Next Article in Journal
Public and Healthcare Professionals’ Knowledge and Attitudes toward Binge Eating Disorder: A Narrative Review
Previous Article in Journal
Impact of High-Dose Multi-Strain Probiotic Supplementation on Neurocognitive Performance and Central Nervous System Immune Activation of HIV-1 Infected Individuals
Article Menu
Issue 11 (November) cover image

Export Article

Nutrients 2017, 9(11), 1268; doi:10.3390/nu9111268

Review
The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update
Carlo Catassi 1, Armin Alaedini 2, Christian Bojarski 3, Bruno Bonaz 4, Gerd Bouma 5, Antonio Carroccio 6Orcid, Gemma Castillejo 7Orcid, Laura De Magistris 8, Walburga Dieterich 9, Diana Di Liberto 10, Luca Elli 11, Alessio Fasano 12, Marios Hadjivassiliou 13, Matthew Kurien 14Orcid, Elena Lionetti 1, Chris J. Mulder 5, Kamran Rostami 15, Anna Sapone 12, Katharina Scherf 16, Detlef Schuppan 17, Nick Trott 14, Umberto Volta 18, Victor Zevallos 17, Yurdagül Zopf 9 and David S. Sanders 14,*
1
Department of Pediatrics, Marche Polytechnic University, 60121 Ancona, Italy
2
Department of Medicine, Columbia University Medical Center, New York, NY 10027, USA
3
Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité, Campus Benjamin Franklin, 12203 Berlin, Germany
4
Department of Gastroenterology and Liver Diseases, CHU, 38043 Grenoble, France
5
Celiac Center Amsterdam, Department of Gastroenterology, VU University Medical Center, 1117 Amsterdam, The Netherlands
6
Department of Internal Medicine, “Giovanni Paolo II” Hospital, Sciacca (AG) and University of Palermo, 92019 Sciacca, Italy
7
Paediatric Gastroenterology Unit, Sant Joan de Reus University Hospital. IISPV, 43003 Tarragona, Spain
8
Department of Internal and Experimental Medicine Magrassi-Lanzara, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
9
Medical Clinic 1, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
10
Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90133 Palermo, Italy
11
Center for the Prevention and Diagnosis of Celiac Disease, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
12
Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, MA 02114, USA
13
Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK
14
Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
15
Gastroenterology Unit, Milton Keynes University Hospital, Milton Keynes MK6 5LD, UK
16
German Research Centre for Food Chemistry, Leibniz Institute, Lise-Meitner-Straße 34, D-85354 Freising, Germany
17
Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany
18
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
*
Correspondence: Tel.: +44-114-226-1179; Fax: +44-114-271-2692
Received: 12 October 2017 / Accepted: 17 November 2017 / Published: 21 November 2017

Abstract

:
Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
Keywords:
gluten sensitivity; celiac disease; wheat allergy; gluten-related disorders; gluten-free diet; amylase-trypsin inhibitors (ATIs)

1. Introduction

Non-celiac gluten sensitivity (NCGS), sometimes referred as gluten sensitivity, gluten intolerance, or non-celiac wheat sensitivity, was already described in 1978 but did not receive much recognition from clinicians until the 21st century [1]. It is characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease (CD) or wheat allergy (WA). This is the original definition based on the Salerno Experts’ Criteria [2]. However, our understanding has evolved since that time and we recognized that the spectrum of symptoms, which occur maybe due not just to the ingestion of gluten proteins but potentially other wheat-related components. In clinical practice, it is crucial to exclude CD in patients who present in this way. A recent PubMed search using the Medical Subject Headings (MeSH) index term of NCGS demonstrates 125 publications prior to 2000 but 490 since the start of the new millennium. Public and commercial interest in a gluten free diet (GFD) has galvanized the scientific community into undertaking research beyond the previously recognized gluten-related disorders such as celiac disease or dermatitis herpetiformis.
Irritable bowel syndrome (IBS) is a common intestinal disorder causing abdominal pain, bloating, gas, diarrhea and constipation. IBS-like complaints are often part of the NCGS clinical picture. Conversely, recent studies support the hypothesis that gluten and other wheat components may trigger IBS symptoms. Due to this overlap and lack of IBS/NCGS biomarkers, and there is a confusing situation for both the primary care physician and the general audience. This review article is aimed to present (1) an update on the complex relationship between NCGS and IBS and (2) the experts’ opinion on this hot topic.

2. Methods

In order to provide consensus and promote collaborative research in this field, a group of 23 experts convened in Meran, Italy in December 2016. Each expert was assigned to separate work streams according to their areas of clinical and research experience. Work streams involved review of recent literature using PubMed and Embase Databases. The previous literature review occurred at the Salerno meeting in October 2014. For this reason, the new MeSH-based literature review encompassed all articles since that time but also key historical papers. Furthermore, experts in attendance were also asked to identify emerging studies (presented in abstract form). The experts were then divided into work streams, with sub-section presentations and break-out focus groups. Based on this current evidence, five areas were identified where significant progress within the medical literature has occurred: (1) Prevalence studies of NCGS; (2) Non-IgE wheat allergy; (3) Potentially harmful wheat components; (4) Pathogenetic mechanisms for IBS triggered by wheat; (5) Overlap between IBS-type symptoms and NCGS. This review provides the summary and consensus (undertaken using a Delphi method) from this International Workshop.

2.1. Prevalence of NCGS: Emerging Data and Ascertainment Pitfalls

We have previously categorized the spectrum of gluten-related disorders and provided a “road map” for clinicians seeking to manage their patients who have gluten-related symptoms [2,3,4]. Considering the uncertainty regarding the prevalence of NCGS, initial efforts at the Center for Celiac Research, University of Maryland (USA) were aimed at clarifying this with an original report of their experience with 5896 patients seen between 2004 and 2010 [3]. The criteria for NCGS were fulfilled by 347 patients suggesting a prevalence in their study population of 6% (1:17). The limitation to this important observation is that this is a tertiary center seeing patients within a fee-paying system. Due to a selection bias, this may not accurately reflect international prevalence figures for NCGS.
Since that time other international groups have tried to estimate the prevalence of NCGS (Table 1) [5,6,7,8,9,10,11,12,13,14]. Of these studies, three report data from the National Health and Nutrition Examination Survey (2009–2010), with the most recent study incorporating data from 2011 to 2012 [6,7,12]. The range when considering the general population and ensuring exclusion of CD, highlights a prevalence between 0.6% and 10.6%. The huge variability in prevalence figures is mainly explained by lack of diagnostic biomarker(s). In order to clarify the diagnosis of NCGS, at a previous consensus meeting the experts’ group recommended a double-blind placebo controlled (DBPC) approach using 8 g of gluten [4]. Although a DBPC approach is the gold standard for a rigorous scientific identification of true cases, this is difficult to undertake in daily clinical practice. Patients frequently refuse to re-introduce gluten into their diet due to the immediate symptom burden which they perceive. This view is further reflected by the high levels of unsuccessful patient recruitment in studies to resolve these specific issues reported in the literature. There is still very limited data on the overlap between NCGS and IBS-type symptoms. The UK population survey undertaken in 1002 adults demonstrated that individuals with NCGS had an increased prevalence of fulfilling the Rome III criteria for irritable bowel syndrome in comparison with those without NCGS (20% vs. 3.89%, odds ratio 6.23, p < 0.0001) [8].
An emerging epidemiological issue is represented by self-reported NCGS, i.e., people excluding gluten-containing food without a medical diagnosis of a specific gluten-related disorder. Many individuals perceive the GFD as healthy life style practice. This group may be termed lifestyles, free from or clean eaters depending on which country they reside in. We propose to define them as people who avoid gluten [5,6,7,8,9,10,11,12,13,14]. These individuals are widely diffused in Western countries, with a prevalence of 6.2–13% [8,13].
They must be treated with great caution and if such patients present to clinicians it is imperative to first exclude celiac disease [2,3,4] or other causes not related to any specific trigger (placebo effect, implementation of a healthier diet, etc.). Such patients can be advised that simply by identifying gluten as a culprit for their symptoms, this gives them a risk ranging from 2% to 42% of having undiagnosed celiac disease (based on the current published literature) [8,15,16,17,18,19]. This extreme variation reflects an ascertainment bias related to the referral patterns of the centers that have published their data. Tertiary and quaternary centers may have a high prevalence of patients presenting with gluten-related symptoms who are subsequently recognized to have celiac disease.

