Abnormalities of mucosal serotonin metabolism and 5-HT3 receptor subunit 3C polymorphism in irritable bowel syndrome with diarrhoea predict responsiveness to ondansetron.

David Gunn,Melanie Lingaya,Peter Whorwell,Gulzar Singh,Beate Niesler,Ching Lam,Ian P Hall,Robin Spiller,Verena Wahl,Amanda Henry,Klara Garsed

doi:10.1111/apt.15420

Abstract

SummaryBackgroundIrritable bowel syndrome with diarrhoea (IBS‐D) is a common condition, greatly reducing the quality of life with few effective treatment options available.AimTo report the beneficial response shown in our trial with the 5‐hydroyxtryptamine (5‐HT) receptor 3 antagonist, ondansetron in IBS‐DMethodsA randomised, placebo‐controlled, cross‐over trial of 5 weeks of ondansetron versus placebo in 125 patients meeting modified Rome III criteria for IBS‐D as previously described. Patients were compared to 21 healthy controls. 5‐HT and 5‐HIAA were measured in rectal biopsies. Whole gut transit time was assessed using a radio‐opaque marker technique. Whole blood DNA was genotyped for an insertion polymorphism in the promoter region of the serotonin transporter gene SLC6A4, as well as single nucleotide polymorphisms (SNPs) of the tryptophan hydroxylase gene TPH1 and 5‐HT3 receptor genes HTR3A, C and E.ResultsPatients’ biopsies showed significantly higher 5‐HIAA levels (2.1 (1.2‐4.2) pmol/mg protein vs 1.1 (0.4‐1.5) in controls, P < .0001). 39 patients used < 4 mg/d (“super‐responders”) while 55 required ≥ 4 mg/d. 5‐HT concentrations in rectal biopsies were significantly lower in super‐responders (21.3 (17.0‐31.8) vs 37.7 (21.4‐61.4), P = .0357) and the increase in transit time on ondansetron was significantly greater (15.6 (1.8‐31) hours vs 3.9 (−5.1‐17.9) hours). Stool consistency responders were more likely to carry the CC genotype of the SNP p.N163K rs6766410 of the HTR3C gene (33% vs 14%, P = .0066).ConclusionIBS‐D patients have significant abnormalities in mucosal 5‐HT metabolism. Those with the lowest concentration of 5‐HT in rectal biopsies showed the greatest responsiveness to ondansetron.

Highlights

When patients with irritable bowel syndrome with diarrhoea (IBS‐D) are asked to report their most bothersome symptoms, erratic bowel habit and urgency are the most common.[1]
Serotonin (5‐hydroxy‐ tryptamine (5‐HT)), a neurotransmitter in the gut has many effects which are relevant to this aspect of IBS, stimulating intestinal secre‐ tion and colonic motility.2 5‐hydroyx‐ tryptamine (5‐HT) 3 (5‐HT3) receptor antagonists includ‐ ing alosetron, cilansetron and ramosetron which block these effects and slow whole gut transit have been shown in meta‐analysis to be effective treatments for IBS‐D.3
We showed in animal models of PI‐IBS6 that colonic mucosal 5‐HT was elevated immedi‐ ately after infection and 5‐hydroxyindole acetic acid (5‐HIAA)/5‐HT ratios were increased while, serotonin transporter gene (SERT gene SLC6A4) mRNA expression was depressed up to 56 days post‐infec‐ tion, these two changes suggesting long‐lasting accelerated mucosal 5‐HT turnover

Summary

Introduction

When patients with irritable bowel syndrome with diarrhoea (IBS‐D) are asked to report their most bothersome symptoms, erratic bowel habit and urgency are the most common.[1] Urgency and the associated occasional faecal incontinence cause significant distress and anxiety, which substantially impair their quality of life. Serotonin (5‐hydroxy‐ tryptamine (5‐HT)), a neurotransmitter in the gut has many effects which are relevant to this aspect of IBS, stimulating intestinal secre‐ tion and colonic motility.2 5‐HT 3 (5‐HT3) receptor antagonists includ‐ ing alosetron, cilansetron and ramosetron which block these effects and slow whole gut transit have been shown in meta‐analysis to be effective treatments for IBS‐D.3. Alosetron was withdrawn because of adverse events including severe constipation and ischaemic colitis.[4] It has been reintroduced under a FDA‐managed risk evaluation and mitigation strategy but is not widely used. Ramosetron, a potent highly specific 5‐HT3 receptor antagonist has been shown to be ef‐ fective and recently another 5‐HT3 receptor antagonist, ondansetron, has been shown to be effective without causing ischaemic colitis

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