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. 2017 Jan;32(1):29-39.
doi: 10.1007/s00384-016-2663-x. Epub 2016 Sep 30.

Long-term Response to Gluten-Free Diet as Evidence for Non-Celiac Wheat Sensitivity in One Third of Patients With Diarrhea-Dominant and Mixed-Type Irritable Bowel Syndrome

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Long-term Response to Gluten-Free Diet as Evidence for Non-Celiac Wheat Sensitivity in One Third of Patients With Diarrhea-Dominant and Mixed-Type Irritable Bowel Syndrome

Christian Barmeyer et al. Int J Colorectal Dis. .
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Purpose: Irritable bowel syndrome (IBS) is common but therapies are unsatisfactory. Food is often suspected as cause by patients, but diagnostic procedures, apart from allergy testing, are limited. Based on the hypothesis of non-celiac wheat sensitivity (WS) in a subgroup of IBS patients, we tested the long-term response to a gluten-free diet (GFD) and investigated HLA-DQ2 or -DQ8 expression as a diagnostic marker for WS in diarrhea-dominant (IBS-D) and mixed-type IBS (IBS-M).

Methods: The response to a GFD served as reference test for WS and HLA-DQ2/8 expression was determined as index test. Patients were classified as responders if they reported complete or considerable relief of IBS symptoms on at least 75 % of weeks over a 4-month period of gluten-free diet. Established questionnaires (IBS-Quality of Life (IBS-QoL), IBS Symptom Severity Scale (IBS-SSS), European Quality of Life-5 Dimensions (EQ-5D)) were used for secondary outcome measures.

Results: Thirty-five patients finished the study. Of these, 12 (34 %) were responders and classified as having WS (95 % CI 21-51 %). HLA-DQ2/8 expression had a specificity of 52 % (95 % CI 33-71 %) and sensitivity of 25 % (95 % CI 8-54 %) for WS. Responders showed improvement in quality of life and symptom scores. At 1-year follow-up, all responders and 55 % of non-responders were still on GFD and reported symptom relief.

Conclusion: Using strict criteria as recommended for IBS studies, about one third of patients with IBS-D or IBS-M are wheat sensitive, with a similar proportion in both IBS types. Expression of HLA-DQ2/8 is not useful as diagnostic marker for WS. Long-term adherence to a GFD is high and can sustain symptomatic improvement.

Keywords: Gluten-free diet; HLA-DQ2; HLA-DQ8; Irritable bowel syndrome; Wheat-sensitivity.

Conflict of interest statement

Compliance with ethical standards The study was approved by the local ethics committee of the Charité—Universitätsmedizin Berlin under the number EA4/044/11. Written informed consent was obtained from all study participants. Funding The study was initiated by the investigators and supported by a grant from Dr. Schär AG. Conflict of interest Reiner Ullrich and Michael Schumann received research grants from Dr. Schär AG. Britta Siegmund received a research grant from Hospira and served as consultant for Janssen, MSD, Abbvie, Takeda, Hospira and received lecture fees from Abbvie, Falk, Ferring, MSD, Merck, Takeda; all money went to the institution. Torsten Zuberbier served as a consultant for ALK, Almirall, Abbvie, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, Meda, Menarini, Merck, MSD, Novartis, Pharmasquire, Quintiles, Serono, Stallergenes, Takeda, Teva, and UCB. Christian Barmeyer, Tim Meyer, Christina Zielinski, Jörg-Dieter Schulzke, and Severin Daum declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.


Fig. 1
Fig. 1
Diagram of the patient flow through the study. Ninety-one Rome III fulfilling patients with self-reported weekly symptoms entered a 4-week observation period during which 45 (49 %) were excluded due to improvement or lack of weekly symptoms (15 patients) and other mainly personal reasons (30 patients). The remaining 46 patients entered a diagnostic stage during which 11 (24 %) were excluded due to a new diagnosis. The remaining 35 patients entered the trial stage. Depicted here is the result of the 75 % criterion (“considerably relieved” or “completely relieved” at 75 % of the time during the GFD). According to this, 12 patients were classified as responders and 23 patients as non-responders with no correlation between response to GFD and HLA-DQ2/8 status
Fig. 2
Fig. 2
Results of the secondary outcome measures obtained by the IBS-SSS. a Comparison of responder (R) versus non-responder (NR) of the 75 % criterion for the indicated measures. Data are presented as box plots for n = 12 R and n = 19 NR. *p < 0.05. b Comparison of responder (R) versus non-responder (NR) of the 50 % criterion for the indicated measures. Data are presented as box plots for n = 18 R and n = 13 NR. *p < 0.05, **p < 0.005
Fig. 3
Fig. 3
Core statistical parameters of the study. Diagram of the false negative (FN), false positive (FP), true negative (TN), and true positive (TP) values in relation to the primary outcome after 4 months of GFD (TN and TP set as 100 %) for the 75 % criterion (a) and the 50 % criterion (c). Diagram of sensitivity (sens), specificity (spec), positive predictive value (ppv), negative predictive value (npv), and accuracy (acc) for the 75 % criterion (b) and the 50 % criterion (d)

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    1. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, Soffern EE, Spiegel BM, Quigley EM, Task Force on the Management of Functional Bowel D American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(Suppl 1):S2–26. doi: 10.1038/ajg.2014.187. - DOI - PubMed
    1. Ford AC, Talley NJ. Irritable bowel syndrome. BMJ. 2012;345:e5836. doi: 10.1136/bmj.e5836. - DOI - PubMed
    1. Systematic review on the management of irritable bowel syndrome in the European Union (2007). Eur J Gastroenterol Hepatol 19 Suppl 1:S11–37. doi:10.1097/01.meg.0000252641.64656.41 - PubMed
    1. Talley NJ, Zinsmeister AR, Van Dyke C, Melton LJ., 3rd Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology. 1991;101(4):927–934. doi: 10.1016/0016-5085(91)90717-Y. - DOI - PubMed
    1. Leong SA, Barghout V, Birnbaum HG, Thibeault CE, Ben-Hamadi R, Frech F, Ofman JJ. The economic consequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med. 2003;163(8):929–935. doi: 10.1001/archinte.163.8.929. - DOI - PubMed

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