2.2. Update on Non-IgE Mediated Wheat Allergy in NCGS

Wheat allergy is an adverse immune response which occurs reproducibly in affected individuals. The immune mechanism may be IgE or non-IgE mediated. Individuals may have a serological IgE response to wheat but this only demonstrates sensitization. To make a diagnosis of wheat allergy, patients must also describe reproducible symptoms and signs which occur quickly following wheat exposure. Typically, these symptoms may be gastrointestinal, respiratory, at skin level and in some rare cases anaphylaxis or angioedema [20,21]. Recent developments have occurred specifically in the field of adult non-IgE-mediated food allergy. Non-IgE-mediated food allergy is a condition well known by pediatricians who recognize at least three gastrointestinal clinical conditions: the food protein-induced enterocolitis syndrome, the food protein-induced proctocolitis, and the food protein-induced enteropathies [20]. In the pediatric population, this condition is mainly due to cow’s milk protein hypersensitivity (CMPH) but also soya (most common triggers). Wheat is also involved in Food Protein Induced Enteropathy in children. It is difficult to diagnose as radioallergosorbent test or skin testing are neither specific nor sensitive. For this reason, a CMPH diagnosis must be posed exclusively on clinical basis by means of elimination diet and successive DBPC food challenge [22]. It is probable that in adults, the allergy-related gastro-intestinal symptoms are common and often underestimated [21] (confocal/review recent papers).
The hypothesis that NCGS could be a non-IgE-mediated wheat allergy is based on some clinical aspects (presence of a personal history of food allergy in the pediatric age, or of coexistent atopic diseases) [22], laboratory and histological data (positive serum anti-gliadin antibodies, positive cytofluorimetric assay revealing in vitro basophil activation by food antigens, and presence of eosinophils in the intestinal mucosa biopsies) [23,24,25] and by new and exciting endoscopic findings (see below) [26]. Further studies are required to explore the putative allergic mechanisms involved in the pathogenesis of NCGS. Recently immunological activation in the intestinal mucosa of the NCGS patients has been demonstrated. In fact, gastrointestinal food allergies are often mediated by IgE-independent mechanisms involving mast cells, eosinophils, and other immune cells [21]. An increase in mucosal lymphocytes has been reported in a consistent percentage of patients with NCGS diagnosed by DBPC challenge [25,27], and in general most of the studies on NCGS showed that about half of the patients have a raised IELs count >25 per 100 enterocytes [23,28,29]. Very recently, an increased infiltration of innate lymphocytes-1 cells, producing IFN-γ, in the rectal mucosa of NCGS patients has been reported; furthermore, this infiltration decreased after resuming a wheat-free diet [30]. Given these conflicting observations further work is required to clarify whether NCGS could have an association with either IgE or non IgE mediated wheat allergy.
There is a lack of consensus about intestinal permeability in NCGS. After a first report suggesting a reduced intestinal permeability [28], more recent studies have demonstrated an increased permeability in NCGS [31,32]. Uhde et al., in particular, were able to demonstrate a state of systemic immune activation, partly in response to translocated microbial components and possibly in conjunction with a compromised intestinal epithelium, which significantly improved on a wheat-free diet. Further studies are needed to decipher how wheat components can contribute to a compromised gut epithelial barrier and subsequent microbial translocation that result in systemic immune activation.
In this respect, the exciting findings by confocal endomicroscopy could be the keystone. Recently a novel strategy to identify IBS patients with food-related symptoms and specified sensitivities has been described [26]. Within five minutes after the administration of defined food suspensions to the duodenal mucosa of sensitive patients, confocal laser endomicroscopy demonstrated an increase in the number of intraepithelial lymphocytes, epithelial shedding and breaks followed by leaks with secretion of fluorescein into the lumen, and edema with increased inter-villous spaces. Characteristic mucosal changes after administration of a wheat suspension were seen in 13 (and after administration of milk, soy and yeast in another 9) of 36 IBS patients, and in all of the dietary elimination of the identified trigger, including wheat as prominent cause, resulted in a long-term improvement of symptoms. The 36% of wheat-sensitive IBS patients is in line with the proportions revealed in other studies [21,22], and suggests that this method may offer a remarkable sensitivity and specificity for NCGS. A German multi-center study (DRKS00010123) is currently recruiting patients to further validate these findings [33]. Finally, it is worth noting that endomicroscopy with several food challenges is a complex investigation requiring the patient’s sedation.

2.3. Potentially Harmful Wheat Components

Several components of wheat are potentially harmful for NCGS and IBS patients including gluten proteins, lipopolysaccharides, amylase/trypsin inhibitors (ATIs), wheat germ agglutinins (WGA) and fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) (Figure 1) [32,34,35,36,37]. Gluten proteins, the storage proteins of wheat, rye and barley, account for 70–80% of the total grain protein and are located exclusively in the starchy endosperm of the grains (Figure 2). The remaining proteins are albumins and globulins (20–30%) that have metabolic, protective or structural functions. Largely insoluble in water and salt solution, gluten can be subdivided into mostly monomeric prolamins (called gliadins in wheat) soluble in aqueous alcohols and polymeric glutelins (called glutenins in wheat) soluble only in the presence of reducing and disaggregating agents [38]. Specific sequences from gluten, e.g., N-terminal peptides from α-gliadin, have been shown to induce an innate immune response in celiac disease [39,40] and could also play a role in NCGS. In general, care is advised when using wheat or gluten for oral challenge, because all wheat is not the same and all gluten is not the same. The composition of the individual components and the overall protein contents can differ in a rather large range depending on wheat species, cultivar, growing conditions (e.g., soil, climate, fertilization) and processing, in the case of gluten and, especially, hydrolyzed gluten. Therefore, each material should be well characterized using proteomic methods and, if possible, standardized [41].
ATIs are a family of at least 11 structurally similar, small and compact mono-, di- or tetrameric wheat proteins, which serve as protective proteins in wheat and other cereals by inhibiting enzymes (amylase and trypsin-like activities) of wheat and some parasites. In the developing grain, ATIs are deposited together with gluten proteins in the endosperm and become associated with the starch granules [42]. Encoded mainly by the B and D genomes, ATIs are high in most modern hexaploid bread wheats, and low in spelt (old hexaploid), tetraploid (durum wheat, emmer) and diploid (einkorn) wheat species. They are also present in other gluten containing cereals such as barley and rye. Long known as major allergens in baker’s asthma [43], ATIs were identified as triggers of innate immune activation in intestinal myeloid cells via stimulation of Toll-like receptor 4 (TLR4) [35]. Notably, nutritional ATIs enhance intestinal inflammation in models of inflammatory bowel disease in mice, and immune activation is higher in the mesenteric lymph nodes than in the intestinal mucosa [44].
Wheat germ agglutinins (WGA) are enriched in the germ of wheat grains with contents from 100 to 500 mg/kg, resulting in typical concentrations of approximately 4 mg/kg in white flour and approximately 30 mg/kg in whole grain flour [37]. Similar to ATIs, WGA are stable against heat and proteolysis and serve as protective proteins. As lectins, WGA are widely recognized as anti-nutrients in foods and bind to glycoproteins, such as human N-Acetylneuraminic acid, on the surface of cell membranes. WGA has been shown to induce the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-12 and IFN-γ) and impair the integrity of the intestinal epithelial layer [45]. However, in contrast to ATIs, no immune stimulatory activity was demonstrated for WGA in vivo.
The term FODMAPs comprises short chain oligosaccharides of fructose (fructans) and galactooligosaccharides (GOS, stachyose, raffinose), disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols), such as sorbitol, mannitol, xylitol and maltitol, that are resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the large intestine. As such, FODMAPs are considered part of dietary fiber (Figure 2). Out of FODMAPs, wheat contains fructans that increase its tolerance to drought and cold. Typical quantities of fructans are 1.5% in white flour and 3.7% in bran [46] and they can be significantly degraded during yeast fermentation (>50%) and almost completely with fermentation [47]. Modern wheat breads contained 0.5–0.7% fructans (based on the product as consumed), spelt bread 0.2% and gluten-free bread 0.2% [48]. However, the fructan content of gluten-free products depends on the specific recipes and the generalized assumption that gluten-free products are always lower in FODMAPs compared to their wheat-containing counterparts is questionable, because e.g., corn flakes and rice bubbles each had 1.1% fructan [48], and another study did not find a significant difference between various wheat breads and gluten-free breads, because the average fructan content was approximately 1% in both [49].

