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45In linewith the latterfindings, the detection of antigliadin antibodiesin >50% of patients with NCGS provides further support toadaptive immunity in NCGS pathogenesis.46Second, discordantdataexistonepithelialbarrierdysfunction.Initialstudiesshowed a reduced intestinal permeability in NCGS, thus sug-gesting an increased intestinal barrier function. Thisfinding hasbeen also supported by a significantly higher expression ofclaudin-4 mRNA, a marker of reduced permeability, in duodenalDe Giorgio R,et al.Gut2016;65:169–178. doi:10.1136/gutjnl-2015-309757171Recent advances in clinical practicegroup.bmj.comon March 9, 2016 - Published by Downloaded from
biopsies of patients with NCGS.44However, more recently,some evidence for increased intestinal permeability in a sub-group of patients with IBS-D carrying the human leucocyteantigen (HLA)-DQ2+/DQ8+ was reported when consuming agluten-containing diet compared with a GFD.47Further studiesare needed. Third, changes of gut microbiota, as detected inCD,48might alsooccurin patients withNCGS. Finally, afurtheraspectpotentiallylinkingNCGSwithIBSisthatHLA-DQ8 transgenic mice sensitised by gliadin displayed anincreased secretion of acetylcholine from the myenteric plexus,enhancing muscle contractility andepithelialhypersecretion.Gluten withdrawal reversed both abnormalities.49Evidence from double-blind placebo-controlled trialsConsistentevidenceindicatestheexistenceofanoverlapbetween IBS and gluten-related disorders. In fact, about 5% ofpatients with IBS tests positive for CD and, conversely, CD maypresent with typical IBS-like symptoms.50 51Moreover, IBS-likesymptoms occur in the majority of patients with NCGS,40whileaboutone-thirdof patientswith IBS mayhaveNCWPS.37Although wheat is now established to be linked to IBS, the com-ponent(s) that actually trigger(s) symptoms remain unknown. Inthis line, the only way to confirm the possible role of gluten orwheat as causative factors of NCGS/NCWPS is a DBPC strat-egy.27This is an expensive and time-consuming procedure and,therefore, it is not yet of routine use being confined to researchsetting.37–39435253So far, few DBPC trials have been per-formed. Their design and results are shown intable 1. Thefind-ings are discordant with a variation from approximately 30% of920 patients with IBS in a routine clinical setting being sensitiveto wheat protein, of whom the majority has NCWPS associatedwithmultiplefoodhypersensitivity,37togreatersymptomsinductionoverallwith glutenor wheat protein,383953togluten-specific responses for current feelings of depression butnot for abdominal symptoms.38 53Reasons for apparent heterogeneity of results require dissec-tion. First, subject selection might be a factor. For example, con-tamination of the cohort with CD can unduly skew results. Thisis why the exclusion of CD by combined histological and sero-logicalassessmentwhileconsumingadequateglutenissoimportant. In this respect, a critical point is to decide whether