Clinical trial NCT03664531: Dietary Triggers of Gastrointestinal Symptoms in IBS Patients
Official title: Crossover Trial of Gluten and Gluten With Amylase-trypsin Inhibitors as Triggers of Gastrointestinal Symptoms in Patients With Irritable Bowel Syndrome
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Irritable Bowel Syndrome
Keywords: crossover
gluten
amylase trypsin inhibitors
diet
challenge
Lead sponsor: McMaster University
Sponsor class: OTHER
First posted: 2018-09-10
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Participants will be required to be on a gluten-free diet for a period of 3 weeks before starting the study. Participants will then be randomized to take muesli bars containing either purified gluten, non-purified gluten with amylase trypsin inhibitors, or nocebo for 1 week followed by 2 weeks of washout, and then repeated for the two remaining dietary challenges so that at the end all participants have been on all dietary challenges. At the beginning and end of each challenge period, participants will visit the clinic to be evaluated for changes in IBS symptoms.
Primary purpose: OTHER

Brief summary: This crossover randomized controlled trial will evaluate the effects of gluten and gluten combined with amylase-trypsin inhibitors (ATIs) on inducing intestinal and extra-intestinal symptoms in irritable bowel syndrome (IBS) patients. All participants will be put on a gluten-free diet and then challenged with muesli bars containing either purified gluten, gluten with ATIs, or nocebo.

Detailed description: Irritable bowel syndrome (IBS) is a heterogenous, common gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. Many IBS patients report symptom relief on a gluten-free diet (GFD), but it is uncertain whether gluten is the true culprit. The gluten-containing grains wheat, rye, and barley all contain amylase-trypsin inhibitors (ATIs), and a GFD is virtually ATI-free.

This double-blinded crossover randomized controlled trial aims to determine which IBS patients are affected by pure gluten and which are affected by gluten combined with ATIs. IBS patients who respond to and have been on a GFD for 3+ weeks will be randomized to receive a dietary challenge of muesli bars containing either 1) pure gluten, 2) non-purified gluten (containing ATIs), 3) or nocebo for a week followed by a 14 day washout. This will be repeated until all participants have had each dietary challenge.

The study will evaluate the effects and potential mechanisms of purified and non-purified gluten on intestinal and extra-intestinal symptoms in IBS. It is likely that some IBS patients respond to gluten, while others respond to gluten combined with ATIs. Thus, this project may lead to better diagnosis and individualized dietary treatments for IBS.

Eligibility criteria: Inclusion Criteria:

* IBS diagnosis based on Rome IV criteria.
* Asymptomatic on a gluten-free diet (IBS-SSS score 0-74).
* Compliance with the study procedures (according to the investigator's own judgement).
* Signing the Study Informed Consent form.

Exclusion Criteria:

* Concurrent systemic disease and/or laboratory abnormalities considered by investigators to be risky or that could interfere with data collection.
* Concurrent organic gastrointestinal disease (i.e. Celiac disease, Inflammatory Bowel Disease, peptic ulcer disease, etc.) other than benign polyps, diverticulosis, hemorrhoids, lipoma and melanosis coli.
* Major abdominal surgery with the exception of hernia repair, appendectomy, Caesarian section, tubal ligation, cholecystectomy, hysterectomy, and hemorrhoidectomy.
* History of active cancer in the last 5 years, other than skin basal cells cancer.
* Pregnant or breastfeeding women.
* Current use of antibiotics or antibiotic treatment within 1 months before the first visit.
* Consumption of probiotics within 1 month prior to the first visit.
* Use of non-authorized medications (see Unauthorized Medications section).
* Patients on a high fibre diet (\>35 g/day for males, \> 25 g/day for females), consuming high inulin containing foods (\>5 g/day), and/or consuming dietary fibre supplements (as assessed by dietary assessment questionnaire) in the 4 weeks prior to the first visit.
* Patients currently participating or having participated in a trial within the past month.

