Food allergy and food hypersensitivity

Chapter 27

Food allergy and food hypersensitivity Prashant Singha, Govind K. Makhariab a

Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, United States, bDepartment of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India

Key Points ●

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Food allergy is a common disorder affecting up to 5–10% of the general population. The most common food allergens are seafood, egg, milk, wheat, and peanuts. Approximately 20–65% of patients with irritable bowel syndrome report food-related symptoms. The spectrum of gluten-related disorders is expanding and includes celiac disease, non-celiac gluten/wheat hypersensitivity, gluten ataxia and dermatitis herpetiformis. Both gluten and fructans are associated with symptoms in non-celiac gluten sensitivity. There is overlap between symptoms of irritable bowel syndrome and non-celiac gluten sensitivity. There is no biomarker for the diagnosis of non-celiac gluten sensitivity. The diagnosis is best established by double blind, placebo-controlled, food challenge test.

A food allergy is defined as an adverse health effect arising from an immunological response that occurs reproducibly upon exposure to a given food [1]. Food allergy is different from food intolerance; the latter refers to a non-immunologically mediated adverse reaction(s) to food such as lactose intolerance [1]. Similar to food allergy, the symptoms due to food intolerance also resolve following dietary elimination, and the symptoms are reproduced up on food re-challenge [2]. Food allergy is a common disorder and up to 5–10% of general population is estimated to be affected by food allergy [1]. The prevalence of food allergy has increased over the last few decades, and it is more prevalent in high income countries compared to low and middle-income countries. Food allergy affects children more often than adults and the prevalence of food allergy tends to decrease with age [1]. While hundreds of food items have been implicated to cause food allergy, the most common foods include peanuts, seafood, egg, milk, wheat and soy. While food allergies due to milk, egg, wheat and soy resolve at a higher rate (45–50%) as children grow into adults, the rate of resolution of food allergies due to peanuts or tree nuts resolve less frequently (10–20%) and tend to persist in adulthood also. Food allergies result from a complex interaction between genetic and environmental factors. Amongst the environmental factors, the timing and route of exposure to a food seems to be a key factor. The “dual allergen exposure hypothesis” suggests that a cutaneous exposure to a food allergen at a low-dose sensitizes an individual and this sensitization is facilitated by impairment in the skin barrier and/or inflammation in the skin. The exposure of food allergen orally (if introduced early), however, may induce immune tolerance [1]. According to this hypothesis, delay in oral ingestion of food allergens along with environmental exposure in the absence of oral exposure is thought to lead to food allergen sensitization and food allergy [1]. The validity of this theory is supported by the efficacy of early peanut feeding in reducing the frequency of the development of peanut allergy among infants having eczema [3]. The importance of cutaneous exposure of a food allergen is further supported by the exposure–response relationship between peanut protein levels in the household dust and likelihood of development of peanut allergy in a cohort of 359 children [4]. This effect was further observed to be modulated by the presence and severity of atopic dermatitis [4].

Types of food allergies Immunologic response to food allergen subsequent to disruption of immune tolerance could be mediated by several pathways. Most commonly, food allergy presents as an immediate hypersensitivity to food allergen in which specific Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00027-3 © 2020 Elsevier Inc. All rights reserved.

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immunoglobulin E (IgE) antibodies bound to mast cells and basophils trigger the release of mediators that mediate subsequent physiological responses. IgE-mediated symptoms develop within minutes to 1–2 h of ingestion of the food allergen. These reactions typically present with symptoms affecting the skin (urticaria, angioedema, erythema, and pruritus), the gastrointestinal tract (vomiting and abdominal pain), the airways (persistent cough, hoarse voice, wheeze, stridor, respiratory distress, and nasal congestion), and less commonly, the circulatory system (pale and floppy infant or young child, hypotension, or collapse). Less commonly, food allergies can be mediated by non-IgE pathways. In general, these conditions tend to be chronic and persistent and are mediated by cellular (as opposed to antibody-mediated) pathways. Non-IgE mediated food allergies include allergic proctocolitis, and food protein-induced enterocolitis, characterized by eosinophil-predominant mucosal inflammation driven by food allergen exposure. Allergic proctocolitis is most commonly seen in otherwise well-seeming infants, who present with rectal feeding, often upon introduction of cow milk protein containing formula or top feeds. A more severe form of gastrointestinal reaction occurs in food protein-induced enterocolitis syndrome which often presents as vomiting, diarrhea, poor growth, lethargy following introduction of specific foods (most commonly cows milk and soy). Non-IgE mediated food allergies can also present as allergic contact dermatitis in response to chemical haptens that are additives or naturally occurring in food. This usually occurs in adult life and metals such as nickel are common culprits. In addition to IgE and cellular mediated pathways, a few food allergies occur due to combination of these pathways. The most common example of mixed pathways includes eosinophilic gastro-enteropathies. Eosinophilic esophagitis (EoE) is the prototype of eosinophilic gastro-enteropathies and generally manifests as non-responsive gastro-esophageal reflux disease, dysphagia, food impaction and esophageal strictures. The process is clearly driven by food allergens, and elimination diets are beneficial. In addition to eosinophilic infiltrates in esophageal mucosa which is the hallmark of EoE, many patients have food-specific IgE antibodies.