2.4. Pathogenetic Mechanisms of IBS in Which Wheat can be the Trigger

Growing evidence indicates that the majority of IBS patients report a significant worsening of symptoms, e.g., abdominal pain, bloating and bowel habit abnormalities, after meals, while experiencing an improvement during fasting [50,51]. Furthermore, some IBS patients clearly identify foods that are thought to be more offending as they evoke more commonly the aforementioned digestive symptoms. Although the relationship between food ingestion and symptom generation in IBS patients has long been established, our understanding of dietary triggers and pathogenic mechanisms involved in IBS is still poorly defined [52]. Wheat is regarded as a possible culprit of symptom generation in some cases of IBS [53]. Wheat administered via endoscopic probe into the duodenal mucosa, was able to alter the integrity of the small intestinal mucosa as shown by epithelial leaks/gaps and widened intervillous spaces confocal detected by using laser endomicroscopy. Taken together both endomicroscopic features and histopathological abnormalities provide a morphological basis to the existence of (inflammatory) wheat sensitivity at least in a substantial subset of patients with IBS [26].
The insufficient degradation of gluten and certain other wheat proteins by small intestinal proteases leaves undigested peptides that can pass through a more permeable epithelial barrier (the so called “leaky gut”), reach the submucosa and activate the resident innate immune cells. Experimental data demonstrated that human leucocyte antigen DQ8 (HLA-DQ8) transgenic mice sensitized by gluten show an altered barrier function and enhanced muscle contractility (likely via an increased release of the excitatory transmitter acetylcholine from myenteric neurons), thereby mimicking mechanisms which are known to occur in patients with IBS. Both enhanced intestinal permeability and increased smooth muscle contractility reverted to normal after gluten withdrawal [54]. A recent clinical trial in patients with IBS with predominant diarrhea (IBS-D) confirmed the close relationship between wheat-containing food and a subgroup of IBS cases [55]. Withdrawal of wheat led to a significant improvement of intestinal symptoms together with a reduced small intestinal permeability, whereas wheat-containing food challenge was followed by the recurrence of symptoms and altered barrier function. These changes were linked to HLA-DQ2/8-positive cases. Markers of intestinal permeability such as small intestinal expression of myosin light chain kinase activity and enhanced colonocyte expression of claudin-15 significantly increased after the challenge and decreased following wheat withdrawal. Furthermore, in addition to gluten-derived peptides, both ATIs and WGA can trigger innate immune pathways.
ATIs elicit innate immune responses in vitro and in vivo, driving intestinal inflammation through the activation of TLR4, as exemplified by the worsening of intestinal inflammation in models of IBD [35,44]. In vitro WGA induces inflammatory response by immune cells leading to the release of IL-4 and IL-13 cytokines from human basophils, and can impair the integrity of intestinal barrier by increasing small intestinal permeability [37]. In addition to proteins, wheat contains fructans that also have a role in IBS symptoms. These are carbohydrates belonging to FODMAPs, which exert an important role in gut homeostasis by modulating the microbiota composition and short chain fatty acid synthesis. Fructans are also contained in fruits, vegetables and dairy products. In IBS, patient symptoms such as bloating, abdominal pain and altered bowel habit may have an association with enhanced bacterial colonic fermentation and gas production in the gut lumen. As a result, luminal distension occurs and through this an activation of enteric mechanoreceptors which generate IBS symptoms. However, it is worthy to mention that FODMAPs do not trigger extra-intestinal (e.g., neurological and fibromyalgia-like) manifestations commonly observed in NCGS, likely elicited by wheat proteins (i.e., gluten, ATIs and possibly WGA). Moreover, FODMAPs are generally considered beneficial by promoting intestinal (epithelial) integrity and health.
Regardless of the identification of the offending components, the scientific community agrees that the withdrawal of wheat from the diet can significantly improve symptoms in a subset of IBS patients, who can sometimes be diagnosed as NCGS. The group of IBS patients with gluten sensitivity gathers the vast majority of wheat sensitive patients, since only a minority of NCGS cases do not display a coexistent IBS [56]. The interplay between the various components of wheat, such as gluten, ATIs, WGA and FODMAPs, may elicit a wide array of both intestinal and extraintestinal symptoms in a subgroup of IBS patients by modulating intestinal permeability, microbiota composition, immune activation which, alone or more likely in combination, also affect the gut-brain axis activity thereby leading to symptom perception. Future research is awaited to decipher the complex interplay between food and digestive sensory-motor function in IBS and allied food-related disorders.

