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Keywords:

  • cytokines;
  • food allergy;
  • functional dyspepsia;
  • irritable bowel syndrome;
  • mast cells;
  • neuroimmune

Abstract

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

Abstract  A significant proportion of adults believe they suffer from food allergy, and 20–65% of patients with irritable bowel syndrome (IBS) attribute their symptoms to something in food that activates an abnormal response. This systematic review evaluates the role of food allergy in aetiology and management of these disorders. Activation of gastrointestinal mucosal immune system may be one of the causative factors in the pathogenesis of functional dyspepsia and IBS. This activation may result from effects of bacterial infection or other luminal factors including commensal microbial flora and food antigens. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients. Further well-controlled studies are needed to establish whether food allergy plays a role in the pathophysiology of functional dyspepsia and IBS.


Introduction: Definition

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

There is an increasing appreciation of the role of the intraluminal milieu to the development of functional gastrointestinal disorders. This has been highlighted by recent observations of changes in mucosal and neuromuscular function in animal models as well as in patients with these disorders. Therapeutic benefit of antibiotics1 or probiotics2 confirms the potential role of modulating the intraluminal bacterial flora. However, given the high frequency with which patients report association of symptoms with food ingestion, it is relevant to systematically explore the evidence for an association of food allergy or intolerance to manifestation of these functional gastrointestinal disorders.

In 1916, Cooke and Van der Veer were the first to consider food allergy as a potential factor in the causation of gastrointestinal symptoms in patients with asthma and hay fever.3 Loveless4 and Graham et al.5 verified the association between the ingestion of food and development of symptoms in adults in the 1950s.

Food adverse reactions consist of any abnormal reaction after the ingestion of a food, and include food allergy, food intolerance and food aversions. Food intolerance is an adverse physiologic reaction, which is mediated by non-immunologic reaction and may be due to factors within foods, such as toxins (e.g. food poisoning) or pharmacologic agents (e.g. caffeine or tyramine), enzyme deficiency of the host (e.g. lactase deficiency) or idiosyncratic responses induced by unknown mechanism. Food aversions are psychological avoidance responses to any type of foods.

Methodology Of Systematic Review

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

We searched the MEDLINE electronic database (1966–March 2005) using the following keywords singly and in different combinations: food allergy, food hypersensitivity, functional dyspepsia (FD), irritable bowel syndrome (IBS), epidemiology, diagnosis, pathogenesis, pathophysiology, treatment. The search was restricted to papers published or having at least an abstract in the English language. We also hand-searched the references of the individual papers retrieved. We retrieved potentially relevant articles and reviewed their reference lists to identify studies that our search strategy may have missed. As shown in Table 1, the evidence is assessed using Jadad criteria (Table 2).6

Table 1.   Clinical trials in IBS patients
ReferenceSubjectsTreatmentChallenge protocolResultFollow-upJadad score (0–5)*
  1. ED, elimination diet; DB, double-blind; AFR, adverse food reactions; DSCG, disodium cromoglycate; * See Table 2.

