The Role of a Low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol Diet in Nonceliac Gluten Sensitivity. (2024)

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1. Introduction

Gluten avoidance has become a popular health trend with nearly 30%of adults avoiding gluten or limiting their intake. Despite conflictingevidence regarding the existence of nonceliac gluten sensitivity (NCGS)as an entity amongst clinicians, it has found prompt and easy acceptancein the general public [1]. NCGS is defined by the presence of intestinaland extraintestinal symptoms related to ingestion of gluten-containingfoods in subjects not affected by either celiac disease (CD) or wheatallergy (WA) [2]. Indirect evidence suggests that NCGS could be moreprevalent than celiac disease [3]. As per Salerno Experts' Criteriaestablished in 2015, "in the absence of sensitive and specificbiomarkers, a closed and standardized monitoring of the patient duringelimination and reintroduction of gluten is the most specific diagnosticapproach and hence could be used as diagnostic hallmark of NCGS"[2]. There is a significant overlap between the gastrointestinalsymptoms of NCGS and irritable bowel syndrome (IBS). The extraintestinalmanifestations of NCGS (lack of well-being, fatigue, headache, brainfog, anemia, anxiety, and numbness) respond to dietary modifications anddifferentiate it from IBS [2]. Additionally, it is recommended thatgluten-unresponsive patients should be investigated for other etiologiesof IBS-like symptoms including fermentable oligosaccharides,disaccharides, monosaccharides, and polyols (FODMAP) that includefructose, lactose, fructans, galactans, xylitol, sorbitol, maltitol, andmannitol intolerance and small intestinal bacterial overgrowth (SIBO).Recent studies suggest that despite following a long-term gluten-freediet (GFD) in NCGS, milder clinical symptoms may still persist [4].

Although the etiology of NCGS remains unknown, the role of FODMAPsis being increasingly investigated. FODMAPs have been postulated toprecipitate functional gastrointestinal (GI) symptoms by inducingdistention of GI lumen through their osmotic effects and production ofgas in the small bowel and proximal colon related to rapid fermentationby gut bacteria in subjects with visceral hypersensitivity or GImotility disorders [5, 6]. Over the last few decades, due to theincreasing westernization of food habits, diet patterns have changed toinclude FODMAPs in significant amounts. A diet low in FODMAPs has beenshown to improve symptoms in patients with IBS, with 70% of patients whofollow a low FODMAP diet experiencing significant improvement insymptoms, particularly abdominal pain and distention [7].Recommendations for a low FODMAP diet were included in the guidelines ofthe British Dietetic Association in 2010 and 2011 and in the Australianguidelines for the treatment of IBS [8].

This review includes studies on patients with NCGS in whom FODMAPseither directly precipitated symptoms or adherence to low FODMAP dietimproved symptoms. In addition, we sought to determine ifNCGS is aheterogeneous entity that consists of patients who may improve on lowFODMAP diet with or without following a GFD.

2. Methods

Relevant articles were identified by systematically searching theCochrane Library, EMBASE, and PubMed for English language articlespublished by April 30, 2018. Manual search for relevant publicationsfrom the references of extracted articles was also performed. Nopublication date or publication status restrictions were applied.Preferred reporting items for systemic reviews and meta-analyses(PRISMA) guidelines were followed to develop a protocol includingeligibility criteria, search strategies, criteria for study selection,methods for data extraction, and assessing study quality and statistics[9].

Full text of these citations was retrieved and examined in moredetail. Six studies were finally included for this review, as shown inTable 1.

3. Results

3.1. Study Design and Inclusion/Exclusion Criteria (Table 1). Allincluded studies were original articles. Only one study was open indesign, and the remaining studies were randomized, double-blindcontrolled trials; four were placebo controlled, and five had acrossover design. The primary inclusion criteria were adult patientswith self-reported NCGS. In all, a total of 197 patients across allstudies were included. The sample size of the studies included variedfrom 22 to 59 patients.

