Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity

Table 1 Summary of studies on irritable bowel syndrome and atopy

Ref.	Study design	Patients	Topic	Main results
White et al[83], 1991	Case-control observational study	11 IBS patients 11 healthy controls 11 organic gut diseases patients	IBS and bronchial hyper-responsiveness	FEV1 reduction induced by methacholine in IBS patients was significantly greater than that observed in healthy subjects. FEV1 decrease in patients with organic disease was not different from that in normal subjects
Yazar et al[84], 2001	Case-control observational study	133 IBS patients 137 healthy controls	IBS and asthma	Twenty-one (15.8%) IBS patients and 2 (1.45%) patients from the control group had the diagnosis of asthma. FEV1, flow after 50% of the vital capacity has been exhaled, peak expiratory flow rate, and maximal mid-expiratory flow rate were significantly different
Jun et al[85], 2005	Case-control observational study	42 IBS patients 42 healthy controls	IBS and bronchial hyper-responsiveness	No statistical difference was found between the two groups with respect to FEV1, FVC, FVC/FEV1, and FEF(25-75)
Roussos et al[86], 2003	Case-control observational study	150 asthma patients 130 other pulmonary disease patients 120 healthy controls	IBS and asthma	IBS prevalence was significantly higher in asthmatics (62/150, 41.3%) than in subjects with other pulmonary disorders (29/130, 22.3%) and healthy controls (25/120, 20.8%). None of the asthma medications were associated with increased or decreased likelihood of IBS
Ozol et al[87], 2006	Case-control observational study	125 asthma patients 95 healthy controls	IBS and asthma	IBS was found in 29.6% and 12.7% (P < 0.005) respectively of asthma patients and healthy controls. Food allergy was reported in 7.2% and 2.1% (P > 0.05) respectively for the two groups. No significant association between asthma related parameters, IBS, and food allergy could be found
Powell et al[88], 2007	Retrospective study	7235 patients attending a general practice	IBS, asthma and allergic rhinitis	IBS was more common in patients with asthma (9.9%) and allergic rhinitis (7.9%) compared to patients with chronic diseases (4.9%, P < 0.002 and 4.9%, P < 0.05 respectively) or the remaining non-asthmatic population (5.5%, P < 0.001 and 5.5%, P < 0.02 respectively)
Cole et al[89], 2007	Nested case-control study	91237 people with asthma 24518 people without asthma	IBS and asthma	Incidence of IBS among people with asthma was 20% higher than in non-asthmatic patients; no association was found between oral steroid intake and IBS among people with asthma
Huerta et al[90], 2002	Population-based cohort study	50000 people with asthma 50000 people without asthma	IBS and asthma	IBS incidence in the asthma cohort was 2.5 per 1000 persons/years and 2.0 in the general population, with a RR of 1.3. In the asthma cohort, oral steroid users had RR of 0.5 for developing IBS, without any difference between short- and long-term users
Panicker et al[91], 2008	Case-control observational study	138 asthma patients 145 healthy controls	IBS and asthma	A large proportion (39.13%) of asthmatics had IBS compared to controls (7.93%) (P < 0.001). IBS was reported in 87% of cases using inhalers, and in 13% with additional oral theophylline (P < 0.001). As many as 66.6% cases, had IBS with relatively short duration of asthma (1-5 yr, P < 000)
Hunskar et al[92], 2012	Cohort study	817 subjects exposed to giardia 1128 subjects not exposed to giardia	Post-infection IBS and asthma	IBS was found in 47.8% of subjects with asthma compared with 45.3% in those without asthma (P = 0.662) in the giardia exposed group. For controls, corresponding percentages were 23.9% and 12.2% (P < 0.001)
Tobin et al[93], 2008	Prospective study	125 consecutive: allergy/immunology (n = 39), gastroenterology (n = 36) general medicine (n = 50)	IBS and atopic diseases	The likelihood of IBS was significantly higher in patients with seasonal allergic rhinitis (2.67 times; P = 0.03), allergic eczema (3.85 times; P = 0.001), and depression (2.56 times; P = 0.04). Patients reporting atopic symptoms (seasonal allergic rhinitis, asthma, and allergic eczema) were 3.20 times (95%; P = 0.02) more likely to fulfill IBS criteria