Jones et al.75
 Study 125, IBSLow allergenic, 1 weekOpen food, daily14/21 (67%) specific offending foods foundNot recorded0
 Study 26, symptom-free subjects from study 1Same diet during challenges onlyDB nasogastric daily10/12 DB challenges provoked symptomsNot recorded5
 Study 35, selected patients from study 1Same diet, 4 daysSB disguised in unspecified flavoured soup daily100% symptomatic with SB challengesNot recorded1
Bentley et al.7627, IBSLow allergenic, unknown durationOpen food 3 days apart; DBPC in responders14/21 (67%) remission after ED; 10/21 (47.7%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge3 responders remained well; duration not stated2
Farah et al.7749, GI clinic patients with symptoms suggestive of food intoleranceLow allergenic, 2 weeksDBPC; open food 1 week apart in responders13/49 (26.5%) remission after ED; 8/49 (16.3%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge6–18 months5
Petitpierre et al.7824, IBS (12, atopic; 12, non-atopic)Low allergenic, 3 weeksOpen and single-blind; unspecified frequency7/24 (29.2%) symptoms unchanged; 3/24 (12.5%) remission with ED but negative challenges; 14/ 24 (58.3%) specific offending foods found and confirmed by blind challenges6 months0
McKee et al.7940, IBSLow allergenic, 1 weekOpen,unspecified frequency6/40 (15%) remission during EDNot recorded0
Zwetchkenbaum et al.8010, IBSExclusion of foods and same-food families linked to IBS symptoms from food diaries; 2 weeksOpen for 2 days apart6/9 (66.7%) symptoms unchanged with ED; 3/9 (33.3%) remission with ED, challenges negative; 0/9 (0%) AFRs identifiedNot recorded1
Nanda et al.13200, IBSLow allergenic, 3 weeksOpen for 2 days91/189 (47.9%) remission during ED; 73/189 (38.6%) specific offending foods found by open food challenge14.7 months average for responders; 12.5 months for non-responder1
Atkinson et al.85150, IBS who had raised IgG antibodies to foodsTrue diet (excluding all foods to which they raised IgG antibodies)/Sham diet (excluding the same number of foods), 12 weeksOpen for 4 weeks10% greater reduction in symptom score in the true diet group than the sham diet group. (P = 0024). Open reintroduction of diet; 24% greater deterioration in symptoms in the true diet group. (P = 0.003)Not recorded5
Bolin8320, Persistent diarrhoeaDSCG/Placebo, 4 weeks, cross-over design 8/20 (40%) remission during DSCGNot recorded5
Lunardi et al.8420, IBSDSCG/Placebo, 8, 4 weeks washout, cross-over design 15/18 (83%) remission during DSCGNot recorded4
Stefanini et al.81101, IBS-diarrhoea (improved after an ED and worsened after a challenge)DSCG, 8 weeks Improvement of symptoms; 50/74 (67%) of the SPT-positive patients 11/27 (40%) of the SPT-negative patients (P < 0.05)Not recorded1
Stefanini et al.82428, IBS-diarrhoea (Multicentre study)DSCG/Low allergenic, 1 month Improvement of symptoms; 118/175 (68%) during DSCG 103/171 (60%) during low allergenicNot recorded1
Table 2.   The Jadad scale6
ItemPoints
Randomization
 Study described as randomized+1
 Randomization method described and appropriate+1
 Randomization method described and inappropriate−1
Blinding
 Study described as double blind+1
 Blinding method described and appropriate+1
 Blinding method described and inappropriate−1
 Blinding method not described0
 Study not described as blind0
Withdrawals and dropouts
 Withdrawals and dropouts described+1
 Withdrawals and dropouts not described0

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

The prevalence of food allergies is greatest in the first few years of life, affecting about 6% of infants less than 3 years of age,7 and decreases over the first decade. In adults, the prevalence of food allergies is lower, and was estimated at 3.7% in a recent US study.8 On the other hand, in several population studies,9–12 20–45% of adults believe that they suffer from adverse reactions to food, and 20–65% of patients with IBS attribute their symptoms to adverse food reactions.13,14 Such perceived adverse reactions may be caused by different mechanisms, and the majority of adverse food reactions are non-immunologic in origin, with lactose intolerance the most common adverse reaction worldwide.15 One uncontrolled study observed a high prevalence of FD and IBS in patients with adverse reactions to food.16 The role of adverse physiologic reactions to food such as lactose intolerance in IBS patients is unclear.17,18 Although perceived food allergy is often not verified by double-blind placebo-controlled food challenge, a perception of food allergy may be associated with a subset of patients with IBS or FD.

Pathophysiology Of Food Allergy In Adults

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

It has been estimated that humans consume approximately 100 ton of food during a lifetime,19 but the fact that only a small portion of the population develops symptoms in relation to the ingestion of food leads to the inference that the gastrointestinal system is uniquely designed to avoid potentially deleterious immune responses to foods. While the gastrointestinal tract acts as a conduit, allowing the transfer of nutrients from the intestinal lumen to the systemic circulation, it also protects against invasion by microbes and other antigens including foods. The gastrointestinal barrier is a complex structure that serves to protect the host against invading pathogens and allergens. It has several components: non-specific defence systems and innate or adaptive immune responses.

The non-specific defence systems consist of gastric acid, digestive enzymes, mucus, an intact epithelial layer forming tight junctions and peristaltic movement. For example, in mice, inhibition of acid secretion by injection of ranitidine or omeprazole was shown to increase sensitization to food antigens.20 The innate immune responses include alternative complement pathways, natural killer cells, polymorphonuclear leukocytes, macrophages, toll-like receptors which are usually associated with the luminal membrane of gut epithelial cells,21 antimicrobial peptides such as defensins and cathelicidins22 and reparative factors called trefoil peptides.23 Adaptive immune responses consist of intraepithelial and lamina propria lymphocytes, Peyer's patches, secretory IgA and cytokines. These provide an active barrier to foreign antigens. Working together, these factors may prevent the development of food allergy. Several studies have shown that intestinal permeability measured by using polyethylene glycol (PEG), mannitol/lactulose, l-rhamnose/lactulose or horseradish peroxidase (HRP) was increased in patients with food allergy compared to healthy volunteers.24–28 In contrast, there is a small study that did not find any difference of intestinal permeability between food allergy patients and healthy volunteers.29 Overall, these results may indicate that intestinal permeability is increased in patients with food allergy, and that the increased permeability may be secondary to inflammatory events such as infection, ischemic injury or malnutrition.