2.5. Overlap between IBS-Type Symptoms and NCGS

The prevalence of IBS globally has been estimated to be between 10% and 20% [57,58]. Approximately 50% of patients with gastrointestinal complaints seen in primary care have IBS-type symptoms [59]. Patients with IBS report a reduced quality of life and there is an associated economic and societal cost [60,61]. It is recommended that clinicians should make a positive diagnosis of IBS based on clinical features alone, currently using the Rome IV criteria [62]. The Rome IV criteria categorize IBS by the most predominant presenting symptom-diarrhea (IBS-D), constipation (IBS-C), mixed (IBS-M) or unspecified (IBS-U).
Patients have always reported that food plays an important role in their IBS-type symptoms with estimates of up to 80% of patients having postprandial symptomology, and up to 40% reporting specific “food intolerances” [63,64,65]. Historically, successful restrictive diets for IBS symptoms have been reported by specific research groups. This work has never been translated into daily clinical practice. However, over the last 10 years there has been renewed interest in the concept of dietary interventions for functional gastrointestinal disorders [66,67].
IBS dietary research has focused on the role of two common components of the western diet, specifically FODMAPs and gluten in relation to the induction of IBS symptoms (Figure 1). Initially a retrospective audit evaluated the effect of a low-fructose/fructan diet demonstrating symptomatic relief in 74% of participants with IBS symptoms [68]. Since then, several randomized control trials (RCTs) have demonstrated the efficacy of the low FODMAP diet (LFD) and probable mechanisms. A recent meta-analysis of six RCTs showed that a LFD lead to a 56% greater likelihood of decreasing IBS-SSS (symptom severity scores), however the analysis was limited by information on adherence figures and numerical quantities of FODMAPs ingested [69,70].
The LFD is a complex diet requiring delivery by an experienced dietitian to help ensure both success and overall nutritional adequacy [57,70,71]. The implementation of a low FODMAP diet, involves a strict reduction of all FODMAP groups for 4–8 weeks. This is then followed by a re-introduction of one FODMAP group per week, as tolerated by the patient. The drastic reduction of FODMAP intake could have negative physiological consequences on the colonocyte metabolism, the intestinal microbiota, and the nutritional status, which need further investigation. A significant reduction in iron and calcium intakes during a four-week trial (elimination phase of the LFD) has been reported [71,72,73]. Another potential problem is that the public may commence a LFD without an appropriate reintroduction phase under the guidance of a specialist dietitian. This is of concern considering that the LFD alters the colonic microbiota. A significant reduction in bifidobacteria after four weeks of a LFD has been observed [74]. A recent Australian trial showed that FODMAP restriction was associated with a higher fecal pH, significantly lower bacterial load and diversity, and a significant reduction in colonic bacterial groups with known health benefits when compared to the typical Australian diet [75]. Both studies suggest further trials are required to assess the long-term effects of FODMAP reduction on the microbiome and overall health.
Dietary adherence is another predictor of response in the LFD that warrants further investigation. Dietetic guidance and supportive written (or digital) information are essential. However, even with these aspects in place, the initial exclusion and reintroduction phases can be difficult to follow. Not all the LFD studies have reported a beneficial outcome for IBS patients and first line dietary advice has also been reported as of similar efficacy to FODMAP reduction [76,77,78,79].
There is overlap between NCGS and IBS-type symptoms [8,10]. The fundamental difference between NCGS and IBS is that patients with NCGS self-report symptoms when consuming gluten and have identified or perceive gluten as the culprit. Conversely IBS patients do not report gluten as a specific stimulus for their symptoms. However, previously published literature has demonstrated that wheat is a commonly reported “food intolerance” when IBS patients are specifically questioned [63,64,65]. There is now a body of literature supporting the role of a GFD as a specific dietary intervention in IBS (Table 2). The mechanism by which wheat or specific wheat components such as gluten or ATIs cause IBS-type symptoms is debated. Wheat (and even gluten) contains a number of compounds, apart from gluten, that could produce a symptomatic response; perhaps the most obvious of these are FODMAPS, specifically fructans (Figure 1 and Figure 2). One trial showed that individuals with self-reported NCGS (and IBS-type symptoms) already on a GFD further benefited when placed on a low FODMAP diet and found no specific or dose-dependent effect of gluten [80]. However, the participants reported very high visual analogue scale ratings for their symptoms at the start of the study when they were already on a GFD. This is unlikely to be representative of the NCGS population. Furthermore, this study’s double-blind placebo-controlled crossover design, where all participants cycled through high-dose, low-dose or no gluten control diets could have produced an anticipatory nocebo response [81]. It is also interesting to note that all the participants returned to a GFD at the end of the trial as they “subjectively described feeling better” [82]. Research into the GFD in the treatment of IBS-D is summarized in Table 2.
Based on current evidence a gluten (and thus wheat) free diet also appears to be a potential dietary intervention for a subgroup of IBS patients and the term of gluten sensitive IBS has been coined. Like a LFD, a GFD has been shown to cause a reduction of lacto and bifidobacteria in the gut. There are also some studies suggesting lower intake of calcium, iron, folate and fiber, when compared to a gluten-containing diet [95,96,97,98]. There is clearly overlap between a GFD and a LFD. One of the key excluded components of a LFD is wheat; furthermore, patients on a long-term LFD (following the reintroduction phase) appear to view the reduced intake of wheat as essential to their maintained symptomatic response [99]. Thus, a GFD may be a more practical option for IBS patients, which does not impair their food-related quality of life to the same level as a LFD (Figure 3).

3. Conclusions

Since our initial consensus document of 2012 there has been a significant expansion of the published data in the field of gluten-related disorders. We now have an appreciation of two groups of patients who may benefit from a GFD, firstly those who present with self-reported gluten-related symptoms and may have NCGS and secondly those who present with IBS-type symptoms and could have gluten or wheat sensitive IBS. Clinicians involved in the management of IBS now have an exciting range of dietary interventions that may benefit their patients (Figure 3).

Author Contributions

All authors provided input on the content of the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest

This paper was made possible by support from Schär Institute for traveling and lodging sponsorship for all co-authors to meet to discuss the object of this paper.