Diagnosis of IgE-mediated food allergy Demonstration of allergen specific serum IgE aids in the diagnosis of IgE-mediated food allergies. Allergen-specific IgE can be detected by skin prick tests and estimation of allergen-specific IgE levels in the serum [5]. Skin prick test is the most commonly used allergy test to diagnose food allergies. For skin testing, allergen in question is introduced into the epidermis using a device to scratch or puncture the skin [5]. If the patient has IgE antibodies, a local allergic reaction develops at the site. Serum food-specific IgE levels can be measured using immune-assays [5]. While the sensitivity of both forms of testing is high (90% for skin testing and 70–90% for serum food-specific IgE measurements), the specificities of the tests are low (<50% for both) [5]. Thus, diagnostic testing should be done only in the context of a convincing clinical history. Sensitization does not equate to clinical allergy and can lead to unnecessary food avoidance [5]. Food-specific immunoglobulin G (IgG) testing is increasingly used to identify food sensitivities. However, this testing has not been validated. In fact, American Academy of Allergy, Asthma and Immunology recommends against diagnosing food allergies based on food specific IgG testing, as there is poor clinical correlation between skin testing and food allergy. The most definitive test for confirmation of food specific allergy is oral food challenge. Gold standard of food challenge is the double-blind, placebo-controlled provocation-challenge tests. However, oral food challenges are cumbersome, expensive, and complex. They require a medically supervised environment, expert personnel and also carry the risk of food challenge induced anaphylaxis.

Management of food allergy With the absence of a cure, effective management of food allergy requires avoidance of ingestion of inciting food and prompt treatment of symptoms in the event of an allergic reaction. Achieving successful food avoidance is complex and requires involvement of the patient, his/her family, school or workplace, food industry, government agencies and public health authorities. Educating patients, their family and encouraging them to ask questions when eating out is crucial. Enforcement of strict food labeling regulations could facilitate better management of food allergies. Allergen avoidance diet can result in nutritional deficiencies, especially for those avoiding milk or multiple food products. Nutritional counseling and growth monitoring are recommended for all having food allergies. Patients with potentially life-threatening food allergy should be given an epinephrine auto-injector, and they should be educated about its use. Epinephrine auto-injectors are available in two fixed doses (0.15 and 0.30 mg). Guidelines suggest the use of 0.30 mg dose, if the person’s weight is 25 kg or higher. It is important to educate patients that epinephrine is both effective and safe. However, several studies suggest that epinephrine is under-utilized during episodes of anaphylactic reactions. Although adverse effects are rare, patients should be educated about transient adverse effects (e.g., tremors, p­ alpitations,



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anxiety), and more serious side-effects (hypertension and angina). Serious cardiovascular side-effects are more likely to occur with intravenous injections compared to intramuscular injection/auto-injections (10% vs. 1%).

