Targeting Serotonin Synthesis to Treat Irritable Bowel Syndrome

Abstract

See “The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome,” by Brown PM, Drossman DA, Wood AJJ, et al, on page 507. See “The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome,” by Brown PM, Drossman DA, Wood AJJ, et al, on page 507. Serotonin (5-hydrodytryptamine; 5-HT) is an important signaling molecule in the gastrointestinal (GI) tract, where it is predominantly produced in the enterochromaffin (EC) cells in the mucosa, and also by a subpopulation of enteric neurons.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar In the brain, 5-HT is a neurotransmitter that plays a pivotal role in the regulation of mood and cognition. Animal studies revealed that 5-HT, released from EC cells and interneurons, is involved in the control of GI secretion, motility, and visceral perception.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar 5-HT is synthesized through the actions of the rate-limiting enzyme tryptophan hydroxylase (TpH), of which 2 different types, TpH1 and TpH2, are expressed by EC cells and neurons (in the enteric and central nervous system), respectively (Figure 1). After release of 5-HT from EC cells or neurons, it is inactivated by uptake into enterocytes or neurons through the 5-HT reuptake transporter, followed by metabolization to 5-hydroxyindole acetic acid, which is excreted in the urine.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar In humans, understanding the role of 5-HT in the control of GI function has been hampered by the presence of multiple 5-HT receptors in the GI tract and the lack of suitable and selective antagonists.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar Indirect approaches to elucidate the role of 5-HT in the human GI tract have included the use of acute tryptophan depletion and acute administration of selective 5-HT reuptake inhibitors.2Geeraerts B. Van O.L. Boesmans W. Vos R. et al.Influence of acute tryptophan depletion on gastric sensorimotor function in humans.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G228-G235Crossref PubMed Scopus (19) Google Scholar, 3Tack J. Broekaert D. Corsetti M. et al.Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man.Aliment Pharmacol Ther. 2006; 23: 265-274Crossref PubMed Scopus (67) Google Scholar, 4Janssen P. Van Oudenhove L. Casteels C. et al.The effects of acute citalopram dosing on gastric motor function and nutrient tolerance in healthy volunteers.Aliment Pharmacol Ther. 2011; 33: 395-402Crossref PubMed Scopus (15) Google Scholar Interpretation of the results of these interventions is difficult because they act on 5-HT availability in the GI tract as well as in the brain.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar, 4Janssen P. Van Oudenhove L. Casteels C. et al.The effects of acute citalopram dosing on gastric motor function and nutrient tolerance in healthy volunteers.Aliment Pharmacol Ther. 2011; 33: 395-402Crossref PubMed Scopus (15) Google Scholar 5-HT has been implicated in the pathophysiology of GI disorders such as the carcinoid syndrome, a rare disorder, and irritable bowel syndrome (IBS), a most common GI disease. Abnormalities of serotonergic signaling, including altered expression of TpH-1 and 5-HT reuptake transporter, and altered release of 5-HT, have been implicated in IBS pathogenesis. To date, a key role of 5-HT in IBS pathogenesis has not been established, because of inconsistent findings between studies, variable correlations with measured GI functions, and a lack of suitable pharmacologic tools.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar, 5Coates M.D. Mahoney C.R. Linden D.R. et al.Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology. 2004; 126: 1657-1664Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 6Camilleri M. Andrews C.N. Bharucha A.E. et al.Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome.Gastroenterology. 2007; 132: 17-25Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 7Bearcroft C.P. Perrett D. Farthing M.J. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study.Gut. 1998; 42: 42-46Crossref PubMed Scopus (278) Google Scholar, 8Dunlop S.P. Coleman N.S. Blackshaw E. et al.Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome.Clin Gastroenterol Hepatol. 2005; 3: 349-357Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 9Atkinson W. Lockhart S. Whorwell P.J. et al.Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome.Gastroenterology. 2006; 130: 34-43Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar LX-1031 is a member of a novel class of orally administrable, small molecule TPH inhibitors, with poor systemic absorption and low penetration through the blood–brain barrier.10Liu Q. Yang Q. Sun W. et al.Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract.J Pharmacol Exp Ther. 2008; 325: 47-55Crossref PubMed Scopus (128) Google Scholar, 11Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin.Neurogastroenterol Motil. 2011; 23: 193-200Crossref PubMed Scopus (40) Google Scholar, 12Brown P. Jackson J. Shi Z.-C. LX1031: a new approach for managing irritable bowel syndrome.Gastroenterology. 2009; 136 (abstract): A237Google Scholar In animal studies, LX-1031 and related compounds dose dependently reduced synthesis of 5-HT in the GI tract; brain 5-HT levels were not affected.10Liu Q. Yang Q. Sun W. et al.Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract.J Pharmacol Exp Ther. 2008; 325: 47-55Crossref PubMed Scopus (128) Google Scholar Among healthy volunteers, single and repeated dose (up to 4 g/d for 14 days) administrations of LX-1031 were well tolerated and dose dependently inhibited urinary 5-OHIAA levels, which confirms the potential of the drug to inhibit 5-HT synthesis in the human GI tract upon oral administration.12Brown P. Jackson J. Shi Z.-C. LX1031: a new approach for managing irritable bowel syndrome.Gastroenterology. 2009; 136 (abstract): A237Google Scholar In this issue of Gastroenterology, Brown et al13Brown P.M. Drossman D.A. Wood A.J.J. et al.The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome.Gastroenterology. 2011; 141: 507-516Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar report the results of a study with LX-1031 in patients with non-constipating IBS.13Brown P.M. Drossman D.A. Wood A.J.J. et al.The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome.Gastroenterology. 2011; 141: 507-516Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar After a 2-week run-in, a total of 155 patients were randomized to a 4-week treatment with placebo or 250 mg or 1000 mg LX-1031 QID. Efficacy on IBS symptoms was assessed by weekly assessment of adequate relief of IBS symptoms and daily diaries to evaluate stool pattern and individual IBS symptoms. After 1 week, a significantly greater number of patients obtained adequate relief of IBS symptoms with the high dose of LX-1031 compared with placebo (48% vs 22%; P = .02). In weeks 2–4, the response to LX-1031 was numerically higher compared with placebo, but no statistical significance was reached. Stool consistency measured with the Bristol Stool Form Scale improved significantly with the high dose compared with placebo during weeks 1, 2, and 4. In a subset of patients, urinary 5-OHIAA was measured as a marker of 5-HT synthesis before and after 4 weeks' treatment with LX-1031. Overall, the high dose decreased 5-OHIAA excretion by approximately 25%. In this subgroup, a significant correlation was found between the percent decrease in urinary 5-OHIAA excretion and adequate relief response at the end of the treatment, indicating that decreased 5-HT synthesis is the mechanism underlying the symptomatic benefit. This is supported further by a post hoc analysis that showed a significantly higher symptomatic benefit in those who achieved a >15% decrease in urinary 5-OHIAA excretion during treatment. In the present cohort, as well as in previous studies in healthy subjects, LX-1031 was well tolerated and no safety issues were observed; however, more studies are needed to establish fully the safety and tolerance profile of this drug. The use of a peripherally acting inhibitor of 5-HT synthesis, LX-1031, has great potential for elucidating the role of 5-HT in the control of GI functions in humans. The effects of LX-1031 on Bristol Stool Form Scale ratings observed in the present study are in agreement with a pivotal role for 5-HT in the control of intestinal peristalsis in man, although additional effects on intestinal secretion cannot be excluded. Based on previous studies with 5-HT3 and 5-HT4 receptor antagonists, 5-HT3 receptors are the most likely target for 5-HT in the control of intestinal peristalsis.14Thumshirn M. Coulie B. Camilleri M. et al.Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome.Aliment Pharmacol Ther. 2000; 14: 869-878Crossref PubMed Scopus (60) Google Scholar, 15Bharucha A.E. Camilleri M. Haydock S. et al.Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans.Gut. 2000; 47: 667-674Crossref PubMed Scopus (84) Google Scholar The use of compounds like LX-1031 in combination with measurements of GI sensorimotor function may permit the evaluation of the role of 5-HT in the control of other GI functions where animal studies showed a role for 5-HT, such as upper GI fasting and postprandial motility, and the control of mechanosensitivity and chemosensitivity of the GI tract in man.1Gershon M.D. Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders.Gastroenterology. 2007; 132: 397-414Abstract Full Text Full Text PDF PubMed Scopus (1102) Google Scholar, 16Kindt S. Tack J. Mechanisms of serotonergic agents for treatment of gastrointestinal motility and functional bowel disorders.Neurogastroenterol Motil. 2007; 19: 32-39Crossref PubMed Scopus (15) Google Scholar Inhibition of GI 5-HT synthesis could provide therapeutic benefit in patients with carcinoid syndrome, and potentially also in the treatment of chemotherapy-induced nausea and vomiting, 2 conditions in which 5-HT from the GI tract plays a pivotal pathophysiologic role.11Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin.Neurogastroenterol Motil. 2011; 23: 193-200Crossref PubMed Scopus (40) Google Scholar The present study indicates a potential for the drug in the treatment of IBS without constipation. Although numerical improvements in several outcome variables were observed at a number of time points, significance was only obtained for the primary end point in the first treatment week, mainly owing to a gradual increase in the placebo response from 22% in week 1 to 43% in week 4. As a result, the therapeutic gain (adequate relief) decreased from 25% to 10%. Symptom improvement was fast in onset, whereas symptoms—in particular stool consistency—returned almost to pretreatment level when treatment was stopped. Beside the small sample size in this phase IIa study, the magnitude of the overall treatment effect and heterogeneity of IBS patients may contribute to variations in symptomatic outcome. Previous studies that measured plasma 5-HT levels after a meal challenge revealed that exaggerated 5-HT release from the GI tract is present in a subset of IBS patients with diarrhea.7Bearcroft C.P. Perrett D. Farthing M.J. Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study.Gut. 1998; 42: 42-46Crossref PubMed Scopus (278) Google Scholar, 8Dunlop S.P. Coleman N.S. Blackshaw E. et al.Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome.Clin Gastroenterol Hepatol. 2005; 3: 349-357Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 9Atkinson W. Lockhart S. Whorwell P.J. et al.Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome.Gastroenterology. 2006; 130: 34-43Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar This group of patients is more likely to respond to inhibition of 5-HT release or function. In the present study, it is unclear whether baseline 5-OHIAA urinary excretion, a measure of 5-HT release from the GI tract, was a predictor of response to treatment with LX-1031. Such a measure, if predictive of responsiveness, would establish urinary 5-OHIAA as a true biomarker, revealing underlying pathophysiology and potentially predicting responsiveness to 5-HT targeting therapy. The current data in this study suggest that the magnitude of inhibition of 5-HT synthesis determines symptomatic outcome, as revealed by the superior response rates in the group that achieved a >15% decrease in 5-OHIAA excretion during treatment. Although this observation may be of great importance, it still implies that responders can only be identified during, but not before, treatment. Moreover, it has to be emphasized that the cutoff of a 15% decrease was selected based on the degree of decrease in 5-OHIAA observed in the subgroup of patients on a high dose of LX-1031. Hence, this cutoff by definition selectively identifies patients treated with the high dose, not surprisingly leading to a higher percent of responders in the subgroup with a >15% decrease in 5-OHIAA. Finally, although symptoms returned to baseline levels and were comparable with the placebo group 2 weeks after treatment, urinary 5-OHIAA was still inhibited for >20% in the high-dose group compared with 6%–7% in the placebo group, questioning the close relationship between 5-OHIAA and symptom improvement. Clearly, more validation is required before accepting urinary 5-OHIAA as a biomarker, but the concept is certainly extremely interesting and worthy of further exploration. In future studies in IBS without constipation, therefore, beside evaluating the predictive value of baseline 5-OHIAA excretion, strategies to increase efficacy of LX-1031 through the use of higher doses or optimized drug delivery could also be considered. The Tryptophan Hydroxylase Inhibitor LX1031 Shows Clinical Benefit in Patients With Nonconstipating Irritable Bowel SyndromeGastroenterologyVol. 141Issue 2PreviewSerotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS). Full-Text PDF