Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity

  • Gry I. Skodje
    Correspondence
    Reprint requests Address requests for reprints to: Gry I. Skodje, MSc, RD, Department of Clinical Nutrition, Division of Cancer Medicine, Oslo University Hospital, PB 4950 Nydalen, 0424 Oslo, Norway.
    Affiliations
    Division of Cancer Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    K. G. Jebsen Celiac Disease Research Centre, University of Oslo, Norway

    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
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  • Vikas K. Sarna
    Affiliations
    K. G. Jebsen Celiac Disease Research Centre, University of Oslo, Norway

    Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway
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  • Ingunn H. Minelle
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
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  • Kjersti L. Rolfsen
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
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  • Jane G. Muir
    Affiliations
    Department of Gastroenterology, Monash University and Alfred Hospital, Melbourne, Victoria, Australia
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  • Peter R. Gibson
    Affiliations
    Department of Gastroenterology, Monash University and Alfred Hospital, Melbourne, Victoria, Australia
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  • Marit B. Veierød
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway

    Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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  • Christine Henriksen
    Affiliations
    K. G. Jebsen Celiac Disease Research Centre, University of Oslo, Norway

    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway
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  • Knut E.A. Lundin
    Affiliations
    K. G. Jebsen Celiac Disease Research Centre, University of Oslo, Norway

    Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway

    Department of Gastroenterology, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway

    Centre for Immune Regulation, University of Oslo, Oslo, Norway
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Published:November 01, 2017DOI:https://doi.org/10.1053/j.gastro.2017.10.040

      Background & Aims

      Non-celiac gluten sensitivity is characterized by symptom improvement after gluten withdrawal in absence of celiac disease. The mechanisms of non-celiac gluten sensitivity are unclear, and there are no biomarkers for this disorder. Foods with gluten often contain fructans, a type of fermentable oligo-, di-, monosaccharides and polyols. We aimed to investigate the effect of gluten and fructans separately in individuals with self-reported gluten sensitivity.

      Methods

      We performed a double-blind crossover challenge of 59 individuals on a self-instituted gluten-free diet, for whom celiac disease had been excluded. The study was performed at Oslo University Hospital in Norway from October 2014 through May 2016. Participants were randomly assigned to groups placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo, concealed in muesli bars, for 7 days. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Symptoms were measured by Gastrointestinal Symptom Rating Scale Irritable Bowel Syndrome (GSRS-IBS) version. A linear mixed model for analysis was used.

      Results

      Overall GSRS-IBS scores differed significantly during gluten, fructan, and placebo challenges; mean values were 33.1 ± 13.3, 38.6 ± 12.3, and 34.3 ± 13.9, respectively (P = .04). Mean scores for GSRS-IBS bloating were 9.3 ± 3.5, 11.6 ± 3.5, and 10.1 ± 3.7, respectively, during the gluten, fructan, and placebo challenges (P = .004). The overall GSRS-IBS score for participants consuming fructans was significantly higher than for participants consuming gluten (P = .049), as was the GSRS bloating score (P = .003). Thirteen participants had the highest overall GSRS-IBS score after consuming gluten, 24 had the highest score after consuming fructan, and 22 had the highest score after consuming placebo. There was no difference in GSRS-IBS scores between gluten and placebo groups.

      Conclusions

      In a randomized, double-blind, placebo-controlled crossover study of individuals with self-reported non-celiac gluten sensitivity, we found fructans to induce symptoms, measured by the GSRS-IBS. Clinicaltrials.gov no: NCT02464150.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      ATI (α-amylase trypsin inhibitor), DBPCFC (double-blind placebo-controlled food challenge), FODMAPs (fermentable oligo-, di-, monosaccharides and polyols), GSRS-IBS (gastrointestinal symptom rating scale irritable bowel syndrome), IBS (irritable bowel syndrome), NCGS (non-celiac gluten sensitivity), SD (standard deviation), SF-36 (Short form-36), VAS (visual analogue scale)
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      References