Food induced GI symptoms and GI diseases Overlap of IBS and food hypersensitivity The perception of food hypersensitivity in patients with irritable bowel syndrome (IBS) seems to be higher than that in the general population, and 20–65% of patients with IBS report food-related symptoms [6–9]. However, whether these symptoms are due to food intolerance or food hypersensitivity is not clear. In a study of 128 IBS patients, adverse reactions to at-least one food was reported by 62.5% of patients; however, skin prick tests were positive only in 52% of patients. In addition, no significant correlation between specific foods reported to cause adverse reactions and those resulting in a positive skin prick tests were noted, suggesting a large proportion of these food-related symptoms in IBS patients are likely due to food intolerance and not true food hypersensitivity [6]. There is some evidence to suggest that symptoms mimicking IBS, especially in individuals with atopy, could be due to IgE mediated food hypersensitivity. Pettepierre et al. evaluated total serum IgE titres, skin prick tests and allergen specific serum IgE measurement in 12 patients with IBS having atopy and 12 without any history of atopy [10]. Patients with IBS having atopy had significantly higher prevalence of elevated total IgE levels, positive skin prick and positive allergen specific IgE levels compared to those without having atopy. There also appeared to be a modest correlation between clinical response to blinded dietary challenge and serological evidence of food allergen specific immunological response in patients with IBS having atopy. However, others have failed to show a correlation between dietary challenge and positive skin prick tests even in IBS patients with personal history of atopy. Further studies are needed to address the role of IgE-based food hypersensitivity in the pathogenesis of IBS. Colonoscopic allergen provocation (COLAP) test is a novel technique to assess mucosal evidence of food hypersensitivity in-vivo [11]. The basis of this test is the submucosal injection of suspected food allergen with subsequent measurement of the resulting wheal and flare response [11]. This allows a semi-quantitative assessment of a food hypersensitivity ­response at target organ level. In a study of 70 patients with IBS-like symptoms and suspected to have food allergies, Bischoff et al. reported a positive COLAP test in 77% of these patients. Furthermore, 83% of patients with positive COLAP testing reported a significant improvement in symptoms after 3 months of avoidance of the inciting food [11].

Specific food-related hypersensitivity Wheat and gluten-related disorders Wheat is the most widely grown crop and one of the most widely consumed food grain, globally. Gluten is the main storage protein of cereals wheat, barley and rye. The gluten in turn is composed of two components named gliadins and glutenins. In general, protein constitutes 10–12% of wheat grain weight, and of that protein, 80% is composed of gluten and rest includes globulins, albumins and others [12]. Therefore, 100 g of wheat will contain approximately 8–12 g of gluten. Gluten is responsible for most of the visco-elastic properties of wheat flour doughs, which helps in making good breads. Because of its visco-elastic properties, gluten is used extensively in the food industry. At the molecular level, gluten is composed of prolamin and gliadin and having a predominance of multiple glutamine (35%) amino acid residues linked to proline (15%) [13]. Proline renders the structure of prolamin complex and sterically inaccessible to proteolytic enzymes of the human stomach and intestine. The proline endopeptidase capable of digesting these bonds, is expressed too inadequately in humans to have any biological activity. Hence the glutamine–proline links are resistant to the action of the main proteases which only succeed in digesting the prolamin into larger oligopeptides which are immunogenic in celiac disease. Some of the known antigenic peptides include the most immunogenic 33 mer peptide 57–89, which has the amino acid sequence LQLQPFPQPQLPYPQPLPYPQPQLPYPQPQPF [13, 14]. A consensus statement on nomenclature of gluten related disorders divided gluten related disorders into allergic (wheat allergy), autoimmune including celiac disease, and dermatitis herpetiformis (DH) and possibly immune mediated (nonceliac gluten sensitivity) [15].

Wheat allergy Similar to other food allergies, wheat allergy is IgE mediated, and allergic reactions occur within minutes to hours after gluten exposure. IgE mediated responses to wheat can be related to either ingestion or inhalation of wheat [16]. Allergy

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due to wheat ingestion is more common in children and can be associated with a severe reaction such as anaphylaxis, and wheat-dependent, exercise-induced anaphylaxis (WDEIA) [16]. An inhalation induced IgE mediated wheat allergy can cause Baker’s asthma or rhinitis, which are common occupational diseases in workers who have significant repetitive exposure to wheat flour, such as bakers. In addition, wheat is a common culprit for eosinophilic esophagitis and eosinophilic gastroenteritis [16]. Diagnosis of IgE mediated wheat allergy is based on the medical history, the detection of specific IgE to wheat, and oral food challenges [16]. Currently, the main treatment for wheat allergy is based on avoidance of wheat altogether.