3.2. Gastrointestinal Symptoms. The abdominal symptoms and bloatingwere associated with fructan challenge in a recent randomized,double-blind, placebo-controlled, crossover challenge (DBPCC) studyinvolving 59 subjects with self-reported NCGS, as measured bygastrointestinal symptom rating scale-irritable bowel syndrome(GSRS-IBS) and GSRS bloating score. Also, visual analogue scale (VAS)for pain, bloating, flatus, nausea, and stool dissatisfaction was higherin the fructan challenge cohort [10]. In an Italian study, GI symptomsnoted in both control and test groups could be attributed to thepresence of FODMAPs in both flours [11]. The presence of FODMAPs wassubstantially higher in the gluten-free flour with 6.8 g lactose, 0.16 gfructans, and 0.04 g sucrose, compared to gluten-containing amyglutenwith 0.8 g fructans, 0.2 g sucrose, and 0.08 g fructose. It is plausiblethat the symptoms of the gluten-free diet were caused by the high FODMAPcontent and thus cannot be distinguished from true clinical symptomsafter gluten stimulation. An eight-week low FODMAP diet stage of anotherstudy by the same group showed that all five dimensions of the GSRS werereduced [12]. This study concluded that the patients reporting glutensensitivity are a heterogeneous population composed of true glutensensitivity and FODMAP sensitivity.

In an Australian DBPCC involving 37 patients, after a two-week runin period of low FODMAP diet and GFD, NCGS patients had significant andconsistent improvement in abdominal pain, bloating, and satisfactionwith stool consistency, flatus, and fatigue. Similar findings were notedin the rechallenge stage of the trial [13]. In another similar study,NCGS patients were placed on FODMAP restriction followed by GFD [14]. Onthe low FODMAP diet, GSRS improved significantly for reflux, abdominalpain, and indigestion. These symptoms improved further during the GFDstage of the trial. This study suggested an additional benefit of GFDwith low FODMAP diet. Similarly, in another trial, studying the effectof gluten challenge in NCGS patients, there was no observable differencein the GI symptoms of the control and test cohorts, once FODMAPs wereremoved from both gluten-free and gluten-containing flours [15]. Thesestudies help establish the causative role of FODMAPs in the GI symptomsof NCGS.

3.3. Extraintestinal Symptoms

3.3.1. Vitality. Health-related quality of life indicated thelowest score for the "vitality" subdimension during fructanchallenge in a Norwegian study [10].

3.3.2. Fatigue. Fatigue and weakness were significantly higherafter fructan challenge and not different between gluten and placeboarms [10]. Similarly, fatigue was associated with FODMAP use andimproved with the elimination of FODMAPs in other studies [11-13].

3.3.3. Depression. Higher depression scores were noted in subjectschallenged with gluten following a low FODMAP diet and GFD [15].Psychological parameters improved remarkably initially after theinitiation of a low FODMAP diet and further improved on a GFD in thisstudy [15].

3.4. Nocebo or Negative Placebo Effect of Gluten. A strong noceboresponse was seen in all the included studies [16, 17]. In the Norwegianstudy, symptom response to placebo (n = 22) was almost as high asresponse to fructan challenge (n = 24) and significantly higher than thegluten challenge (n = 13) cohort [10].

About one-fifth of participants in an Italian study did not reportworsening of symptoms after a challenge with either gluten-rich orgluten-free flour [11]. As there was no placebo arm in this trial, theauthors speculated that in real-life situations, patients might beexperiencing their symptoms due to psychological anticipation ofintolerance when exposed to gluten and thereby suggesting a noceboeffect. Although it has been shown that NCGS patients did not show anincreased tendency for general somatization, emotional factors may stillplay a role [18]. Only 8% of participants specifically showed truesensitivity to gluten in trial conditions, much lower than real-lifeconditions, possibly attributable to the nocebo effect [13].

The strong nocebo effect raises the concern of feasibility or eventhe usefulness of a DBPCC in clinical practice for the diagnosis ofNCGS.

3.5. Biomarkers. In an emerging area of study, the use ofbiomarkers in monitoring response in NCGS is uncommon [13,14]. In onestudy, only one participant was found to have a positive T-cell responseafter a high-gluten challenge. No significant difference across thetreatment groups for other biomarkers including eosinophil cationicprotein, radio allegro-sorbent test, fecal pH and fecal concentrationsof human ^-defensin-2, calprotectin, and ammonia levels was noted [13].In another study, intraepithelial lymphocytes (IELs) were moderatelyincreased in roughly 42% patients with NCGS, but the extent was lowerthan typically seen in CD [14]. IELs and goblet cells reducedsignificantly on GFD as compared to baseline, thereby suggesting theadded benefit of GFD.