Primary outcomes:
measure: Irritable Bowel Syndrome (IBS) symptoms
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
Secondary outcomes:
measure: General gastrointestinal symptoms
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Orocecal transit
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Anti-gliadin antibody (AGA) levels
timeFrame: Serum AGAs will be measured at baseline and after the challenge
measure: Gut microbiota profiles
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Genetic predisposition for celiac disease
timeFrame: Patient HLA DQ2/8 status will be measured at baseline
measure: Depression, anxiety and stress
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Somatic symptoms
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Stool consistency
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
measure: Gluten levels in stool
timeFrame: Procedure will be explained at baseline
measure: Diet assessment
timeFrame: Patients will be asked to take pictures of all meals during each of the 1 week diet challenges
measure: IBS symptom duration
timeFrame: Completed daily for 7 days after each diet challenge
measure: Systemic immune reactivity
timeFrame: 1 week gluten or gluten+ATIs intervention compared to nocebo
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
Study officials:
affiliation: McMaster University
name: Premysl Bercik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Maria Ines Pinto-Sanchez, MD
role: STUDY_DIRECTOR
References:
citation: Boivin M. Socioeconomic impact of irritable bowel syndrome in Canada. Can J Gastroenterol. 2001 Oct;15 Suppl B:8B-11B. doi: 10.1155/2001/401309.
citation: Sanger GJ, Alpers DH. Development of drugs for gastrointestinal motor disorders: translating science to clinical need. Neurogastroenterol Motil. 2008 Mar;20(3):177-84. doi: 10.1111/j.1365-2982.2008.01084.x.
citation: Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010 Feb;25(2):252-8. doi: 10.1111/j.1440-1746.2009.06149.x.
citation: McKenzie YA, Alder A, Anderson W, Wills A, Goddard L, Gulia P, Jankovich E, Mutch P, Reeves LB, Singer A, Lomer MC; Gastroenterology Specialist Group of the British Dietetic Association. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet. 2012 Jun;25(3):260-74. doi: 10.1111/j.1365-277X.2012.01242.x. Epub 2012 Apr 10.
citation: Gaesser GA, Angadi SS. Gluten-free diet: imprudent dietary advice for the general population? J Acad Nutr Diet. 2012 Sep;112(9):1330-1333. doi: 10.1016/j.jand.2012.06.009. No abstract available.
citation: El-Chammas K, Danner E. Gluten-free diet in nonceliac disease. Nutr Clin Pract. 2011 Jun;26(3):294-9. doi: 10.1177/0884533611405538.
citation: van Overbeek FM, Uil-Dieterman IG, Mol IW, Kohler-Brands L, Heymans HS, Mulder CJ. The daily gluten intake in relatives of patients with coeliac disease compared with that of the general Dutch population. Eur J Gastroenterol Hepatol. 1997 Nov;9(11):1097-9. doi: 10.1097/00042737-199711000-00013.
citation: Catassi C, Fabiani E, Iacono G, D'Agate C, Francavilla R, Biagi F, Volta U, Accomando S, Picarelli A, De Vitis I, Pianelli G, Gesuita R, Carle F, Mandolesi A, Bearzi I, Fasano A. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007 Jan;85(1):160-6. doi: 10.1093/ajcn/85.1.160.
citation: Lebwohl B, Granath F, Ekbom A, Montgomery SM, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Mucosal healing and mortality in coeliac disease. Aliment Pharmacol Ther. 2013 Feb;37(3):332-9. doi: 10.1111/apt.12164. Epub 2012 Nov 28.
citation: Leonard MM, Sapone A, Catassi C, Fasano A. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. JAMA. 2017 Aug 15;318(7):647-656. doi: 10.1001/jama.2017.9730.
citation: Maiuri L, Picarelli A, Boirivant M, Coletta S, Mazzilli MC, De Vincenzi M, Londei M, Auricchio S. Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients. Gastroenterology. 1996 May;110(5):1368-78. doi: 10.1053/gast.1996.v110.pm8613040.
citation: Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008 Jul;135(1):194-204.e3. doi: 10.1053/j.gastro.2008.03.023. Epub 2008 Mar 21.
citation: Caio G, Volta U, Tovoli F, De Giorgio R. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 2014 Feb 13;14:26. doi: 10.1186/1471-230X-14-26.
citation: Ferch CC, Chey WD. Irritable bowel syndrome and gluten sensitivity without celiac disease: separating the wheat from the chaff. Gastroenterology. 2012 Mar;142(3):664-6. doi: 10.1053/j.gastro.2012.01.020. Epub 2012 Jan 24. No abstract available.
citation: Verdu EF. Editorial: Can gluten contribute to irritable bowel syndrome? Am J Gastroenterol. 2011 Mar;106(3):516-8. doi: 10.1038/ajg.2010.490.