Celiac disease Celiac disease is defined as chronic small intestinal immune mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [17]. Once considered a disease of the western world, it is being increasingly recognized in other parts of world. It affects 0.7% of the global population and the prevalence seems to be increasing over time [18]. Celiac disease was once considered a disease of children; however, it is now recognized that it can present at any age including in adults and the elderly. Although symptoms of malabsorption such as steatorrhea and weight loss were thought to be classical manifestations, several studies in different parts of the world have shown that the majority of patients now present with atypical symptoms which include anemia, asthenia, short stature, liver disease, osteopenia/osteoporosis, infertility, dermatitis herpetiformis etc. [19]. Moreover, with increasing awareness, readily available serological testing and simplification of diagnostic algorithms over the years, celiac disease is also being diagnosed in high-risk groups with minimal or no symptoms such as Type 1 diabetes, and first degree relatives of patients with celiac disease [19]. Diagnosis of celiac disease can be established based on clinical manifestations, presence of circulating celiac auto-­ antibodies (anti-tissue transglutaminase antibodies, anti-endomysial antibodies, or anti-deamidated gliadin peptide antibodies), and demonstration of small intestinal villous atrophy in the and/or an unequivocal response to a gluten-free diet (GFD) [20]. The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) has recommended that celiac disease may be diagnosed without a duodenal biopsy in a small subset of patients with high titres of anti-tTG-ab [>10 times upper limit of normal (ULN)] and who are HLA DQ2/DQ8- and anti-endomysial antibody-positive on a second serological sample [20]. Once diagnosis is confirmed, life-long, strict adherence to a GFD is the only approved treatment for celiac disease.

Dermatitis herpetiformis DH is a blistering, intensely pruritic rash with a predilection for the elbows, forearms, knees, buttocks, back and scalp, and could be the sole manifestation of a gluten-related disorder. The majority of patients with DH have concomitant villous atrophy on duodenal biopsies, but this is not always the case. Skin biopsy is needed for the diagnosis and shows neutrophils, eosinophils, fibrin accumulation and micro-abscesses along dermal papillae. Direct immunofluorescence is the gold standard for diagnosing DH and shows granular IgA deposits in the dermal papillae and/or basement membrane. Similar to celiac disease, GFD is the first-line therapy for DH.

Non-celiac gluten sensitivity NCGS is a condition characterized by intestinal and extra-intestinal symptoms related to wheat in individuals who are not affected by either celiac disease or wheat allergy [17, 21]. Unlike wheat allergy or celiac disease, these manifestations are not allergic or autoimmune in nature. NCGS is also termed as “gluten sensitivity,” “gluten hypersensitivity,” or “non-celiac wheat sensitivity.” The reason why some patients develop celiac disease and others NCGS is not clear. While up to 90% of patients with celiac disease have specific genetic susceptibility (presence of HLA DQ2 and/or HLA DQ8 genotype), these genes are only present in up to 50% of patients with NCGS. Furthermore, it is possible that the gut microbiota plays a role in driving the immune process in towards celiac disease or NCGS. Prevalence of NCGS The exact prevalence of NCGS is not clear but is thought to be higher than that of celiac disease [22]. The first effort at estimating the prevalence of NCGS was from the Center for celiac Research, University of Maryland that reported a study prevalence of 6% in their clinic population of 5896 patients [22]. However, due to selection bias, this might not accurately reflect the prevalence of NCGS in general population. Since then, several groups have tried estimating the prevalence of NCGS in general population after ensuring exclusion of CD. Given the lack of a biomarker for NCGS, most of these studies are based on estimating the prevalence of individuals who avoid gluten [22]. The prevalence of individuals who avoid gluten