3.6. Intestinal Microbiota. Only one trial examined changes in thegut microbiota [14]. In healthy controls, relative to NCGS patients,colonies of bacteria belonging to the phylum Bacteroidetes were higher,and phylum Firmicutes were lower compared to NCGS patients. Similarfindings with phylum dysbalance have been observed in IBS patients [19,20]. In NCGS patients, a significant increase in Bacteroidetes and areduction of Firmicutes were noted with a GFD compared to a low FODMAPdiet. This study highlighted that the microbiota from NCGS patients aremore susceptible to the various dietary modifications compared tohealthy controls. GFD also was associated with a significant increase inBacteroidetes compared to low FODMAP diet. Notably, while healthycontrols did not display any significant variations in microbioticsignatures, NCGS patients displayed significant changes in bacteriaresponsible for dehalogenation, ammonia oxidation, xylan and cellulosedegradation, sulfate reduction, and nitrogen fixation especially whileadhering to GFD. These effects were less prominent with low FODMAP dietin this study. These findings strengthen the evidence for the additivebenefits of low FODMAP diet and GFD.

3.7. Discussion. Our review presents the evidence that NCGSpatients could potentially benefit from FODMAP restriction with orwithout gluten restriction. The results suggest that a subset of NCGSpatients actually has FODMAP intolerance. This raises the question ofNCGS as an entity specifically used in the context of gluten sensitivityas well as its distinction from FODMAP intolerance. FODMAPs may be acausative factor in GI symptoms and to some extent in extraintestinalsymptoms such as fatigue and loss of vitality in some NCGS patients.NCGS may be a heterogeneous entity with multiple factors such as FODMAPsin addition to gluten contributing to symptom generation.

In a landmark study that established the current existence of NCGSas a separate entity, gluten was shown to induce both GI andextraintestinal symptoms in patients without CD [21]. Notably, in thisstudy test, gluten was devoid of FODMAPs. In another study from the samegroup, subjects who were already slightly improved on GFD improvedfurther on a low FODMAP diet [13]. Also, they failed to worsen with agluten challenge. A strong association of FODMAPs with GI symptoms suchas bloating and indigestion was noted across all studies. Thiscorrelation was noted in multiple ways like symptomatic improvement onlow FODMAP diet or worsening of symptoms with a fructan challenge or theequal presence of symptoms in both placebo and study cohorts if theywere both being exposed to fructans [10-15].

Extraintestinal manifestations of NCGS, such as fatigue,depression, and anxiety, were mostly evaluated as secondary outcomes.Fatigue and vitality were significantly worse after a fructan challengein some studies [10, 12]. Furthermore, fatigue improved significantlywith a FODMAP-free run-in period and subsequently increased during thedietary challenge arm, irrespective of the dietary challenge. Theextraintestinal symptoms in these patients could possibly be attributedeither independently to the neurological effects of gluten present inwheat or combined effect of FODMAPs and gluten as in real-lifescenarios. A low FODMAP diet followed by 14 days on GFD resulted inreduced IELs indicating the additive benefit of the two diets. Sinceintestinal biopsies were not performed immediately after low FODMAP dietin this study, it is hard to comment if the reduction was due toadherence to GFD or low FODMAP diet. These investigators suggested thatNCGS patients could benefit from following low FODMAP and GFDsimultaneously. The cumulative, beneficial effects of low FODMAP dietand GFD on gut microbiota suggest that adherence to both diets may provesuperior to choosing to follow only one diet [14].

Similar synergic effects of a low FODMAP diet and GFD were noted inother studies [10, 11, 13, 15].

