Efficacy of a Gluten-Free Diet in Subjects With Irritable Bowel Syndrome-Diarrhea Unaware of Their HLA-DQ2/8 Genotype

Published:December 31, 2015DOI:

      Background & Aims

      A gluten-containing diet alters bowel barrier function in patients with irritable bowel syndrome with diarrhea (IBS-D), particularly those who are positive for HLA allele DQ2/8. We studied the effects of a gluten-free diet (GFD) in patients with IBS-D who have not previously considered the effects of gluten in their diet and were unaware of their HLA-DQ2/8 genotype.


      We performed a prospective study of 41 patients with IBS-D (20 HLA-DQ2/8-positive and 21 HLA-DQ2/8-negative) at the Royal Hallamshire Hospital in Sheffield, United Kingdom, from September 2012 through July 2015. All subjects were placed on a 6-week GFD following evaluation by a dietician. Subjects completed validated questionnaires at baseline and Week 6 of the GFD. The primary endpoint was mean change in IBS Symptom Severity Score; a 50-point reduction was considered to indicate a clinical response. Secondary endpoints were changes in hospital anxiety and depression score, fatigue impact score, and Short Form-36 results. Clinical responders who chose to continue a GFD after the study period were evaluated on average 18 months later to assess diet durability, symptom scores, and anthropometric and biochemical status.


      A 6-week GFD reduced IBS Symptom Severity Score by ≥50 points in 29 patients overall (71%). The mean total IBS Symptom Severity Score decreased from 286 before the diet to 131 points after 6 weeks on the diet (P < .001); the reduction was similar in each HLA-DQ group. However, HLA-DQ2/8-negative subjects had a greater reduction in abdominal distention (P = .04). Both groups had marked mean improvements in hospital anxiety and depression scores, fatigue impact score, and Short Form-36 results, although HLA-DQ2/8-positive subjects had a greater reduction in depression score and increase in vitality score than HLA-DQ2/8-negative subjects (P = .02 and P = .03, respectively). Twenty-one of the 29 subjects with a clinical response (72%) planned to continue the GFD long term; 18 months after the study they were still on a GFD, with maintained symptom reductions, and demonstrated similar anthropometric and biochemical features compared with baseline.


      A dietitian-led GFD provided sustained benefit to patients with IBS-D. The symptoms that improved differed in magnitude according to HLA-DQ status. Clinical no: NCT02528929.


      Abbreviations used in this paper:

      CD (celiac disease), FIS (Fatigue Impact Scale), GFD (gluten-free diet), HADS (Hospital Anxiety and Depression Scale), IBS (irritable bowel syndrome), IBS-D (irritable bowel syndrome with diarrhea), IBS-SSS (Irritable Bowel Syndrome–Symptom Severity Score), QOL (quality of life), SF-36 (Short Form-36)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Chey W.D.
        • Kurlander J.
        • Eswaran S.
        Irritable bowel syndrome: a clinical review.
        JAMA. 2015; 313: 949-958
        • Lin S.
        • Mooney P.D.
        • Kurien M.
        • et al.
        Prevalence, investigational pathways and diagnostic outcomes in differing irritable bowel syndrome subtypes.
        Eur J Gastroenterol Hepatol. 2014; 26: 1176-1180
        • Lazaraki G.
        • Chatzimavroudis G.
        • Katsinelos P.
        Recent advances in pharmacological treatment of irritable bowel syndrome.
        World J Gastroenterol. 2014; 20: 8867-8885
        • Simrén M.
        Diet as a therapy for irritable bowel syndrome: progress at last.
        Gastroenterology. 2014; 146: 10-12
        • Böhn L.
        • Störsrud S.
        • Törnblom H.
        • et al.
        Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life.
        Am J Gastroenterol. 2013; 108: 634-641
        • Aziz I.
        • Hadjivassiliou M.
        • Sanders D.S.
        The spectrum of noncoeliac gluten sensitivity.
        Nat Rev Gastroenterol Hepatol. 2015; 12: 516-526
        • Halmos E.P.
        • Power V.A.
        • Shepherd S.J.
        • et al.
        A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
        Gastroenterology. 2014; 146: 67-75.e65
        • Murray K.
        • Wilkinson-Smith V.
        • Hoad C.
        • et al.
        Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI.
        Am J Gastroenterol. 2014; 109: 110-119
        • Vazquez-Roque M.I.
        • Camilleri M.
        • Carlson P.
        • et al.
        HLA-DQ genotype is associated with accelerated small bowel transit in patients with diarrhea-predominant irritable bowel syndrome.
        Eur J Gastroenterol Hepatol. 2011; 23: 481-487
        • Vazquez-Roque M.I.
        • Camilleri M.
        • Smyrk T.
        • et al.
        A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
        Gastroenterology. 2013; 144: 903-911.e903
        • Wahnschaffe U.
        • Schulzke J.D.
        • Zeitz M.
        • et al.
        Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome.
        Clin Gastroenterol Hepatol. 2007; 5 (quiz 769): 844-850
        • Ford A.C.
        • Chey W.D.
        • Talley N.J.
        • et al.
        Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis.
        Arch Intern Med. 2009; 169: 651-658
        • Aziz I.
        • Mumtaz S.
        • Bholah H.
        • et al.
        High prevalence of idiopathic bile acid diarrhea among patients with diarrhea-predominant irritable bowel syndrome based on Rome III criteria.
        Clin Gastroenterol Hepatol. 2015; 13: 1650-1655
        • Leeds J.S.
        • Hopper A.D.
        • Sidhu R.
        • et al.
        Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency.
        Clin Gastroenterol Hepatol. 2010; 8: 433-438
        • Halpin S.J.
        • Ford A.C.
        Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis.
        Am J Gastroenterol. 2012; 107: 1474-1482
        • Murray J.A.
        • Watson T.
        • Clearman B.
        • et al.
        Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease.
        Am J Clin Nutr. 2004; 79: 669-673
        • Biagi F.
        • Bianchi P.I.
        • Marchese A.
        • et al.
        A score that verifies adherence to a gluten-free diet: a cross-sectional, multicentre validation in real clinical life.
        Br J Nutr. 2012; 108: 1884-1888
        • Williams E.A.
        • Stimpson J.
        • Wang D.
        • et al.
        Clinical trial: a multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a double-blind placebo-controlled study.
        Aliment Pharmacol Ther. 2009; 29: 97-103
        • Ford A.C.
        • Moayyedi P.
        Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome.
        Aliment Pharmacol Ther. 2010; 32: 144-158
        • Shahbazkhani B.
        • Sadeghi A.
        • Malekzadeh R.
        • et al.
        Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: a double-blind randomized placebo-controlled trial.
        Nutrients. 2015; 7: 4542-4554
        • Böhn L.
        • Störsrud S.
        • Liljebo T.
        • et al.
        Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.
        Gastroenterology. 2015; 149: 1399-1407
        • Staudacher H.M.
        • Lomer M.C.
        • Anderson J.L.
        • et al.
        Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome.
        J Nutr. 2012; 142: 1510-1518
        • Halmos E.P.
        • Christophersen C.T.
        • Bird A.R.
        • et al.
        Diets that differ in their FODMAP content alter the colonic luminal microenvironment.
        Gut. 2015; 64: 93-100
        • De Palma G.
        • Nadal I.
        • Collado M.C.
        • et al.
        Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects.
        Br J Nutr. 2009; 102: 1154-1160
        • Sanz Y.
        Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans.
        Gut Microbes. 2010; 1: 135-137
        • Mujagic Z.
        • Ludidi S.
        • Keszthelyi D.
        • et al.
        Small intestinal permeability is increased in diarrhoea predominant IBS, while alterations in gastroduodenal permeability in all IBS subtypes are largely attributable to confounders.
        Aliment Pharmacol Ther. 2014; 40: 288-297
        • Fritscher-Ravens A.
        • Schuppan D.
        • Ellrichmann M.
        • et al.
        Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.
        Gastroenterology. 2014; 147: 1012-1020.e1014
        • Verdu E.F.
        • Huang X.
        • Natividad J.
        • et al.
        Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.
        Am J Physiol Gastrointest Liver Physiol. 2008; 294: G217-G225
        • Peters S.L.
        • Biesiekierski J.R.
        • Yelland G.W.
        • et al.
        Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity: an exploratory randomised clinical study.
        Aliment Pharmacol Ther. 2014; 39: 1104-1112


        • Francis C.Y.
        • Morris J.
        • Whorwell P.J.
        The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress.
        Aliment Pharmacol Ther. 1997; 11: 395-402
        • Zigmond A.S.
        • Snaith R.P.
        The hospital anxiety and depression scale.
        Acta Psychiatr Scand. 1983; 67: 361-370
        • Fisk J.D.
        • Ritvo P.G.
        • Ross L.
        • et al.
        Measuring the functional impact of fatigue: initial validation of the fatigue impact scale.
        Clin Infect Dis. 1994; 18: S79-S83
        • Ware J.E.
        • Gandek B.
        Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project.
        J Clin Epidemiol. 1998; 51: 903-912