Jones et al[94], 2014	Retrospective study	30000 patients from primary care medical records	FGIDs and atopic diseases	In patients suffering from IBS alone, functional dyspepsia alone and multiple functional gastrointestinal disorders, there was higher asthma prevalence compared to controls (OR = 1.43, 1.41 and 1.92 respectively)
Olén et al[96], 2014	Birth cohort study	2610 children	Recurrent abdominal pain and atopic diseases in children	237 (9%) children reported abdominal pain when 12 yr old. Asthma in the first two years of life and food allergy at age 8 yr were significantly associated with abdominal pain at 12 yr (P < 0.001). There was an increased risk of abdominal pain at 12 yr in children sensitized to food allergens at 4 or 8 yr
Smith et al[97], 1985	Prospective study	29 patients with perceived food hypersensitivity	Self-reported food hypersensitivity and allergy	17 (60%) of the 26 patients were positive to skin prick tests to inhalant allergens
Lillestøl et al[98], 2010	Prospective study	71 patients with perceived food hypersensitivity	Self-reported food hypersensitivity and allergy	66 (93%) patients suffered from IBS and 43 (61%) had atopic diseases (predominantly rhinoconjunctivitis). Atopic patients had increased density of IgE-bearing cells and intestinal permeability but gastrointestinal symptoms did not differ between groups (P = 0.02). IgE-positive cells and intestinal permeability did not differ between patients who were sensitized to inhalants and those who were only sensitized to food
Berstad et al[99], 2012	Prospective study	84 patients with perceived food hypersensitivity	Self-reported food hypersensitivity, IBS, chronic fatigue and fibromyalgia	83 patient were diagnosed with IBS, 58% with severe symptoms. 85% reported symptoms suggestive of chronic fatigue and 71% fibromyalgia. These symptoms could not be explained either by IgE-mediated food allergy or by organic pathology
Lind et al[100], 2013	Case-control observational study	38 patients with self-reported food allergy 42 healthy controls	Self-reported food hypersensitivity, IBS, fatigue	FIS scores were higher in patients (median 85.0, interquartile range 36.8-105.3) than in controls (median 14.0, interquartile range 3.0-29.0, P ≤ 0.0001)
McKee et al[12], 1987	Observational study	40 IBS patients	IBS and elimination diet	Patients received an antigen-exclusion. 15% showed improvement in their IBS-symptoms. A further 12.5% reported increased well-being but this did not seem to be related to the exclusion of any particular food. The diarrhea prevalent subgroup responded the best (3/8) whereas the constipation subgroup consistently failed to improve
Heizer et al[17], 2009	Review	NA	IBS and elimination diet	25% of IBS patients reported their symptoms may be caused or exacerbated by one or more dietary components. Diet restricted in fermentable, poorly absorbed carbohydrates, including fructose, fructans, sorbitol, and other sugar alcohols seemed to be beneficial
Zar et al[101], 2005	Prospective study	25 IBS patients	IBS and elimination diet	Patient IgG4 antibodies to milk, eggs, wheat, beef, pork and lamb were measured, and were commonly elevated. Significant improvement was reported in pain severity (P < 0.001), pain frequency (P = 0.034), bloating severity (P = 0.001), satisfaction with bowel habits (P = 0.004) and effect of IBS on life in general (P = 0.008) at 3 and 6 mo of elimination diet
Atkinson et al[102], 2004	Randomized trial	150 IBS patients	IBS and elimination diet	Patients received either a diet excluding all foods to which they had raised IgG antibodies or a sham diet for 3 mo. The true diet resulted in a 10% (26% in fully compliant) greater reduction in symptom score than the sham diet