Yet, despite these barriers, about 2% of ingested food antigens are absorbed even through the mature gut and they are transported throughout the body in an intact form that may result in immunological responses.30 The neonate or infant is exposed to dietary antigens since ‘closure’ of the gut, which is determined by non-immunologic as well as immunologic mechanisms in the gut,31 is required for tolerance to develop. Oral tolerance, as characterized by Chase32 in 1946, refers to a state of active inhibition of immune responses to an antigen by means of prior exposure to that antigen through the oral route.33 Thus, food antigens generally do not cause clinical symptoms because most individuals acquire oral tolerance. Some studies showed that exclusive breast-feeding in infants may promote the development of oral tolerance and prevent some food allergy and atopic dermatitis in infancy,34,35 whereas other studies have reported an increased risk for development of atopic eczema and food allergies in breast-fed infants.36,37 Tolerance is, therefore, key to the maintenance of immunologic homeostasis in the gut and the prevention of disease. The fact that mice raised in a germ-free environment from birth fail to develop normal tolerance38 suggests that commensal gut flora could play an important role in the development of oral tolerance.

Sensitization to food antigens could be attributed to immaturity of the host or breakdown of these defence mechanisms due to a variety of factors such as enteric infections39 or genetic alterations.40,41 Sensitization could lead to the development of food allergy. Sensitization may occur in the gastrointestinal tract after ingestion of a food, considered a traditional or class-1 food allergy, or after inhalation of an airborne allergen that cross-reacts with a specific food, considered a class-2 food allergy.42 In adults, peanuts, tree nuts, fish and shellfish are responsible for most allergic reactions in North America.43 The list of foods inducing allergic reactions varies somewhat in different countries where cultural habits result in ingestion of different kind of foods.15 Food allergy is an abnormal or exaggerated immunologic response to a food antigen, and it can be mediated by a classic type 1, immediate hypersensitivity, IgE-mediated reaction to the offending food, or by type 4 delayed hypersensitivity, cell-mediated response, or a mixed IgE and cell-mediated response.

Diagnosis Of Food Allergy In Adults

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

Allergy to specific foods is suspected by many patients, but is confirmed objectively in very few. Although relatively rare in adults compared to infants and young children, food allergy should be considered in patients with characteristic signs and symptoms or suggestive immunologic responses or biopsy findings when other causes for the symptoms are not identified.

Diagnosis of food allergy requires a suspicion that certain symptoms or signs may be caused by or be related to food allergy. Clinical evaluation should be used to rule out non-immunological adverse reactions to food such as lactose, sorbitol or fructose intolerance, pharmacologic effects of ingested caffeine, histamine or tyramine, psychological disorders manifesting with gastrointestinal symptoms, and pathological gastrointestinal diseases. This involves careful history, physical examination and diagnostic tests such as breath hydrogen tests for lactose,44 fructose44 or sorbitol.45 When food allergy is considered possible, the next step is confirmation of diagnosis and identification of the implicated foods by appropriate skin and/or in vitro testing, followed by double-blind, placebo-controlled food challenges.46–48 A careful history may establish a suspicion of a food-induced allergic reaction, the type of food involved and the timing of ingestion relative to symptom onset. This timing may suggest which allergic mechanism (IgE-mediated, mixed IgE and cell-mediated or cell-mediated) was likely involved. IgE-mediated reactions are typically rapid in onset; non-IgE mediated disorders become evident hours to days after allergen ingestion. It is less likely to identify the implicated food in chronic disorders compared to situations associated with acute reactions to food.