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in these studies ranges from 0.6% to 10.6% [22]. Two studies based on nationally representative US non-­institutionalized population reported that 0.55–0.8% of the US population follow a GFD in absence of celiac disease [22]. However, it is important to note that a significant proportion of these individuals who avoid gluten perceive a GFD as healthy lifestyle practice and might not necessarily experience gluten related symptoms. [22] There is no report of prevalence of NCGS from Asia. Clinical manifestations The clinical manifestations of NCGS begin after ingestion of wheat and symptoms improve with removal of wheat from diet, and symptoms re-appear on wheat re-challenge, usually within hours or days. The classical gastrointestinal presentation of NCGS includes IBS like symptoms including abdominal pain, bloating, change in bowel habits (diarrhea more common than constipation) and extra-intestinal manifestations such as “brain fog,” headache, fatigue, arthralgia, myalgias, numbness, dermatitis, depression, and anemia [19] (Table 1). In children, NCGS manifests typically with gastrointestinal symptoms while the extra-intestinal manifestations seem to be uncommon, the most common systemic symptom being fatigue [23]. Recently, there has been increasing interest in association of NCGS with neuro-psychiatric diseases (such as autism, and schizophrenia), however, the data is conflicting [23]. Clinically, it is hard to differentiate Celiac disease and NCGS given considerable clinical overlap. Given the long-term complications and the burden of strict GFD, a thorough work-up to rule out Celiac disease must be done before making a diagnosis of NCGS. Pathophysiology of NCGS The pathophysiology of NCGS is not entirely clear. The current literature suggests that NCGS is an immune mediated disorder. Although initial studies suggested only the activation of innate immune system, recent evidence suggests a possible involvement of adaptive immune system. The activation of innate immunity has been demonstrated by the finding of higher expression of Toll like receptor-2 (TLR-2) in the duodenal mucosa of patients with NCGS [24]. Another study showed higher serum levels of lipopolysaccharide binding protein (LPB) and soluble CD14 (CSD14), well known markers of innate immunity activation in them [25]. In addition, eosinophilic infiltration of the duodenal and colon mucosa along with cytometric basophil activation in in-vitro assay has also been reported in patients with NCGS [26]. In the initial study evaluating the immune response of NCGS patients, Sapone et al. reported lack of activation of adaptive immunity (suggested by decreased expression of IFN-γ, IL-6, IL-21 and IL-17) [24, 27]. However, other studies have shown higher expression of IFN- γ in NCGS patients in response to a gluten challenge [28]. Moreover, a substantial proportion of patients with NCGS also have positive AGA [29]. Taken together, these findings suggest a possibility of activation of adaptive immunity in these patients. However, very little is known about how gliadin, start the immune response in vivo in patients with NCGS. One of the possible mechanisms includes gliadin mediated increase in small bowel permeability via tight junction

TABLE 1  Manifestations of non-celiac gluten sensitivity Frequency

Intestinal symptoms

Extra-intestinal symptoms

Very common

Bloating

Lack of well being

Abdominal pain

Tiredness

Alternating bowel habits

Headache

Diarrhea

Joint/muscle pain

Epigastric pain

Anxiety

Nausea

Foggy mind

Aphthous stomatitis

Numbness

Constipation

Skin rash/dermatitis

Common

Weight loss Anemia Depression

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dysfunction. While some studies have not shown increased small intestinal permeability in patients with NCGS, others have demonstrated higher small bowel intestinal permeability along with decreased expression of tight junction proteins in both the small bowel as well as rectosigmoid mucosa [24, 30, 31]. A recent study demonstrated higher levels of intestinal fatty acid binding protein (FABP-2) in patients with NCGS suggesting higher enterocyte death and higher small bowel permeability in these patients [25]. This finding is also supported by the presence of anti-flagellin and anti-core endotoxin antibodies in patients with NCGS that indicate microbial translocation from the lumen to bloodstream due to intestinal barrier dysfunction [25].

Investigating patients who are suspected to have gluten related disorders Treatment naïve patients suspected to have gluten related disorder (NCGS or celiac disease), who are not on a GFD, should undergo screening for celiac disease using celiac serology testing with IgA anti-tissue transglutaminase antibody (antitTG ab) or IgA anti-endomysial antibody (EMA). If the clinical suspicion is high, celiac serology is positive or patient is serum IgA deficient, patient should undergo an upper endoscopy to obtain duodenal biopsies for assessment of villous abnormalities. If a patient is seeking medical attention for suspected gluten-related disorder and is already on a GFD, the serological markers and duodenal biopsies might be normal in them despite presence of underlying celiac disease. In this scenario, HLA-DQ typing can be useful given extremely high negative predictive value of a negative HLA-DQ2 and HLA-DQ8 in ruling out celiac disease. However, if HLA-DQ typing is not readily available or is positive for HLA-DQ2 and/or HLA-DQ8, then a gluten challenge might be needed to reliably exclude the diagnosis of celiac disease. Leffler et al. have shown that 14-day gluten challenge at ≥3 g of gluten per day might be sufficient to induce histological and serological changes in majority of adult patients with celiac disease. Once celiac disease is reliably excluded, patients who were already on a GFD for reported sensitivity to gluten or wheat could continue a GFD. Patients with symptoms suggestive of NCGS who have not tried a GFD could be trialed on a GFD to assess the response to a GFD. Still there is no biomarker for NCGS, the expert-consensus statement on NCGS recommends a double or single-blind placebo-controlled cross-over trial to establish a diagnosis of NCGS. It is generally not feasible to perform blinded placebo-controlled cross-over trials in clinical practice, therefore, for patient with fluctuating symptoms, a symptomatic assessment of a patient adhering vs. not adhering to a GFD for at-least 1 week is suggested.