References

  1. Ellis, A.; Linaker, B.D. Non-coeliac gluten sensitivity? Lancet 1978, 1, 1358–1359. [Google Scholar] [CrossRef]
  2. Catassi, C.; Elli, L.; Bonaz, B.; Bouma, G.; Carroccio, A.; Castillejo, G.; Cellier, C.; Cristofori, F.; de Magistris, L.; Dolinsek, J.; et al. Diagnosis of non-celiac gluten sensitivity (NCGS): The salerno experts’ criteria. Nutrients 2015, 7, 4966–4977. [Google Scholar] [CrossRef] [PubMed]
  3. Sapone, A.; Bai, J.C.; Ciacci, C.; Dolinsek, J.; Green, P.H.; Hadjivassiliou, M.; Kaukinen, K.; Rostami, K.; Sanders, D.S.; Schumann, M.; et al. Spectrum of gluten-related disorders: Consensus on new nomenclature and classification. BMC Med. 2012, 10, 13. [Google Scholar] [CrossRef] [PubMed]
  4. Catassi, C.; Bai, J.C.; Bonaz, B.; Bouma, G.; Calabro, A.; Carroccio, A.; Castillejo, G.; Ciacci, C.; Cristofori, F.; Dolinsek, J.; et al. Non-celiac gluten sensitivity: The new frontier of gluten related disorders. Nutrients 2013, 5, 3839–3853. [Google Scholar] [CrossRef] [PubMed]
  5. Tanpowpong, P.; Ingham, T.R.; Lampshire, P.K.; Kirchberg, F.F.; Epton, M.J.; Crane, J.; Camargo, C.A., Jr.; New Zealand Asthma and Allergy Cohort Study Group. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Child. 2012, 97, 12–16. [Google Scholar] [CrossRef] [PubMed]
  6. Rubio-Tapia, A.; Ludvigsson, J.F.; Brantner, T.L.; Murray, J.A.; Everhart, J.E. The prevalence of celiac disease in the United States. Am. J. Gastroenterol. 2012, 107, 1538–1544. [Google Scholar] [CrossRef] [PubMed]
  7. DiGiacomo, D.V.; Tennyson, C.A.; Green, P.H.; Demmer, R.T. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: Results from the continuous national health and nutrition examination survey 2009–2010. Scand. J. Gastroenterol. 2013, 48, 921–925. [Google Scholar] [CrossRef] [PubMed]
  8. Aziz, I.; Lewis, N.R.; Hadjivassiliou, M.; Winfield, S.N.; Rugg, N.; Kelsall, A.; Newrick, L.; Sanders, D.S. 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. [Google Scholar] [CrossRef] [PubMed]
  9. Lis, D.M.; Stellingwerff, T.; Shing, C.M.; Ahuja, K.D.; Fell, J.W. Exploring the popularity, experiences, and beliefs surrounding gluten-free diets in nonceliac athletes. Int. J. Sport Nutr. Exerc. Metab. 2015, 25, 37–45. [Google Scholar] [CrossRef] [PubMed]
  10. Volta, U.; Bardella, M.T.; Calabro, A.; Troncone, R.; Corazza, G.R.; The Study Group for Non-Celiac Gluten Sensitivity. An italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014, 12, 85. [Google Scholar] [CrossRef] [PubMed]
  11. Golley, S.; Corsini, N.; Topping, D.; Morell, M.; Mohr, P. Motivations for avoiding wheat consumption in australia: Results from a population survey. Public Health Nutr. 2015, 18, 490–499. [Google Scholar] [CrossRef] [PubMed]
  12. Mardini, H.E.; Westgate, P.; Grigorian, A.Y. Racial differences in the prevalence of celiac disease in the us population: National health and nutrition examination survey (NHANES) 2009–2012. Dig. Dis. Sci. 2015, 60, 1738–1742. [Google Scholar] [CrossRef] [PubMed]
  13. Van Gils, T.; Nijeboer, P.; IJssennagger, C.E.; Sanders, D.S.; Mulder, C.J.; Bouma, G. Prevalence and characterization of self-reported gluten sensitivity in The Netherlands. Nutrients 2016, 8, 714. [Google Scholar] [CrossRef] [PubMed]
  14. Carroccio, A.; Giambalvo, O.; Blasca, F.; Iacobucci, R.; D’Alcamo, A.; Mansueto, P. Self-reported non-celiac wheat sensitivity in high school students: Demographic and clinical characteristics. Nutrients 2017, 9, 771. [Google Scholar] [CrossRef] [PubMed]
  15. Kaukinen, K.; Turjanmaa, K.; Maki, M.; Partanen, J.; Venalainen, R.; Reunala, T.; Collin, P. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 2000, 35, 942–946. [Google Scholar] [CrossRef] [PubMed]
  16. Kabbani, T.A.; Vanga, R.R.; Leffler, D.A.; Villafuerte-Galvez, J.; Pallav, K.; Hansen, J.; Mukherjee, R.; Dennis, M.; Kelly, C.P. Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am. J. Gastroenterol. 2014, 109, 741–746. [Google Scholar] [CrossRef] [PubMed]
  17. Raju, S.A.; Mooney, P.D.; Aziz, I.; Kurien, M.; Sanders, D.S. Letter: Gluten challenge in the era of noncoeliac gluten sensitivity—A change in clinical practice? Aliment. Pharmacol. Ther. 2016, 43, 656. [Google Scholar] [CrossRef] [PubMed]
  18. Coburn, J.A.; Vande Voort, J.L.; Lahr, B.D.; Van Dyke, C.T.; Kroning, C.M.; Wu, T.T.; Gandhi, M.J.; Murray, J.A. Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet. J. Clin. Gastroenterol. 2013, 47, 828–833. [Google Scholar] [CrossRef] [PubMed]
  19. Aziz, I.; Hadjivassiliou, M.; Sanders, D.S. Self-reported gluten sensitivity: An international concept in need of consensus? Am. J. Gastroenterol. 2014, 109, 1498–1499. [Google Scholar] [CrossRef] [PubMed]
  20. Turnbull, J.L.; Adams, H.N.; Gorard, D.A. Review article: The diagnosis and management of food allergy and food intolerances. Aliment. Pharmacol. Ther. 2015, 41, 3–25. [Google Scholar] [CrossRef] [PubMed]
  21. Bischoff, S.; Crowe, S.E. Gastrointestinal food allergy: New insights into pathophysiology and clinical perspectives. Gastroenterology 2005, 128, 1089–1113. [Google Scholar] [CrossRef] [PubMed]
  22. Carroccio, A.; Mansueto, P.; D’Alcamo, A.; Iacono, G. Non-celiac wheat sensitivity as an allergic condition: Personal experience and narrative review. Am. J. Gastroenterol. 2013, 108, 1845–1852. [Google Scholar] [CrossRef] [PubMed]
  23. Volta, U.; Tovoli, F.; Cicola, R.; Parisi, C.; Fabbri, A.; Piscaglia, M.; Fiorini, E.; Caio, G. Serological tests in gluten sensitivity (nonceliac gluten intolerance). J. Clin. Gastroenterol. 2012, 46, 680–685. [Google Scholar] [CrossRef] [PubMed]
  24. Carroccio, A.; Brusca, I.; Mansueto, P.; Pirrone, G.; Barrale, M.; Di Prima, L.; Ambrosiano, G.; Iacono, G.; Lospalluti, M.L.; La Chiusa, S.M.; et al. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 2010, 8, 254–260. [Google Scholar] [CrossRef] [PubMed]
  25. Carroccio, A.; Mansueto, P.; Iacono, G.; Soresi, M.; D’Alcamo, A.; Cavataio, F.; Brusca, I.; Florena, A.M.; Ambrosiano, G.; Seidita, A.; et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: Exploring a new clinical entity. Am. J. Gastroenterol. 2012, 107, 1898–1906. [Google Scholar] [CrossRef] [PubMed]
  26. Fritscher-Ravens, A.; Schuppan, D.; Ellrichmann, M.; Schoch, S.; Rocken, C.; Brasch, J.; Bethge, J.; Bottner, M.; Klose, J.; Milla, P.J. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014, 147, 1012–1020. [Google Scholar] [CrossRef] [PubMed]
  27. Carroccio, A.; Soresi, M.; D’Alcamo, A.; Sciume, C.; Iacono, G.; Geraci, G.; Brusca, I.; Seidita, A.; Adragna, F.; Carta, M.; et al. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: A prospective observation study. BMC Med. 2014, 12, 230. [Google Scholar] [CrossRef] [PubMed]