Bolin[103], 1980	Randomized trial	20 patients suffering from persistent diarrhea	IBS and DSCG	18 patients reported significant improvement in diarrhea while taking sodium cromoglycate and this did not correlate with the presence of other atopic diseases, history of food intolerance, or lactase deficiency
Paganelli L et al[104], 1990	Prospective study	14 IBS patients	IBS, elimination diet and DSCG	7 (50%) patients improved after elimination diet with (5/7) and without (2/5) DSCG
Lunardi et al[105], 1991	Double-blind cross-over trial	20 IBS patients	IBS and DSCG	18 patients completed the study; analysis of patients' diary card scores showed a statistically significant difference in favor of DSCG
Stefanini et al[106], 1992	Prospective study	101 IBS patients (diarrhea type)	IBS, atopy and DSCG	Patients were then tested for 48 commercial alimentary antigens by SPT and underwent 8 wk of oral DSCG. Symptom improvement was observed in 67% of the 74 SPT-positive patients, whereas only in 41% of the 27 SPT-negative patients
Stefanini et al[107], 1995	Multicenter trial	428 IBS patients (diarrhea type)	IBS, elimination diet and DSCG	IBS symptoms improved in 60% of patients treated with elimination diet and in 67% of those treated with DSCG. In both groups clinical results were significantly better in the patients positive to the skin prick test than in the negative ones
Leri et al[108], 1997	Randomized study	120 IBS patients (diarrhea type)	IBS, elimination diet and DSCG	66 patients had positive SPT; they were randomly treated with elimination diet (30) or with elimination diet plus DSCG. 18 (60%) of the 30 patients that had received the only exclusion diet reported symptom improvement, whereas 32 of the 36 patients (89%) who had undergone both dietary and DSCG treatments showed an improvement that was clinically and statistically significant (P = 0.01)

DSCG: Disodium cromoglycate; FCV: Forced vital capacity; FEF: Forced expiratory flow; FEV1: Forced expiratory volume in 1 s; FGIDs: Functional gastrointestinal disorders; FIS: Fatigue impact scale; IBS: Irritable bowel syndrome; RR: Relative risk; SPT: Skin prick test; NA: Not available.

Table 2 Identification of foods triggering symptoms in irritable bowel syndrome patients

Ref.	Patients	Diagnostic methods	Foods	Comment
Nanda et al[13], 1989	91 of 200 IBS patients reported symptomatic improvement after 3 wk of elimination diet	Open challenge	Cheese 35.2% Onions 35.2% Milk 31.9% Wheat 29.7% Chocolate 27.5% Butter 25.3% Yoghurt 24.7% Coffee 24.2% Eggs 23.3% Nuts 18.0% Others 34.1%	73 of the 91 improved patients were able to identify one or more foods responsible for their symptoms in the open challenge. All except one remained well on clinical follow-up
Carroccio et al[71], 2011	160 IBS patients	DBPCFC to wheat and milk	Wheat and milk 18.75% Only milk 3.75% Only wheat 2.5%	40 (25%) patients were found to suffer from food hypersensitivity. These patients had increased levels of fecal eosinophil cationic protein and tryptase, indicating that they might cause inflammation in patients with IBS
Dainese et al[112], 1999	128 IBS patients	Self-reported intolerance questionnaires vs SPT	Milk (28.8% vs 3%) Wheat (17.5% vs 1.5%) Pepper (2.5% vs 6%) Peanut (6.3% vs 6%) Pear (5% vs 7.5%) Tomato (12.5% vs 9%) Onion (3.8% vs 9%) Celery (2.5% vs 9%) Banana (2.5% vs 9%) Carrot (0% vs 10.5%) Garlic (0% vs 10.5%) Parsley (0% vs 16%) Walnut (6.3% vs 18%) Apple (10% vs 18%)	More than 50% of IBS patients were found sensitized to some food or inhalant without any symptom. There is a substantial lack of correlation between self-perceived food intolerance and SPT sensitization
Locke et al[115], 2000	76 IBS patients of 643 subjects from Olmsted County general population	Self-reported intolerance questionnaires	Beans 22.3% Chocolate 23.6% Dairy products 52.6% Eggs 21.0% Nuts 23.6% Onions 57.8% Spicy food 81.5%	Among the 643 subjects, IBS symptoms were reported by 12% (76). IBS was significantly associated with use of analgesics, food allergy or sensitivity