Overlap between IBS and gluten-related disorders Although the relationship between food ingestion and symptom generation in patients with IBS has long been established, our understanding of dietary triggers and pathogenic mechanisms involved in IBS is still not well defined [32]. Wheat has been considered as a possible culprit for symptom generation in some patients with IBS [32]. 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,”) and reach the submucosa, and activate the resident innate immune cells. Experimental data have 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 [33]. Both enhanced intestinal permeability and increased smooth muscle contractility reverted to normal after gluten withdrawal [33]. There is considerable overlap between the symptoms of IBS, celiac disease and NCGS. The prevalence of celiac disease is four times higher in patients with IBS compared to the general population [34]. Based on the evidence suggesting overlap in symptomology of IBS and celiac disease along with significantly high prevalence of celiac disease in patients with IBS, the American College of Gastroenterology Task Force has recommended serological screening for celiac disease in patients with IBS especially those with IBS-D and IBS-mixed subtypes (IBS-M) [35]. It is important to note that not all studies estimating prevalence of celiac disease in IBS have reported higher prevalence of celiac disease in patients with IBS [34]. However, given the long-term complications of celiac disease and significant difference in management of these two entities, patients with IBS-D and IBS-M should be screened for celiac disease. Even if celiac disease is ruled out, patients with IBS could have NCGS. In-fact, wheat is one of the most common food item that patients with IBS report having adverse reactions [36]. Recent literature suggests that a substantial proportion of patients with IBS (especially those with IBS-D) improve on when they are put on a GFD. In a randomized controlled 4-week trial of GFD or gluten containing diet in 45 patients with IBS-D, the stool frequency per day was higher in the group randomized to gluten containing diet compared to those who received a GFD [30]. The effect on stool frequency was more pronounced in patients with HLA-DQ2 or -DQ8 haplotype

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compared to those who were HLA-DQ2/-DQ8 negative [30]. Patients on a gluten-containing diet also had higher small bowel permeability and under-expression of zonula occluden-1 in the small intestinal mucosal biopsies compared to those on a GFD. These effects were also more pronounced on HLA-DQ2/-DQ8 positive patients suggesting a role of glutenmediated increase in small intestinal permeability in a subset of patients with IBS [30]. Beneficial effect of GFD on IBS symptoms has also been shown in a few other non-randomized studies [37]. Although there is evidence that gluten-containing cereals can induce symptoms, it is not clear whether these symptoms are related to gluten or fructans [38]. Analysis of several food products show that gluten tend to co-exist with fructans and other poorly absorbable carbohydrates such as galacto-oligosaccharides [39]. Thus, a GFD also reduces the intake of fermentable oligo, di- and mono-saccharides, and polyols (FODMAPs) [39]. This is important because several randomized controlled trials have shown that low-FODMAP diet might be beneficial in patients with IBS [40]. In-fact, a recent meta-analysis of seven randomized controlled trials showed that a low FODMAP diet leads to a 31% greater likelihood of decreasing global symptoms [40]. Two double-blind cross-over trials have addressed the question whether gluten is responsible for the generation of symptoms reported by patients with NCGS [38, 41]. In a double-blind cross-over trial of 37 subjects with NCGS and IBS, participants were placed on a 2-week low FODMAP diet after which they were randomly assigned to high-gluten (16 g gluten/day), low-gluten (2 g gluten/day) or control (16 g whey protein/day) for 1 week, followed by a washout period of at least 2 weeks [41]. In all participants, gastrointestinal symptoms consistently and significantly improved during low FODMAP intake, but significantly worsened to a similar degree when they were put again on gluten or whey protein [41]. This trial suggested that majority of patients with self-perceived gluten sensitivity might not be sensitive to gluten. However, there is also a contribution of anticipatory “nocebo” response to gluten challenge in these individuals with perceived gluten sensitivity. Most recently, Skodje et al. performed a randomized, double-blind trial of 59 individuals with NCGS involving cross-over challenge with gluten, fructans or placebo, concealed in muesli bars [38]. They found that overall gastrointestinal severity score for those consuming fructans was significantly higher than that for gluten or placebo [38]. This suggest that a significant proportion of patients who consider themselves gluten sensitive might actually be sensitive to FODMAPs or fructans and not gluten [38]. In a study of non-celiac, non-lactose and non-fructose IBS patients, fructan breath test was positive in 64% [42]. Overall, the above evidence suggests non-celiac gluten sensitivity may be renamed as non-celiac wheat sensitivity. Other soluble proteins in the wheat which could play a role in pathogenesis of NCGS include amylase/trypsin inhibitors (ATIs) or wheat germ agglutinins (WGAs). ATIs are a family of several structurally similar, small and compact mono-, di or tetrametric wheat proteins, which serve as protective proteins in wheat by inhibiting enzymes (amylase and trypsin like activities) produced by parasites. ATIs are known to be a major allergen in Baker’s asthma and are identified as triggers for innate immune activation in intestinal myeloid cells via stimulation of Toll-like receptor 4 (TLR-4). In addition, they have also been shown to enhance intestinal inflammation in mice models of inflammatory bowel disease. Similar to ATIs, WGAs are also protective proteins and bind to glycoproteins on the surface of cell membranes. WGAs have been shown to induce the release of pro-inflammatory cytokines (TNF-α, IL-1, IL-12 and IFN-Y) and impair the integrity of the intestinal epithelial layer. However, in contrast to ATIs, no innate stimulatory activity has been demonstrated for WGA in-vivo.    