Increasing evidence indicates that only a very small percentage(16-30%) of patients were actually found to have NCGS in rechallengestudies. Two separate meta-analyses of double-blind placebo-controlledgluten challenge trials in NCGS explore the possibility of gluten notbeing responsible for symptoms in self-reported NCGS [1, 22]. In onemeta-analysis, the percentage of relapse correlated significantly withthe amount of gluten used and the duration of the challenge [22]. Thesame study also found that if Salerno Criteria were strictly followed,the percentage of relapse was notably higher (up to 40%) after glutenchallenge when compared to placebo. Another meta-analysis concluded thatgluten may not be responsible for the intestinal and extraintestinalsymptoms in a large majority of patients with self-reported NCGS [1]. Inaddition, these authors argued that the Salerno Experts' Criteria(an expert committee recommendation, not evidence-based) may be animperfect tool to diagnose NCGS. Since a prominent nocebo effect wasuniform to all studies, it could be argued that the very design of thestudies (a placebo control) could have contributed to the effects noted.Carryover effects in crossover trials or placebos containingunintentional substances that could precipitate symptoms are somealternate explanations of the observed nocebo effect. These authors alsoproposed a "melting pot hypothesis" for NCGS. In thishypothesis, between the two distinct entities of CD and WA are variousentities including the "gluten sensitivity" group,wheatinduced symptom group (with negative results after a glutenchallenge, nocebo effect), and FODMAP intolerance group [1]. They alsoemphasized the importance of accurately excluding CD as it wasinadequately ruled out in approximately 61% patients in one survey [23].These authors recommended more sensitive assays (than the usual testing)be used for patients with gluten-related symptoms and HLA DQ2/8haplotypes [24, 25]. They also considered FODMAP intolerance as animportant subgroup in the grey zone patients between CD and WA. Thedistinction between patient groups is clinically important as trulygluten-sensitive patients must adhere to a GFD and patients with FODMAPintolerance could benefit from low FODMAP diet, not necessarily glutenrestriction.

Despite the success of these diets in study conditions, or evenclinically, adherence to a restrictive diet like low FODMAP shouldalways be initiated and monitored by a registered dietician trained inthis area. As a concept, low FODMAP diet is complex, and it has alwaysbeen meant to be a dietician-delivered diet [26]. This would potentiallyavoid nutritional deficiencies including lower fiber and calcium in thefollowers of this diet. In addition, this would present as anopportunity to personalize the diet to patients' individual,specific dietary sensitivities. Despite all the negative GI effects seenin susceptible NCGS and IBS patients, FODMAPs have many beneficialeffects on the colon including "prebiotic effects" as theyselectively stimulate the growth and activity of potentially beneficialcolonic bacteria, specifically Bifidobacteria and Lactobacilli [27, 28].In addition, FODMAPs are fermented in the gut to short-chain fatty acidsby bacteria that have a trophic effect on the colonic epithelium andprotective effect against the colon cancer [29, 30]. Dietary FODMAPsincrease stool bulk, improve calcium absorption, modulate immunefunction, and decrease serum cholesterol, triglycerides, andphospholipids [31]. A low FODMAP diet may also be deficient in naturalantioxidants like flavanoids, carotenoids, and vitamin C contained invegetables like cauliflower, onion, and garlic and phenolic acid andanthrocyanins in fruits like blackberries [31]. At this time, it is alsonot clear if NCGS is a transient or a permanent condition. Since thelong-term effects of following a low FODMAP diet on other systems andcolon carcinogenesis are not known, it must be continued with cautionand careful monitoring of adverse effects. Once initiated on this diet,patients should be periodically rechallenged in a graded fashion toidentify specific dietary triggers and limits of tolerance [32]. Theoriginal proponents of this diet recommend "all FODMAP-freeperiod" of 6-8 weeks, followed by reintroduction of one FODMAP perweek [33].

3.8. Limitations. First, due to a high nocebo response, the role ofa DBPCC, the current gold standard for the diagnosis of NCGS, may bequestionable [10]. Even if DBPCC studies produced results that arestatistically significant, they may not have sufficient clinicalrelevance due to prominent nocebo effect seen across the studies. SinceNCGS at this time is a poorly defined condition with highly subjectivesymptoms, a common clinical approach of eliminating suspectedsymptom-inducing foods followed by clinician-supervised rechallenge withclose symptom monitoring has been advocated. This may prove superior toDBPCC due to its ease of administration and being more informative.

Second, the symptomatic effect of gluten with fructans and othercomponents of wheat may be additive or even synergistic. The fructans inthe food matrix may give a different clinical response than the studymaterials (supplements of pure fructans added to muesli bars derivedfrom chicory roots versus real-world wheat sources) [10]. Other wheatproteins like alpha-amylase trypsin inhibitors, lectins, and wheat germagglutinin may play a role in the causation of the symptoms. Opiate-likeeffects of gluten and IgE WA are other proposed hypotheses [34, 35].Current understanding of the pathogenesis of NCGS is quite limited anddata is scarce. Third, variable methodological designs make the dataheterogeneous and difficult to compare. Fourth, the period of followingGFD before entering the study was variable from six weeks to six months.A large placebo effect could be seen with shorter periods of pretrialGFD adherence [11]. Finally, recall bias is common to all the studiesthat monitor response during gluten challenge, and the studiesconsidered in this review were no exception.