There is no gold standard diagnostic procedure for gastrointestinal food allergy.49 The methods include in vitro tests, ex vivo stimulation tests or in vivo provocation tests. Skin prick tests and the radioallergosorbent test (RAST) for IgE suggest the presence of systemic food-specific IgE, or so-called sensitization. However, sensitization can exist without clinical reactions and, hence, a positive test does not imply food allergy. Colonoscopic allergen provocation test (COLAP) assesses local IgE responses and appears mechanistically more convincing, but its clinical relevance is still unclear.50 Other laboratory techniques have not proven useful in blinded studies. At present, a double-blind, placebo-controlled food challenge is considered the only conclusive method for diagnosing food allergy.15 However, it is associated with several practical problems: the lack of a read-out system, the variable time interval between ingestion and the onset of symptoms, and the lack of discrimination between food allergy and food intolerance.49

Role Of Food Allergy In Functional Dyspepsia

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

Functional dyspepsia is conventionally defined as persistent or recurrent pain or discomfort centred in the upper abdomen that is not relieved by defecation or caused by organic diseases.51 Genetic predisposition, psychological factors, inflammation and Helicobacter pylori infection may contribute to the development of FD, although the aetiology is unknown. Patients with FD often report that meals rich in fat cause discomfort.52 There are no controlled studies to investigate the association between food allergy and FD.

A case-control study from Italy investigated the incidence of several gastrointestinal diseases in 236 adult patients with food allergy or intolerance, and data from patients admitted to hospitals in the same region were used for comparison.16 The prevalence of FD was 2–4% higher in patients with adverse reactions to food relative to controls. Further, well-controlled studies are needed to evaluate the relationship between food allergy and FD.

Role Of Food Allergy In IBS

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

Multiple factors such as altered bowel motility, visceral hypersensitivity, psychological dysfunction, genetic factors, imbalance in neurotransmitters and infection and inflammation may lead to the development and maintenance of symptoms of IBS, but the pathogenesis of IBS still remains uncertain.53

A subgroup of IBS patients describes an acute onset of persistent symptoms after an episode of gastroenteritis characterized by at least two of the following: fever, vomiting, diarrhoea or positive stool culture.54 In 1962, Chaudhary and Truelove reported for the first time that 34 of 130 patients with irritable colon syndrome dated the onset of their symptoms to an attack of either bacillary or amebic dysentery.55 After four decades, recent studies have shown that 4–31% of people develop new onset IBS after infective gastroenteritis;56–62 and the odds of developing IBS was significantly higher in the group with prior gastroenteritis compared to a control group in some of these studies.60–62 However, a recent prospective cohort study showed that there was no significant difference in the incidence of IBS between those exposed to enteric infection during travel and the non-exposed groups.63

Several studies suggest that low-grade mucosal inflammation may play a role in the pathogenesis of IBS in both unselected and postinfectious IBS patients. The mucosal inflammation is characterized by increased numbers usually of ileal mast cells,63–67 increased nitric oxide synthetase (iNOS),68 lymphocyte infiltration in the myenteric plexus69 and an increase in T lymphocytes.70 Although there is a great deal of overlap in the quantitation data of controls and IBS for all these markers to inflammation, it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.71 It is important to note that mucosal inflammation and immune system activation in the mucosa of these IBS patients can also be caused by other factors, including food antigens, changes in the resident microbial flora or endogenous chemical irritants such as bile salts. Mucosal activation of these immune cells results in changes in the function of submucosal and myenteric neurons,72,73 linking these two effector systems in the causation of disorders of gastrointestinal functions, e.g., secretion, absorption, blood flow and motility.

Relationship Of Food Allergy, Immune Hypersensitivity And IBS

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

The mucosal surface of the gastrointestinal tract defends the organism from the constant challenge of antigens, such as microorganisms, and enables assimilation of antigens from food that remains innocuous in most individuals. In order to maintain the homeostasis of the gut, the intestine is in a state of continuous immune responsiveness, with a delicate balance between concomitant facilitation and suppression of inflammatory responses. However, food antigens can activate the mucosal immune system when there is immaturity of the gut barrier, pathological destruction of that barrier, infection or inflammation and genetic susceptibility.74 It is hypothesized that mucosal immune activation caused by food antigens may contribute to the development of food allergy and IBS, but further work is needed in order to understand the interaction of food with the gastrointestinal immune system.

There are several lines of evidence suggesting that IBS can be caused by food allergy or generalized immune hypersensitivity. First, several studies demonstrate a positive response to elimination diets and disodium cromoglycate (DSCG), and these may indicate that, in a subset of IBS patients, symptoms can be attributed to food allergy or food intolerance (Table 1).13,75–85 Second, the prevalence of atopic conditions is increased in patients with diarrhoea-predominant IBS,81,86 and airway responsiveness to inhaled methacholine was increased in IBS patients with no clinical evidence of atopic disease in comparison to two control groups (healthy controls and positive diseases controls with inflammatory bowel disease87). Third, a recent study revealed that patients with bronchial asthma have an increased prevalence of IBS relative to the patients with other pulmonary disorders and healthy subjects.88

The mechanisms underlying food allergy may be mediated by IgE and/or IgG antibodies in these patients.