Farah et al[116], 1985	13 of 49 patients suspected of food intolerance after elimination diet	DBPCFC	1/13 peas 1/13 coffee 1/13 eggs	After DBPCFC 3 patients were confirmed to suffer from food intolerance. Authors found that 10 patients reacted to placebo, suggesting a psychogenic cause for their disturbances
Carlson et al[121], 2014	25 children suffering from gastrointestinal disorders and their parents	Child-reported intolerance questionnaires vs parent- reported intolerance questionnaires	Spicy food 68% vs 60% Pizza 52% vs 48% Cow’s milk 56% vs 48% Fired foods 48% vs 36% Fast Foods 40% vs 40% Sodas 40% vs 36% Cheese 40% vs 36%	Specific foods are perceived to exacerbate gastrointestinal symptoms in children with functional gastrointestinal disorders. No differences were found in severity or frequency of symptoms with ingestion of the foods between children and parents with respect to the 10 most frequent foods/food types
Böhn et al[126], 2013	197 IBS patients	Self-reported intolerance questionnaires	Dairy products 49.2% Beans 36.0% Apple 27.9% Wheat 24.4% Fried foods 52.3% Plum 23.4% Peas 19.3% Chocolate 16.8% Foods rich in biogenic amines (58%) Histamine-releasing foods (43%)	Most IBS patients believe that certain foods could be triggers of their symptoms. They identified FODMAP containing foods, histamine-releasing foods, fried foods and foods rich in biogenic amines as the main culprits. Self-reported food intolerance seems to be associated with high symptom burden and reduced quality of life
Monsbakken et al[127], 2006	84 IBS patients	Self-reported intolerance questionnaires	Milk 41.7%	70% of subjects perceived a food intolerance (mean 4.8 food items related to symptoms), 62% limited or excluded food items from their daily intake (mean 2.5 food items reduced or eliminated), and 12% made drastic changes in their diet potentially causing nutritional deficiencies in the long run
			Cheese 14.3%
			Eggs 11.9%
			Peas 21.4%
			Onions 35.7%
			Cabbage 34.5%
			Wheat 14.3%
			Coffee 26.2%
			Chocolate 25.0% Beer 16.9%
Parker et al[130], 2001	122 IBS patients	LHBT, lactose elimination diet and DBPCFC (with 5/10/15 g of lactose)	33/122 (27%) positive to LHBT 9/33 (27.7%) improved on lactose elimination diet 5/9 (55.5%) worsened on DBPCFC with 15 g of lactose	Lactose intolerance was demonstrated in IBS patients with positive (33/122) or negative (13/122) LHBT. DBPCC were inconclusive
Yang et al[131], 2013	60 IBS patients vs 60 controls	LHBT and self-reported lactose intolerance	18% vs 3% with 10 g LHBT 47% vs 22% with 20 g LHBT 85% vs 68% with 40 g LHBT 63% vs 22% with self- reported intolerance	The risk of lactose intolerance is related to the dose ingested and is higher in IBS patients than in controls. Self-reported intolerance is associated with avoidance of dairy products
Dainese et al[132], 2014	51 IBS patients	LHBT (50 g) and self-reported lactose intolerance	21/51 (41.1%) self-perceived lactose intolerance 24/51 (47%) positive LHBT 14/51 (27.4%) reported symptoms during LHBT	Patients who experienced symptoms during LHBT had more severe IBS symptoms and higher anxiety, depression, and fatigue scores. Increase in hydrogen production and in the severity of IBS influenced the symptoms of lactose intolerance during LHBT
Carroccio et al[145], 2010	24/120 IBS patients who underwent DPBCFC after elimination diet	DBPCFC and flow-CAST	12.5% cow milk only on DBPCFC 8.3% wheat only on DBPCFC 79.1% both cow milk and wheat on DBPCFC 86.3% cow milk on Flow-CAST 85.7% wheat on Flow-CAST	Flow-CAST had higher sensitivity than serum total IgE and serum food-specific IgE, both in the diagnosis of cow’s milk allergy and wheat protein allergy. Flow-CAST diagnostic accuracy proved higher than the two traditional techniques both for cow’s milk allergy and for wheat protein allergy diagnoses

DBPCFC: Double blind place controlled food challenge; FODMAP: Fermentable Oligo-, Di-, and Monosaccharides And Polyols; IBS: Irritable bowel syndrome; LHBT: Lactose hydrogen breath test; SPT: Skin prick tests.