        • Lebwohl B.
        • Leffler D.A.
        Exploring the strange new world of non-celiac gluten sensitivity.
        Clin Gastroenterol Hepatol. 2015; 13: 1613-1615
        • Lundin K.E.
        • Alaedini A.
        Non-celiac gluten sensitivity.
        Gastrointest Endosc Clin N Am. 2012; 22: 723-734
        • Ludvigsson J.F.
        • Leffler D.A.
        • Bai J.C.
        • et al.
        The Oslo definitions for celiac disease and related terms.
        Gut. 2013; 62: 43-52
        • Catassi C.
        • Elli L.
        • Bonaz B.
        • et al.
        Diagnosis of non-celiac gluten sensitivity (NCGS): the Salerno Experts' Criteria.
        Nutrients. 2015; 7: 4966-4977
        • Asero R.
        • Fernandez-Rivas M.
        • Knulst A.C.
        • et al.
        Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a reappraisal of their limitations and real indications.
        Curr Opin Allergy Clin Immunol. 2009; 9: 379-385
        • Gibson P.R.
        • Skodje G.I.
        • Lundin K.E.A.
        Non-celiac gluten sensitivity.
        J Gastroenterol Hepatol. 2017; 32: 86-89
        • Sapone A.
        • Lammers K.M.
        • Casolaro V.
        • et al.
        Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
        BMC Med. 2011; 9: 23
        • Brottveit M.
        • Beitnes A.C.
        • Tollefsen S.
        • et al.
        Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity.
        Am J Gastroenterol. 2013; 108: 842-850
        • Carroccio A.
        • Mansueto P.
        • Iacono G.
        • et al.
        Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity.
        Am J Gastroenterol. 2012; 107 (quiz 1907): 1898-1906
        • Biesiekierski J.R.
        • Newnham E.D.
        • Irving P.M.
        • et al.
        Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.
        Am J Gastroenterol. 2011; 106 (quiz 515): 508-514
        • 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
        • Biesiekierski J.R.
        • Peters S.L.
        • Newnham E.D.
        • et al.
        No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.
        Gastroenterology. 2013; 145 (e1-e3): 320-328
        • Di Sabatino A.
        • Volta U.
        • Salvatore C.
        • et al.
        Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial.
        Clin Gastroenterol Hepatol. 2015; 13: 1604-1612.e3
        • Elli L.
        • Tomba C.
        • Branchi F.
        • et al.
        Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: results from a multicenter randomized double-blind placebo-controlled gluten challenge.
        Nutrients. 2016; 8: 84
        • Zanini B.
        • Baschè R.
        • Ferraresi A.
        • et al.
        Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-celiac gluten sensitivity.
        Aliment Pharmacol Ther. 2015; 42: 968-976
        • Junker Y.
        • Zeissig S.
        • Kim S.J.
        • et al.
        Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
        J Exp Med. 2012; 209: 2395-2408
        • 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.e5
        • Longstreth G.F.
        • Thompson W.G.
        • Chey W.D.
        • et al.
        Functional bowel disorders.
        Gastroenterology. 2006; 130: 1480-1491
        • Cox J.
        • Mann M.
        MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
        Nat Biotechnol. 2008; 26: 1367-1372
        • Shan L.
        • Molberg O.
        • Parrot I.
        • et al.
        Structural basis for gluten intolerance in celiac sprue.
        Science. 2002; 297: 2275-2279
        • Wiklund I.K.
        • Fullerton S.
        • Hawkey C.J.
        • et al.
        An irritable bowel syndrome-specific symptom questionnaire: development and validation.
        Scand J Gastroenterol. 2003; 38: 947-954
        • Mykletun A.
        • Stordal E.
        • Dahl A.A.
        Hospital Anxiety and Depression (HAD) scale: factor structure, item analyses and internal consistency in a large population.
        Br J Psychiatry. 2001; 179: 540-544
        • Loge J.H.
        • Kaasa S.
        Short form 36 (SF-36) health survey: normative data from the general Norwegian population.
        Scand J Soc Med. 1998; 26: 250-258
        • Spangenberg L.
        • Brähler E.
        [The Giessen-Test – new norm values in a representative German sample (14–92 years)].