4. Conclusions and Future Directions

This review suggests a multifactorial etiology of NCGS. FODMAPsmaybe responsible for gastrointestinal and extra-intestinal symptoms ina subset of patients with NCGS [13]. In addition, some evidence suggeststhat gluten and FODMAPs together may have additive effects on theclinical symptomatology of NCGS and at least some patients may improveby adhering to low FODMAP diet alone or in combination with GFD. Also,this review highlights the immense potential for specific dietaryinterventions in NCGS and other related functional GI disorders. Even asour knowledge and understanding of NCGS are still in infancy, thecombination of translational studies on potential mechanisms, along withlarger, high-quality clinical studies on the role of dietaryinterventions and possibly revision of criteria to better define NCGS inclinical settings, would help us better understand this elusive andcomplex condition. As proposed in one of the meta-analysis of NCGSrechallenge studies, "Nonceliac Wheat Sensitivity" might be amore accurate term to cover the spectrum of patients showing sensitivityto wheat through a non-IgE mechanism. Finally, as patients look foranswers, our limited knowledge and understanding of NCGS should behonestly discussed with them.

https://doi.org/10.1155/2018/1561476

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

P. Priyanka is assigned in topic selection, study concept anddesign, acquisition of data, analysis and interpretation of data,drafting of the manuscript, literature search, and writing, editing, andsubmitting the manuscript. S. Gayam and J. T. Kupec are assigned in thecritical revision of the manuscript for important intellectual contentand editing.

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P. Priyanka (iD), (1) S. Gayam, (2) and J. T. Kupec (iD) (2)

(1) Department of Medicine, West Virginia University Hospitals,Morgantown, WV, USA

(2) Department of Medicine, Section of Digestive Diseases, WestVirginia University Hospitals, Morgantown, WV, USA

Correspondence should be addressed to P. Priyanka;[emailprotected]