  28. Sapone, A.; Lammers, K.M.; Casolaro, V.; Cammarota, M.; Giuliano, M.T.; De Rosa, M.; Stefanile, R.; Mazzarella, G.; Tolone, C.; Russo, M.I.; 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. [Google Scholar] [CrossRef] [PubMed]
  29. Sapone, A.; Lammers, K.M.; Mazzarella, G.; Mikhailenko, I.; Carteni, M.; Casolaro, V.; Fasano, A. Differential mucosal il-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease. Int. Arch. Allergy Immunol. 2010, 152, 75–80. [Google Scholar] [CrossRef] [PubMed]
  30. Di Liberto, D.; Mansueto, P.; D’Alcamo, A.; Lo Pizzo, M.; Lo Presti, E.; Geraci, G.; Fayer, F.; Guggino, G.; Iacono, G.; Dieli, F.; et al. Predominance of type 1 innate lymphoid cells in the rectal mucosa of patients with non-celiac wheat sensitivity: Reversal after a wheat-free diet. Clin. Transl. Gastroenterol. 2016, 7, e178. [Google Scholar] [CrossRef] [PubMed]
  31. Hollon, J.; Puppa, E.L.; Greenwald, B.; Goldberg, E.; Guerrerio, A.; Fasano, A. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients 2015, 7, 1565–1576. [Google Scholar] [CrossRef] [PubMed]
  32. Uhde, M.; Ajamian, M.; Caio, G.; De Giorgio, R.; Indart, A.; Green, P.H.; Verna, E.C.; Volta, U.; Alaedini, A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 2016, 65, 1930–1937. [Google Scholar] [CrossRef] [PubMed]
  33. Prospective, Double-Blind Diagnostic Study of Confocal Laser Endomicroscopy (CLE) for Wheat Sensitivity (WS) in Patients with Irritable Bowel Syndrome. German Clinical Trials Register. Available online: http://apps.who.int/trialsearch/trial2.Aspx?Trialid=drks00010123 (accessed on 18 August 2017).
  34. Pinto-Sanchez, M.I.; Verdu, E.F. Non-coeliac gluten sensitivity: Are we closer to separating the wheat from the chaff? Gut 2016, 65, 1921–1922. [Google Scholar] [CrossRef] [PubMed]
  35. Junker, Y.; Zeissig, S.; Kim, S.J.; Barisani, D.; Wieser, H.; Leffler, D.A.; Zevallos, V.; Libermann, T.A.; Dillon, S.; Freitag, T.L.; et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 2012, 209, 2395–2408. [Google Scholar] [CrossRef] [PubMed]
  36. Gibson, P.R.; Varney, J.; Malakar, S.; Muir, J.G. Food components and irritable bowel syndrome. Gastroenterology 2015, 148, 1158–1174. [Google Scholar] [CrossRef] [PubMed]
  37. De Punder, K.; Pruimboom, L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients 2013, 5, 771–787. [Google Scholar] [CrossRef] [PubMed]
  38. Scherf, K.A.; Koehler, P.; Wieser, H. Gluten and wheat sensitivities—An overview. J. Cereal Sci. 2016, 67, 2–11. [Google Scholar] [CrossRef]
  39. Maiuri, L.; Ciacci, C.; Ricciardelli, I.; Vacca, L.; Raia, V.; Auricchio, S.; Picard, J.; Osman, M.; Quaratino, S.; Londei, M. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 2003, 362, 30–37. [Google Scholar] [CrossRef]
  40. Frossi, B.; Tripodo, C.; Guarnotta, C.; Carroccio, A.; De Carli, M.; De Carli, S.; Marino, M.; Calabro, A.; Pucillo, C.E. Mast cells are associated with the onset and progression of celiac disease. J. Allergy Clin. Immunol. 2017, 139, 1266–1274. [Google Scholar] [CrossRef] [PubMed]
  41. Hajas, L.; Scherf, K.A.; Torok, K.; Bugyi, Z.; Schall, E.; Poms, R.E.; Koehler, P.; Tomoskozi, S. Variation in Protein Composition among Wheat (Triticum aestivum L.) Cultivars to Identify Cultivars Suitable as Reference Material for Wheat Gluten Analysis. Food Chem. 2017. [Google Scholar] [CrossRef]
  42. Tatham, A.S.; Shewry, P.R. Allergens to wheat and related cereals. Clin. Exp. Allergy 2008, 38, 1712–1726. [Google Scholar] [PubMed]
  43. Gomez, L.; Martin, E.; Hernandez, D.; Sanchez-Monge, R.; Barber, D.; del Pozo, V.; de Andres, B.; Armentia, A.; Lahoz, C.; Salcedo, G.; et al. Members of the alpha-amylase inhibitors family from wheat endosperm are major allergens associated with baker’s asthma. FEBS Lett. 1990, 261, 85–88. [Google Scholar] [CrossRef]
  44. Zevallos, V.F.; Raker, V.; Tenzer, S.; Jimenez-Calvente, C.; Ashfaq-Khan, M.; Russel, N.; Pickert, G.; Schild, H.; Steinbrink, K.; Schuppan, D. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology 2017, 152, 1100–1113. [Google Scholar] [CrossRef] [PubMed]
  45. Dalla Pellegrina, C.; Perbellini, O.; Scupoli, M.T.; Tomelleri, C.; Zanetti, C.; Zoccatelli, G.; Fusi, M.; Peruffo, A.; Rizzi, C.; Chignola, R. Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights from an experimental model of immune/epithelial cell interaction. Toxicol. Appl. Pharmacol. 2009, 237, 146–153. [Google Scholar] [CrossRef] [PubMed]
  46. Haska, L.; Nyman, M.; Andersson, R. Distribution and characterisation of fructan in wheat milling fractions. J. Cereal Sci. 2008, 48, 768–774. [Google Scholar] [CrossRef]
  47. Brouns, F.; Delzenne, N.; Gibson, G. The dietary fibers-FODMAPs controversy. Cereal Foods World 2017, 62, 768–774. [Google Scholar] [CrossRef]
  48. Biesiekierski, J.R.; Rosella, O.; Rose, R.; Liels, K.; Barrett, J.S.; Shepherd, S.J.; Gibson, P.R.; Muir, J.G. Quantification of fructans, galacto-oligosacharides and other short-chain carbohydrates in processed grains and cereals. J. Hum. Nutr. Diet. 2011, 24, 154–176. [Google Scholar] [CrossRef] [PubMed]
  49. Whelan, K.; Abrahmsohn, O.; David, G.J.; Staudacher, H.; Irving, P.; Lomer, M.C.; Ellis, P.R. Fructan content of commonly consumed wheat, rye and gluten-free breads. Int. J. Food Sci. Nutr. 2011, 62, 498–503. [Google Scholar] [CrossRef] [PubMed]
  50. Chey, W.D. Food: The main course to wellness and illness in patients with irritable bowel syndrome. Am. J. Gastroenterol. 2016, 111, 366–371. [Google Scholar] [CrossRef] [PubMed]
  51. Volta, U.; Pinto-Sanchez, M.I.; Boschetti, E.; Caio, G.; De Giorgio, R.; Verdu, E.F. Dietary triggers in irritable bowel syndrome: Is there a role for gluten? J. Neurogastroenterol. Motil. 2016, 22, 547–557. [Google Scholar] [CrossRef] [PubMed]
  52. Hayes, P.A.; Fraher, M.H.; Quigley, E.M. Irritable bowel syndrome: The role of food in pathogenesis and management. Gastroenterol. Hepatol. 2014, 10, 164–174. [Google Scholar]
  53. De Giorgio, R.; Volta, U.; Gibson, P.R. Sensitivity to wheat, gluten and FODMAPs in IBS: Facts or fiction? Gut 2016, 65, 169–178. [Google Scholar] [CrossRef] [PubMed]
  54. Natividad, J.M.; Huang, X.; Slack, E.; Jury, J.; Sanz, Y.; David, C.; Denou, E.; Yang, P.; Murray, J.; McCoy, K.D.; et al. Host responses to intestinal microbial antigens in gluten-sensitive mice. PLoS ONE 2009, 4, e6472. [Google Scholar] [CrossRef] [PubMed]
  55. Wu, R.L.; Vazquez-Roque, M.I.; Carlson, P.; Burton, D.; Grover, M.; Camilleri, M.; Turner, J.R. Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression. Lab. Investig. 2017, 97, 14–23. [Google Scholar] [CrossRef] [PubMed]
  56. Volta, U.; Caio, G.; Karunaratne, T.B.; Alaedini, A.; De Giorgio, R. Non-coeliac gluten/wheat sensitivity: Advances in knowledge and relevant questions. Expert Rev. Gastroenterol. Hepatol. 2017, 11, 9–18. [Google Scholar] [CrossRef] [PubMed]