        Psychotherapie Psychosomatik medizinische Psychologie. 2011; 61 ([Article in German]): e15-e18
        • Brottveit M.
        • Vandvik P.O.
        • Wojniusz S.
        • et al.
        Absence of somatization in non-celiac gluten sensitivity.
        Scand J Gastroenterol. 2012; 47: 770-777
        • Senn S.
        Statistics in Practice.
        Cross-over Trials in Clinical Research. Ch 5: Normal Data from Designs with Three or More Treatments. Ed 2. John Wiley & Sons Ltd, West Sussex, England2002: 157-185
        • Oberhuber G.
        • Granditsch G.
        • Vogelsang H.
        The histopathology of celiac disease: time for a standardized report scheme for pathologists.
        Eur J Gastroenterol Hepatol. 1999; 11: 1185-1194
        • Sarna V.K.
        • Skodje G.I.
        • Reims H.M.
        • et al.
        HLA-DQ:gluten tetramer test in blood gives better detection of celiac patients than biopsy after 14-day gluten challenge.
        Gut. 2017; ([Epub ahead of print])
        • Molina-Infante J.
        • Carroccio A.
        Suspected nonceliac gluten sensitivity confirmed in few patients after gluten challenge in double-blind, placebo-controlled trials.
        Clin Gastroenterol Hepatol. 2017; 15: 339-348
        • Shepherd S.J.
        • Parker F.C.
        • Muir J.G.
        • et al.
        Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence.
        Clin Gastroenterol Hepatol. 2008; 6: 765-771
        • Erickson J.
        • Korczak R.
        • Wang Q.
        • et al.
        Gastrointestinal tolerance of low FODMAP oral nutrition supplements in healthy human subjects: a randomized controlled trial.
        Nutr J. 2017; 16: 35
        • de Punder K.
        • Pruimboom L.
        The dietary intake of wheat and other cereal grains and their role in inflammation.
        Nutrients. 2013; 5: 771-787
        • 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
        • Ostgaard H.
        • Hausken T.
        • Gundersen D.
        • et al.
        Diet and effects of diet management on quality of life and symptoms in patients with irritable bowel syndrome.
        Mol Med Rep. 2012; 5: 1382-1390
        • Aziz I.
        • Trott N.
        • Briggs R.
        • et al.
        Efficacy of a gluten-free diet in subjects with irritable bowel syndrome-diarrhea unaware of their HLA-DQ2/8 genotype.
        Clin Gastroenterol Hepatol. 2016; 14: 696-703.e1
        • Vazquez-Roque M.
        • Oxentenko A.S.
        Nonceliac gluten sensitivity.
        Mayo Clin Proc. 2015; 90: 1272-1277
        • Yao C.K.
        • Gibson P.R.
        • Shepherd S.J.
        Design of clinical trials evaluating dietary interventions in patients with functional gastrointestinal disorders.
        Am J Gastroenterol. 2013; 108: 748-758
        • Laatikainen R.
        • Koskenpato J.
        • Hongisto S.M.
        • et al.
        Randomised clinical trial: low-FODMAP rye bread vs. regular rye bread to relieve the symptoms of irritable bowel syndrome.
        Aliment Pharmacol Ther. 2016; 44: 460-470
        • Tavakkoli A.
        • Lewis S.K.
        • Tennyson C.A.
        • et al.
        Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease.
        Dig Dis Sci. 2014; 59: 1255-1261
        • Volta U.
        • Bardella M.T.
        • Calabro A.
        • et al.
        An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.
        BMC Med. 2014; 12: 85
        • Aziz I.
        • Lewis N.R.
        • Hadjivassiliou M.
        • et al.
        A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care.
        Eur J Gastroenterol Hepatol. 2014; 26: 33-39
        • Zingone F.
        • Bartalini C.
        • Siniscalchi M.
        • et al.
        Alterations in diets of patients with nonceliac gluten sensitivity compared with healthy individuals.
        Clin Gastroenterol Hepatol. 2017; 15: 63-68.e2
        • Skodje G.I.
        • Henriksen C.
        • Salte T.
        • et al.
        Wheat challenge in self-reported gluten sensitivity: a comparison of scoring methods.
        Scand J Gastroenterol. 2017; 52: 185-192
        • Muir J.G.
        • Rose R.
        • Rosella O.
        • et al.
        Measurement of short-chain carbohydrates in common Australian vegetables and fruits by high-performance liquid chromatography (HPLC).
        J Agric Food Chem. 2009; 57: 554-565

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