Received 18 May 2018; Accepted 26 July 2018; Published 6 August2018

Academic Editor: Aldona Dlugosz

Table 1: Studies for FODMAPs role in NCGS.Authors, year, Design/method of Number ofcountry studying FODMAP subjects (n)Skodje et al., 2018, effect n = 59 self-Norway [10] RDBPCC fructan reported NCGS challenge (2.1 g), gluten (5.7 g), and placebo given as a muesli barDieterich et al., Open low FODMAP diet n = 19 self-2018, Germany [14] adherence for 2wk reported NCGS, n = 10 healthy controlsZanini et al., 2015, RDBPCC GCF had n = 35 self-Italy [11] fructans 0.8 g/100 g. GFF reported NCGS had 0.16 g/100 g fructans present in both study arm materials.Zanini et al., 2014, RDBCC fructans present n = 25 self-Italy [12] in both study arm reported NCGS materials and low FODMAP diet for 8 weeksBiesiekierski et al., RDPBPCC, low n = 37 IBS2013, Australia [13] FODMAP diet patients adherence for 2wk fulfilling NCGS criteriaPeters et al., 2014, RDBPCC low FODMAP n = 22 IBS withAustralia [15] diet adherence for the improvement on entire duration of study GFDAuthors, year,country CD exclusion method ProtocolSkodje et al., 2018, Negative HLA DQ2/DQ8 GFD for 6m, 7 d onNorway [10] or normal duodenal first diet challenge, biopsy (marsh 0) on 7 d washout, then GFD if positive for crossover to next arm above haplotypesDieterich et al., IgA/G to TTG and GCD with 10 g gluten2018, Germany [14] deamidated gliadin for 4 wk, 2 wk low peptides, EGD, and FODMAP diet, then 5 d duodenal biopsy in transition, GFD 2wk NCGS patients follow up EGD in 17 patients (with persisting symptoms)Zanini et al., 2015, Negative t-TG and/or GCF or GFF for 10Italy [11] endomysial antibodies days, then 2 wk and normal villous washout period, then structure on duodenal crossed over to biopsies (marshes 0, another group 1, 2)Zanini et al., 2014, Negative t-TG and/or GFD, 10 g glutenItaly [12] endomysial antibodies versus 10 g gluten- and normal villous free flour for 10 d, structure on duodenal then 2wk washout, biopsies (marshes 0, then low FODMAP diet 1, 2) for 8 wkBiesiekierski et al., Negative HLA DQ2/DQ8 GFD and 2-week low2013, Australia [13] or normal duodenal FODMAP diet, then one biopsy (marsh 0) on of the arms--high GFD if positive for gluten (16 g), low the above haplotypes gluten (2 g gluten and 14 g whey protein), control for 3 d, washout 2 weeks, crossover 3 dPeters et al., 2014, Negative HLA DQ2/DQ8 GFD and low FODMAPAustralia [15] or normal duodenal diet for the duration biopsy (marsh 0) on of study followed by GFD if positive for 1 of the 3 dietary above haplotypes challenges --gluten, whey, and placebo 3 d, then 3 d crossover to next dietAuthors, year,country Primary outcome/resultsSkodje et al., 2018, GSRS-IBS, recorded for pain,Norway [10] bloating, constipation, diarrhea, satiety Overall GSRS-IBS borderline signi?cant for fructan (38.6) versus gluten (33.1) and placebo (34.3) Significant difference in GSRS-IBS for bloating after fructanDieterich et al., Improvement of GI2018, Germany [14] symptoms by GSRS on low FODMAP diet for NCGS pts. for re?ux, abdominal pain, and indigestion Further improvement on GFD for abdominal pain, diarrhea, and constipationZanini et al., 2015, GFD for 6m, ability toItaly [11] identify gluten-containing flour n =12 (34%) Inaccurate, n =17 (49%) Unable to distinguish (17%)Zanini et al., 2014, Able to identify gluten-Italy [12] containing flour n =8 Inaccurate, n =12 nable to distinguish, n =5Biesiekierski et al., VAS for overall abdominal2013, Australia [13] symptoms, pain, bloating, wind, stool consistency satisfaction, and tiredness nausea improved in low FODMAP run-in period. 6 (16%) pts. had worsening of overall symptoms in high- gluten arm; only 3 pts. had worsening in placebo arm.Peters et al., 2014, Depression by STPI worseAustralia [15] with gluten versus placebo but similar to wheyAuthors, year,country Secondary outcomes/resultsSkodje et al., 2018, Daily GI symptoms by VAS forNorway [10] overall GI symptoms higher with fructan Health-related quality of life by SF-36 lowest for fructan for vitality Depression and anxiety by Hospital Anxiety and Depression Scale and fatigue by VAS and GSCL highest after fructanDieterich et al., Psychological well-being by2018, Germany [14] PGWB improved on low FODMAP diet and further on GFD Reduced IELs on GFD Stool microbiota showed differences in NCGS and controls with reduced Bifidobacteriae on low FODMAP diet. Near normalization of gut flora on GFDZanini et al., 2015, GSRS score for pain, reflux,Italy [11] indigestion, diarrhea, and constipation and VAFS for fatigue increased with GCF in NCGS and GFF in GFF-sensitive. No changes in t-TG IgA and antigliadin IgA and IgGZanini et al., 2014, GSRS score for pain, reflux,Italy [12] indigestion, diarrhea, and constipation improved on low FODMAP diet with worsening on GFF. VAS for fatigue unchanged with GCF. No changes in t-TG IgA and antigliadin IgA and IgGBiesiekierski et al., Fatigue with D-FIS was the2013, Australia [13] lowest with low FODMAP diet and worse with all the 3 challenges. No effects on physical activity or sleep by accelerometry in any arm; only 1 subject elicited positive gliadin-specific T-cell response. No significant difference across the arms for ECF protein, RAST, serologicalmarkers, fecal wet and dry weight, pH, human [beta]-defensin-2, calprotectin, and ammonia levelsPeters et al., 2014, GI symptoms by VAS, cortisolAustralia [15] levels similar across all the treatment armsRDBPCC: randomized double-blind placebo-controlled crossoverchallenge; G: Gram; GSRS-IBS: gastrointestinal symptom rating scaleirritable bowel syndrome; VAS: visual analogue scale; VAFS: visualanalogue fatigue score; GSRS: gastrointestinal symptom ratingscale; GSCL: Giessen Subjective Complaint List; STPI: SpielbergerState-Trait Personality Inventory; PGWB: Psychological GeneralWell-Being Index; GCF: gluten-containing flour; GFF: gluten-freeflour; GCD: gluten-containing diet; t-TG: tissue transglutaminase;EGD: esophagogastroduodenoscopy; wk: week; IEL: intraepitheliallymphocyte; pt: patient; D-FIS: daily-fatigue impact scale; ECF:eosinophil cationic protein; RAST: radioallergosorbent test; d:days.

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