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This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin). ispartof: Gut vol:66 issue:5 pages:966-974 ispartof: location:England status: published

BACKGROUND: Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS: 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS: The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS: Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia. ispartof: Gut vol:63 issue:9 pages:1401-1409 ispartof: location:England status: published

OBJECTIVES: A subgroup of children with functional constipation (FC) are unresponsive to conventional treatment. Abnormal rectal function due to increased distensibility (compliance) might be an underlying mechanism of therapy-resistant FC. It is hypothesised that rectal compliance is normal in patients who are successfully recovered from FC (RC). METHODS: Using a barostat, a pressure-controlled intermittent distension protocol was performed in FC patients, RC subjects free of symptoms for at least 4 years and healthy volunteers (HVs). Rectal compliance was calculated using a non-linear mixed-effect model for volume-pressure curves. RESULTS: Forty-seven FC patients, median (range) age of 12 (11-17) years, and 20 RC subjects, 15 (11-18) years, were studied and compared with 22 HVs, 14 (8-16) years. The median (5th-95th percentile) rectal compliance in HVs was 16 (12-20) ml/mm Hg. FC patients had a median rectal compliance of 25 (13-47) ml/mm Hg and RC subjects 20 (12-35) ml/mm Hg, which was significantly higher compared with HVs (p 95th percentile of HVs), which was significantly less compared with 75% of FC patients (p = 0.02). CONCLUSION: While rectal compliance in RC subjects is lower when compared with adolescents with FC, almost half of the RC subjects showed an increased rectal compliance. The role of rectal compliance in therapy-resistant FC seems limited, because recovery is possible despite an increased rectal compliance

The Authors' reply We would like to thank Dr O'Sullivan for her positive comment1 on our paper recently published in Gut .2 We agree that the exact mechanism of action of ketotifen, either through mast cell stabilisation or H1 receptor blockade, needs further study. We tend to disagree, however, that we may have missed differences between patients with irritable bowel syndrome (IBS) and healthy subjects by …