HT3 antagonists in IBS-D.8 
One factor that could modulate mucosal 5-HT availability is the activity or expression of the 5-HT selective reuptake transporter (SERT), which terminates hormone action and prevents receptor desensitization by removing it from the interstitial space. While SERT mRNA is widely expressed, the quantities found in the gut epithelium are very low, particularly in the colon. It may thus not be surprising that conflicting results have been reported concerning colonic SERT mRNA in IBS.9-12 
Conceivably, 5-HT biosynthesis is another process potentially influencing mucosal signaling. Tryptophan hydroxylase-1 (TPH1) is the rate-limiting enzyme in the biosynthesis of 5-HT in EC and mast cells. Both TPH1 and TPH2 are expressed in the gut, but TPH2 is expressed by enteric and central neurons, while TPH1 is the predominant enzyme in EC cells.13 Although the activity of TPH1 is controlled at multiple levels including posttranslational regulation,14 recent evidence from animal studies indicates that changes in TPH1 transcription can affect proportional changes in intestinal and plasma 5-HT levels.15 TPH1 is therefore an intriguing candidate gene for conditions with altered 5-HT bioavailability as proposed for the distinct bowel habit subtypes in IBS.
This idea is the basis for the development of an oral TPH inhibitor acting locally on the GI mucosa.15 A recent phase II clinical trial demonstrated the efficacy of this novel compound in relieving symptoms of non-constipating IBS.16-18 The clinical response to therapy correlated with a decrease in 24-h urine excretion of the metabolite 5-hydroxyindoleacetic acid reflecting reduced 5-HT biosynthesis, which is promising particularly since there is currently a lack of established biomarkers to predict treatment response in IBS.