  57. Dalrymple, J.; Bullock, I. Diagnosis and management of irritable bowel syndrome in adults in primary care: Summary of nice guidance. BMJ 2015, 350, h1216. [Google Scholar] [CrossRef] [PubMed]
  58. Lovell, R.M.; Ford, A.C. Global prevalence of and risk factors for irritable bowel syndrome: A meta-analysis. Clin. Gastroenterol. Hepatol. 2012, 10, 712–721. [Google Scholar] [CrossRef] [PubMed]
  59. Canavan, C.; West, J.; Card, T. The epidemiology of irritable bowel syndrome. Clin. Epidemiol. 2014, 6, 71–80. [Google Scholar] [PubMed]
  60. Whitehead, W.E.; Palsson, O.; Jones, K.R. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 2002, 122, 1140–1156. [Google Scholar] [CrossRef] [PubMed]
  61. Akehurst, R.L.; Brazier, J.E.; Mathers, N.; O’Keefe, C.; Kaltenthaler, E.; Morgan, A.; Platts, M.; Walters, S.J. Health-related quality of life and cost impact of irritable bowel syndrome in a UK primary care setting. Pharmacoeconomics 2002, 20, 455–462. [Google Scholar] [CrossRef] [PubMed]
  62. Drossman, D.A. Functional gastrointestinal disorders: History, pathophysiology, clinical features and Rome IV. Gastroenterology 2016, 150, 1262–1279. [Google Scholar] [CrossRef] [PubMed]
  63. Morcos, A.; Dinan, T.; Quigley, E.M. Irritable bowel syndrome: Role of food in pathogenesis and management. J. Dig. Dis. 2009, 10, 237–246. [Google Scholar] [CrossRef] [PubMed]
  64. Bohn, L.; Storsrud, S.; Tornblom, H.; Bengtsson, U.; Simren, M. 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. [Google Scholar] [CrossRef] [PubMed]
  65. McKenzie, Y.A.; Thompson, J.; Gulia, P.; Lomer, M.C. British dietetic association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J. Hum. Nutr. Diet. 2016, 29, 576–592. [Google Scholar] [CrossRef] [PubMed]
  66. Jones, V.A.; McLaughlan, P.; Shorthouse, M.; Workman, E.; Hunter, J.O. Food intolerance: A major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982, 2, 1115–1117. [Google Scholar] [CrossRef]
  67. King, T.S.; Elia, M.; Hunter, J.O. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998, 352, 1187–1189. [Google Scholar] [CrossRef]
  68. Shepherd, S.J.; Gibson, P.R. Fructose malabsorption and symptoms of irritable bowel syndrome: Guidelines for effective dietary management. J. Am. Diet. Assoc. 2006, 106, 1631–1639. [Google Scholar] [CrossRef] [PubMed]
  69. Marsh, A.; Eslick, E.M.; Eslick, G.D. Does a diet low in FODMAPs reduce symptoms associated with functional gastrointestinal disorders? A comprehensive systematic review and meta-analysis. Eur. J. Nutr. 2016, 55, 897–906. [Google Scholar] [CrossRef] [PubMed]
  70. 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. [Google Scholar] [CrossRef] [PubMed]
  71. Staudacher, H.M.; Lomer, M.C.E.; Whelan, K.; Irving, P. Pth-064 implementation of the low-fermentable oligo-, di-, mono-saccharides and polyols diet in the UK: How easy is it and does it work? Abstract pth-064. Gut 2010, 59. [Google Scholar] [CrossRef]
  72. Staudacher, H.; Ross, F.S.; Briscoe, Z.M.; Irving, P.M.; Whelan, K.; Lomer, M.C. Ptu-183 advice from a dietitian regarding the low FODMAP diet broadly maintains nutrient intake and does not alter fibre intake. Gut 2015, 64. [Google Scholar] [CrossRef]
  73. Rao, S.S.; Yu, S.; Fedewa, A. Systematic review: Dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Aliment. Pharmacol. Ther. 2015, 41, 1256–1270. [Google Scholar] [CrossRef] [PubMed]
  74. Staudacher, H.M.; Lomer, M.C.; Anderson, J.L.; Barrett, J.S.; Muir, J.G.; Irving, P.M.; Whelan, K. Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. J. Nutr. 2012, 142, 1510–1518. [Google Scholar] [CrossRef] [PubMed]
  75. Halmos, E.P.; Christophersen, C.T.; Bird, A.R.; Shepherd, S.J.; Gibson, P.R.; Muir, J.G. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015, 64, 93–100. [Google Scholar] [CrossRef] [PubMed]
  76. Bohn, L.; Storsrud, S.; Liljebo, T.; Collin, L.; Lindfors, P.; Tornblom, H.; Simren, M. 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. [Google Scholar] [CrossRef] [PubMed]
  77. Whigham, L.; Joyce, T.; Harper, G.; Irving, P.M.; Staudacher, H.M.; Whelan, K.; Lomer, M.C. Clinical effectiveness and economic costs of group versus one-to-one education for short-chain fermentable carbohydrate restriction (low FODMAP diet) in the management of irritable bowel syndrome. J. Hum. Nutr. Diet. 2015, 28, 687–696. [Google Scholar] [CrossRef] [PubMed]
  78. Chey, W.D.; Whelan, K. Dietary guidelines for irritable bowel syndrome are important for gastroenterologists, dietitians and people with irritable bowel syndrome. J. Hum. Nutr. Diet. 2016, 29, 547–548. [Google Scholar] [CrossRef] [PubMed]
  79. Eswaran, S.L.; Chey, W.D.; Han-Markey, T.; Ball, S.; Jackson, K. A randomized controlled trial comparing the low FODMAP diet vs. Modified nice guidelines in US adults with IBS-D. Am. J. Gastroenterol. 2016, 111, 1824–1832. [Google Scholar] [CrossRef] [PubMed]
  80. Biesiekierski, J.R.; Peters, S.L.; Newnham, E.D.; Rosella, O.; Muir, J.G.; Gibson, P.R. 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, 320–328. [Google Scholar] [CrossRef] [PubMed]
  81. Aziz, I.; Hadjivassiliou, M.; Sanders, D.S. The spectrum of noncoeliac gluten sensitivity. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 516–526. [Google Scholar] [CrossRef] [PubMed]
  82. Peters, S.L.; Biesiekierski, J.R.; Yelland, G.W.; Muir, J.G.; Gibson, P.R. Randomised clinical trial: Gluten may cause depression in subjects with non-coeliac gluten sensitivity—An exploratory clinical study. Aliment. Pharmacol. Ther. 2014, 39, 1104–1112. [Google Scholar] [CrossRef] [PubMed]
  83. Wahnschaffe, U.; Ullrich, R.; Riecken, E.O.; Schulzke, J.D. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001, 121, 1329–1338. [Google Scholar] [CrossRef] [PubMed]
  84. Wahnschaffe, U.; Schulzke, J.D.; Zeitz, M.; Ullrich, R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 2007, 5, 844–850. [Google Scholar] [CrossRef] [PubMed]
  85. Biesiekierski, J.R.; Newnham, E.D.; Irving, P.M.; Barrett, J.S.; Haines, M.; Doecke, J.D.; Shepherd, S.J.; Muir, J.G.; Gibson, P.R. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 2011, 106, 508–514. [Google Scholar] [CrossRef] [PubMed]
  86. Vazquez-Roque, M.I.; Camilleri, M.; Smyrk, T.; Murray, J.A.; O’Neill, J.; Carlson, P.; Lamsam, J.; Eckert, D.; Janzow, D.; Burton, D.; et al. Association of hla-dq gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G1262–G1269. [Google Scholar] [CrossRef] [PubMed]
  87. Vazquez-Roque, M.I.; Camilleri, M.; Smyrk, T.; Murray, J.A.; Marietta, E.; O’Neill, J.; Carlson, P.; Lamsam, J.; Janzow, D.; Eckert, D.; 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. [Google Scholar] [CrossRef] [PubMed]