Management of NCGS In comparison to celiac disease where life-long and strict adherence to a GFD is recommended, patients with NCGS might not require life-long and/or strict adherence to a GFD. While the natural history of NCGS is not well known, it has been suggested that NCGS might not persist life-long. Therefore, recommendation from experts is patients with NCGS should follow a GFD for 12–24 months, and then should be re-challenged with gluten to test for gluten tolerance. Furthermore, in contrast to that with patients of celiac disease, those with NCGS may be allowed to consume minimum amounts of gluten that can be tolerated without symptoms. However, for many extremely sensitive patients with NCGS, a very strict GFD may be required.

Predictors of response to GFD in patients with IBS At present, there are no guidelines or consensus document that helps in identifying predictors of a response to a GFD in patients with IBS in whom celiac disease and/or wheat allergy has been ruled out. As described above, Vazquez-Roque identified that the response of a GFD in patients with IBS is more pronounced in patients with IBS-D patients having HLA-DQ2 and/or HLA-DQ8 [30]. Similar observation was made by Wahnschaffe, et al. in two other cohorts of IBS-D patients in whom celiac disease was ruled out [29, 43]. In the second study of 145 patients with IBS-D, Wahnschaffe et al.

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also identified the presence of IgG (but not IgA) anti-tTG ab and anti-gliadin antibodies (AGA) as potential predictors for response to a GFD [29]. Subsequently, AGA was identified as potential marker for response to a GFD in a few other studies [44]. However, a placebo response related to patients’ awareness about gliadin related antibodies is possible as patients were not blinded to results of serological testing. In an interesting study, Fritscher-Ravens et al. using confocal laser endomicroscopy showed immediate epithelial breaks and leakage in response to a mucosal wheat challenge in 13 of 22 patients with food-related IBS in whom celiac disease and common food allergies were excluded [45]. All positively identified patients later reported a dramatic, long-term (12 months) improvement on GFD [45].

Conclusions A substantial subset of patients with functional gastrointestinal disorders have food-related symptoms or food intolerance. Among the several food allergens, gluten is particularly interesting and has been implicated in the pathogenesis of both celiac disease and NCGS. Although preliminary data suggests NCGS is common, there is a need for population-based studies to learn about the exact prevalence of NCGS. The exact trigger for NCGS is not clear and possibilities include gluten, fructans and ATIs. In addition, a significant proportion of patients with perceived gluten sensitivity may have “nocebo” effect from gluten. Future research should focus on identifying the culprit antigen/antigens and understand the underlying physiological changes at the level of intestinal epithelium and adaptive/innate immunity. Eventually, identifying a serum biomarker for NCGS will help us to appropriately identify and manage these patients. Moreover, a significant proportion of patients with IBS-D also seem to respond to a GFD. Better data from placebo controlled, blinded studies are needed to confirm these findings. Exploring the role of gluten in IBS-D may also be used to develop a better understanding of food intolerance/hypersensitivity in IBS.

Acknowledgment PS was supported by 5T32DK007760-19.

Conflicts of Interest None.

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