citation: Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011 Mar;40(1):141-62. doi: 10.1016/j.gtc.2010.12.012.
citation: Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
citation: Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA. Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G217-25. doi: 10.1152/ajpgi.00225.2007. Epub 2007 Nov 15.
citation: Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011 Mar;106(3):508-14; quiz 515. doi: 10.1038/ajg.2010.487. Epub 2011 Jan 11.
citation: Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2007 Jul;5(7):844-50; quiz 769. doi: 10.1016/j.cgh.2007.03.021. Epub 2007 Jun 5.
citation: Schuppan D, Pickert G, Ashfaq-Khan M, Zevallos V. Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol. 2015 Jun;29(3):469-76. doi: 10.1016/j.bpg.2015.04.002. Epub 2015 May 8.
citation: Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Russel N, Pickert G, Schild H, Steinbrink K, Schuppan D. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017 Apr;152(5):1100-1113.e12. doi: 10.1053/j.gastro.2016.12.006. Epub 2016 Dec 16.
citation: Major G, Pritchard S, Murray K, Alappadan JP, Hoad CL, Marciani L, Gowland P, Spiller R. Colon Hypersensitivity to Distension, Rather Than Excessive Gas Production, Produces Carbohydrate-Related Symptoms in Individuals With Irritable Bowel Syndrome. Gastroenterology. 2017 Jan;152(1):124-133.e2. doi: 10.1053/j.gastro.2016.09.062. Epub 2016 Oct 14.
citation: Wilson B, Whelan K. Prebiotic inulin-type fructans and galacto-oligosaccharides: definition, specificity, function, and application in gastrointestinal disorders. J Gastroenterol Hepatol. 2017 Mar;32 Suppl 1:64-68. doi: 10.1111/jgh.13700.
citation: Spiller R. How do FODMAPs work? J Gastroenterol Hepatol. 2017 Mar;32 Suppl 1:36-39. doi: 10.1111/jgh.13694.
citation: Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, Zevallos V, Libermann TA, Dillon S, Freitag TL, Kelly CP, Schuppan D. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012 Dec 17;209(13):2395-408. doi: 10.1084/jem.20102660. Epub 2012 Dec 3.
citation: El-Salhy M, Ostgaard H, Gundersen D, Hatlebakk JG, Hausken T. The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). Int J Mol Med. 2012 May;29(5):723-31. doi: 10.3892/ijmm.2012.926. Epub 2012 Feb 24.
citation: Mitchell CM, Drossman DA. Survey of the AGA membership relating to patients with functional gastrointestinal disorders. Gastroenterology. 1987 May;92(5 Pt 1):1282-4. doi: 10.1016/s0016-5085(87)91099-7. No abstract available.
citation: Pietzak M. Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad. JPEN J Parenter Enteral Nutr. 2012 Jan;36(1 Suppl):68S-75S. doi: 10.1177/0148607111426276.
citation: Marcason W. Is there evidence to support the claim that a gluten-free diet should be used for weight loss? J Am Diet Assoc. 2011 Nov;111(11):1786. doi: 10.1016/j.jada.2011.09.030. No abstract available.
citation: Higgins JA. Whole grains, legumes, and the subsequent meal effect: implications for blood glucose control and the role of fermentation. J Nutr Metab. 2012;2012:829238. doi: 10.1155/2012/829238. Epub 2011 Oct 30.
citation: Rosen LA, Ostman EM, Shewry PR, Ward JL, Andersson AA, Piironen V, Lampi AM, Rakszegi M, Bedo Z, Bjorck IM. Postprandial glycemia, insulinemia, and satiety responses in healthy subjects after whole grain rye bread made from different rye varieties. 1. J Agric Food Chem. 2011 Nov 23;59(22):12139-48. doi: 10.1021/jf2019825. Epub 2011 Oct 31.
citation: Russo F, Riezzo G, Chiloiro M, De Michele G, Chimienti G, Marconi E, D'Attoma B, Linsalata M, Clemente C. Metabolic effects of a diet with inulin-enriched pasta in healthy young volunteers. Curr Pharm Des. 2010;16(7):825-31. doi: 10.2174/138161210790883570.
citation: Harris KA, Kris-Etherton PM. Effects of whole grains on coronary heart disease risk. Curr Atheroscler Rep. 2010 Nov;12(6):368-76. doi: 10.1007/s11883-010-0136-1.
citation: Kelly G. Inulin-type prebiotics: a review. (Part 2). Altern Med Rev. 2009 Mar;14(1):36-55.
citation: Abrams SA, Griffin IJ, Hawthorne KM, Liang L, Gunn SK, Darlington G, Ellis KJ. A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am J Clin Nutr. 2005 Aug;82(2):471-6. doi: 10.1093/ajcn.82.2.471.
citation: Reddy BR. Noncaloric Benefits of Carbohydrates. Nestle Nutr Inst Workshop Ser. 2015;82:27-37. doi: 10.1159/000381999. Epub 2015 Oct 20.
citation: Tarini J, Wolever TM. The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl Physiol Nutr Metab. 2010 Feb;35(1):9-16. doi: 10.1139/H09-119.