  88. Aziz, I.; Trott, N.; Briggs, R.; North, J.R.; Hadjivassiliou, M.; Sanders, D.S. 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. [Google Scholar] [CrossRef] [PubMed]
  89. Di Sabatino, A.; Volta, U.; Salvatore, C.; Biancheri, P.; Caio, G.; De Giorgio, R.; Di Stefano, M.; Corazza, G.R. 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. [Google Scholar] [CrossRef] [PubMed]
  90. Shahbazkhani, B.; Sadeghi, A.; Malekzadeh, R.; Khatavi, F.; Etemadi, M.; Kalantri, E.; Rostami-Nejad, M.; Rostami, K. Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: A double-blind randomized placebo-controlled trial. Nutrients 2015, 7, 4542–4554. [Google Scholar] [CrossRef] [PubMed]
  91. Zanini, B.; Basche, R.; Ferraresi, A.; Ricci, C.; Lanzarotto, F.; Marullo, M.; Villanacci, V.; Hidalgo, A.; Lanzini, A. Randomised clinical study: Gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity. Aliment. Pharmacol. Ther. 2015, 42, 968–976. [Google Scholar] [CrossRef] [PubMed]
  92. Zanwar, V.G.; Pawar, S.V.; Gambhire, P.A.; Jain, S.S.; Surude, R.G.; Shah, V.B.; Contractor, Q.Q.; Rathi, P.M. Symptomatic improvement with gluten restriction in irritable bowel syndrome: A prospective, randomized, double blinded placebo controlled trial. Intest. Res. 2016, 14, 343–350. [Google Scholar] [CrossRef] [PubMed]
  93. Elli, L.; Tomba, C.; Branchi, F.; Roncoroni, L.; Lombardo, V.; Bardella, M.T.; Ferretti, F.; Conte, D.; Valiante, F.; Fini, L.; 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. [Google Scholar] [CrossRef] [PubMed]
  94. Barmeyer, C.; Schumann, M.; Meyer, T.; Zielinski, C.; Zuberbier, T.; Siegmund, B.; Schulzke, J.D.; Daum, S.; Ullrich, R. 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. Int. J. Colorectal Dis. 2017, 32, 29–39. [Google Scholar] [CrossRef] [PubMed]
  95. De Palma, G.; Nadal, I.; Collado, M.C.; Sanz, Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br. J. Nutr. 2009, 102, 1154–1160. [Google Scholar] [CrossRef] [PubMed]
  96. Nistal, E.; Caminero, A.; Vivas, S.; Ruiz de Morales, J.M.; Saenz de Miera, L.E.; Rodriguez-Aparicio, L.B.; Casqueiro, J. Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients. Biochimie 2012, 94, 1724–1729. [Google Scholar] [CrossRef] [PubMed]
  97. Wild, D.; Robins, G.G.; Burley, V.J.; Howdle, P.D. Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet. Aliment. Pharmacol. Ther. 2010, 32, 573–581. [Google Scholar] [CrossRef] [PubMed]
  98. Kinsey, L.; Burden, S.T.; Bannerman, E. A dietary survey to determine if patients with coeliac disease are meeting current healthy eating guidelines and how their diet compares to that of the british general population. Eur. J. Clin. Nutr. 2008, 62, 1333–1342. [Google Scholar] [CrossRef] [PubMed]
  99. Martin, L.; Van Vuuren, C.; Seamark, L.; Williams, M.; Staudacher, H.; Irving, P.M.; Whelan, K.; Lomer, M.C. Long-term effectiveness of short chain fermentable carbohydrate (FODMAP) restriction in patients with IBS. In Proceedings of the 2nd Digestive Disorders Federation Conference, London, UK, 22–25 June 2015. [Google Scholar]
Figure 1. Potential triggers in wheat that may account for both intestinal and extra-intestinal symptoms.
Figure 1. Potential triggers in wheat that may account for both intestinal and extra-intestinal symptoms.
Nutrients 09 01268 g001
Figure 2. Wheat components.
Figure 2. Wheat components.
Nutrients 09 01268 g002
Figure 3. IBS treatment pathway.
Figure 3. IBS treatment pathway.
Nutrients 09 01268 g003
Table 1. Prevalence studies of people avoiding gluten-based products.
Table 1. Prevalence studies of people avoiding gluten-based products.
AuthorYear of PublicationCountryGroupSample SizeAvoidance of Gluten-Based ProductsKnown Previous Diagnosis of CD
Tanpowpong et al. [5]2012New ZealandChildren-general population9165% (n = 48)1% (n = 9)
Rubio-Tapia et al. [6]2013USAAge ≥ 6 years, National Health and Nutrition Examination Survey (NHANES) 2009–201077980.63% (n = 55)0.1% (n = 6)
DiGiacomo et al. [7]2013USANHANES77620.6%
Aziz et al. [8]2014UKAdults-general population10023.7% (n = 37)0.8% (n = 8)
Lis et al. [9]2014AustraliaAdults-athletes91041.2% (n = 375)None
Volta et al. [10]2014ItalyAdult and pediatric GI clinic population12,225391 (3.2%)Within same population 340 (2.8%) coeliac patients diagnosed
Golley et al. [11]2015AustraliaAdults-general population118410.6% (n = 126)1.2% (n = 14)
Mardini et al. [12]2015USAAge ≥ 6 years, NHANES
2009–2010 & 2011–2012 data combined
14,7010.9% (n = 142)0.1% (n = 21)
Van Gils T et al. [13]2016The NetherlandsAdults-general population7856.2% (49/785)0.25% (2/785)
Carroccio A et al. [14]2017ItalyAge 14–185482.9% (16/548)1.26% (7/555)
Table 2. Summary of studies examining the role of gluten and wheat in IBS.
Table 2. Summary of studies examining the role of gluten and wheat in IBS.
Lead AuthorCountryYearPatientsOutcome
Wahnschaffe [83] Germany2001102 IBS-D without CDStool frequency significantly improved in patients HLA DQ2/DQ8 + ve
Wahnschaffe [84]Germany2007145 IBS-D without CDHLA-DQ2 predicted response to GFD
Biesikierski [85] Australia201034 NCGWSSignificant reduction in symptoms in GFD group
Carroccio [25]Italy2012920 patients with IBS 70 patients wheat-sensitive and 206 food sensitivities
Vazquez-Roque [86]USA201245 patients with IBS-DIncreased intestinal permeability in patients receiving gluten
Vazquez-Roque [87]USA201345 patients with IBS-DReduction in stool frequency in patients on GFD
Biesikierski [80]Australia201337 NCGWS on GFDPatients responded to reduction in FODMAPs during run-in but no difference between GFD and gluten-containing arms
Fritscher-Ravens [26] Germany201436 patients with food-sensitive IBS 13/36 GFD after positive wheat challenge in CLEAll patients improved significantly on the GFD for at least one year
Aziz [88]UK201540 patients with IBS-D 70% had reduced symptomology with GFD for 6 weeks
Di Sabatino [89] Italy201559 self-reported NCGWS4 g of gluten per day for 1 week increased overall clinical symptoms compared with placebo in (p = 0.034)
Shahbazkhani [90]Iran201572 patients with IBS (Based on Rome III criteria)Worsening of intestinal symptoms with gluten compared to placebo
Zanini [91] Italy201535 NCGWS on a GFDGiven either and containing or gluten-free flour. 34% symptomatic with gluten-containing flour, 49% symptomatic with gluten-free flour, 17% no response
Zanwar [92] India201660 patients with IBS (Based on Rome III criteria) GFD for 4 weeks. Significant reduction in visual analogue scales (VAS) of symptomology
Elli [93] Italy2016140 patients enrolled14% of patients shown to have symptomatic response to gluten on repeat challenge
Barmeyer [94] Germany201734 patients with IBS34% responded to a GFD and continued on a GFD at 1 year
Nutrients EISSN 2072-6643 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top