citation: Neyrinck AM, Delzenne NM. Potential interest of gut microbial changes induced by non-digestible carbohydrates of wheat in the management of obesity and related disorders. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):722-8. doi: 10.1097/MCO.0b013e32833ec3fb.
citation: Lee A, Newman JM. Celiac diet: its impact on quality of life. J Am Diet Assoc. 2003 Nov;103(11):1533-5. doi: 10.1016/j.jada.2003.08.027.
citation: Lee AR, Ng DL, Zivin J, Green PH. Economic burden of a gluten-free diet. J Hum Nutr Diet. 2007 Oct;20(5):423-30. doi: 10.1111/j.1365-277X.2007.00763.x.
citation: Verdu EF, Armstrong D, Murray JA. Between celiac disease and irritable bowel syndrome: the "no man's land" of gluten sensitivity. Am J Gastroenterol. 2009 Jun;104(6):1587-94. doi: 10.1038/ajg.2009.188.
citation: Mills EJ, Chan AW, Wu P, Vail A, Guyatt GH, Altman DG. Design, analysis, and presentation of crossover trials. Trials. 2009 Apr 30;10:27. doi: 10.1186/1745-6215-10-27.
citation: Hodge A, Patterson AJ, Brown WJ, Ireland P, Giles G. The Anti Cancer Council of Victoria FFQ: relative validity of nutrient intakes compared with weighed food records in young to middle-aged women in a study of iron supplementation. Aust N Z J Public Health. 2000 Dec;24(6):576-83. doi: 10.1111/j.1467-842x.2000.tb00520.x.
citation: Leffler DA, Dennis M, Edwards George JB, Jamma S, Magge S, Cook EF, Schuppan D, Kelly CP. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol. 2009 May;7(5):530-6, 536.e1-2. doi: 10.1016/j.cgh.2008.12.032. Epub 2009 Jan 11.
citation: Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988 Feb;33(2):129-34. doi: 10.1007/BF01535722.
citation: Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998 Feb;43(2):400-11. doi: 10.1023/a:1018831127942.
citation: Kim ER, Rhee PL. How to interpret a functional or motility test - colon transit study. J Neurogastroenterol Motil. 2012 Jan;18(1):94-9. doi: 10.5056/jnm.2012.18.1.94. Epub 2012 Jan 16.
citation: Megiorni F, Mora B, Bonamico M, Nenna R, Di Pierro M, Catassi C, Drago S, Mazzilli MC. A rapid and sensitive method to detect specific human lymphocyte antigen (HLA) class II alleles associated with celiac disease. Clin Chem Lab Med. 2008;46(2):193-6. doi: 10.1515/CCLM.2008.049.
citation: Zar S, Benson MJ, Kumar D. Food-specific serum IgG4 and IgE titers to common food antigens in irritable bowel syndrome. Am J Gastroenterol. 2005 Jul;100(7):1550-7. doi: 10.1111/j.1572-0241.2005.41348.x.
citation: Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
citation: Roalfe AK, Roberts LM, Wilson S. Evaluation of the Birmingham IBS symptom questionnaire. BMC Gastroenterol. 2008 Jul 23;8:30. doi: 10.1186/1471-230X-8-30.
citation: Adam B, Liebregts T, Holtmann G. [Irritable bowel syndrome]. Dtsch Med Wochenschr. 2005 Feb 25;130(8):399-401. doi: 10.1055/s-2005-863064. German.
citation: Fennerty MB. Traditional therapies for irritable bowel syndrome: an evidence-based appraisal. Rev Gastroenterol Disord. 2003;3 Suppl 2:S18-24.
citation: Johanson JF. Options for patients with irritable bowel syndrome: contrasting traditional and novel serotonergic therapies. Neurogastroenterol Motil. 2004 Dec;16(6):701-11. doi: 10.1111/j.1365-2982.2004.00550.x.
citation: Drossman DA, Patrick DL, Whitehead WE, Toner BB, Diamant NE, Hu Y, Jia H, Bangdiwala SI. Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire. Am J Gastroenterol. 2000 Apr;95(4):999-1007. doi: 10.1111/j.1572-0241.2000.01941.x.
citation: Missbach B, Schwingshackl L, Billmann A, Mystek A, Hickelsberger M, Bauer G, Konig J. Gluten-free food database: the nutritional quality and cost of packaged gluten-free foods. PeerJ. 2015 Oct 22;3:e1337. doi: 10.7717/peerj.1337. eCollection 2015.
citation: Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13. doi: 10.1186/1741-7015-10-13.
citation: Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol. 2011 Aug;30(4):219-31. doi: 10.3109/08830185.2011.602443.
citation: Natividad JM, Huang X, Slack E, Jury J, Sanz Y, David C, Denou E, Yang P, Murray J, McCoy KD, Verdu EF. Host responses to intestinal microbial antigens in gluten-sensitive mice. PLoS One. 2009 Jul 31;4(7):e6472. doi: 10.1371/journal.pone.0006472.
citation: Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011 Aug;141(2):599-609, 609.e1-3. doi: 10.1053/j.gastro.2011.04.052. Epub 2011 Apr 30.
citation: Volta U, Pinto-Sanchez MI, Boschetti E, Caio G, De Giorgio R, Verdu EF. Dietary Triggers in Irritable Bowel Syndrome: Is There a Role for Gluten? J Neurogastroenterol Motil. 2016 Oct 30;22(4):547-557. doi: 10.5056/jnm16069.