IgE-mediated food hypersensitivity89

Several studies suggest a causative role of IgE-mediated food hypersensitivity in a subgroup of IBS patients, typically those with atopy.50,78,90–92 Petitpierre et al. evaluated 24 IBS patients, 12 atopic, 12 non-atopic, who underwent total serum IgE test, skin prick test, RAST to various food antigens, and 3 weeks of low-allergenic diet followed by open challenge.78 Responders underwent blind dietary provocation. In 14 patients, one or more foods and food additives reproduced the typical IBS symptoms. Nine of these 14 patients showed elevated total serum IgE and positive skin tests which suggest systemic IgE-mediated food hypersensitivity. All these patients had evidence of atopy. In another study, nine of 17 paediatric IBS patients with personal and/or family history of allergy and/or raised total serum IgE levels had increased intestinal permeability (estimated by the differential urinary elimination of oral lactulose and mannitol) in response to food challenges.93

The Fc fragment of IgE contains the C-terminal domains of the heavy immunoglobulin chains; it has no antigen-binding sites or effector functions. Andre et al. showed increased Fc fragment of IgE in faecal extracts of 236/312 patients (73%) with food hypersensitivity based on history, positive skin prick test and RAST test. In contrast, 95 healthy subjects had undetectable faecal IgE.94 In a subgroup analysis, 22 of the 32 (68.8%) IBS patients were found to have detectable Fc fragment of IgE in faeces. In 70 adult patients with abdominal symptoms suspected to be related to food allergy and in five healthy volunteers, the COLAP test was performed by Bischoff et al.50 Food antigens were selected according to the patients’ history of food intolerance and presence of specific IgE in serum. Three food antigens were injected into the mucosa of the cecum during colonoscopy. A standard set of three antigens (milk, wheat, hazelnut) was used for challenge in the five healthy volunteers. The mucosal weal and flare reaction was classified semiquantitatively 20 min after challenge using a scale of 0–4: 0 = no reaction, 1 = questionable reaction, 2 = moderate reaction (<1 cm diameter), 3 = strong reaction (1–2 cm) and 4 = maximal reaction (>2 cm). The reaction was classified as positive if the grade of weal or flare reaction was ≥2. Colonoscopic allergen provocation test was positive in response to at least one food antigen in 77% (54/70) overall and a similar 74% (39/53) with a putative diagnosis of IBS. In contrast, no reaction was detected in the five healthy volunteers. Biopsies taken from the test positive site showed both mast cell and eosinophil activation.94 Following the dietary elimination of suspected food antigens in COLAP positive patients, 29/35 (89%) reported a significant clinical response after 3 months. The COLAP results corresponded strongly to a positive history of food intolerances, but they corresponded poorly to results of skin prick tests and specific serum IgE levels. These findings suggest that, in IBS patients, clinically relevant food antigens can be identified by the COLAP test, but not by skin test and measurement of specific serum IgE. The data also suggest that the mechanism of intestinal food allergy in IBS seems to be different from the classic type-1 hypersensitivity reactions of the skin or the respiratory mucosa. Prospective studies are needed to confirm the clinical relevance of these observations.

IgG-mediated food hypersensitivity

Although several studies suggested that IgG and IgG4 production may be part of a normal immunologic response to dietary antigens,91,92,95,96 other studies have demonstrated that serum IgG4 levels are elevated in patients with a history of food allergy or IBS.97–100 IgG4 receptors are located on basophils and mast cells and are distinct from IgE receptors.101 An increased prevalence of serum IgG antibodies to dietary proteins was demonstrated in 58 IBS patients compared with 46 controls, suggesting that IgG food antibodies may have some role in IBS.97 Similarly, food specific IgG4 antibodies to common food antigens are elevated in IBS patients.100 El Rafei et al. compared specific IgG4 and IgE levels to double-blind food challenges in 25 patients with suspected food allergy. They observed raised serum IgE or IgG4 levels in 63% of patients with a positive history of food hypersensitivity and either IgE or IgG4 in 91% of patients.97 Similar results have been reported in other studies.99,102 These results suggest that the combination of specific IgE and IgG4 antibodies to food antigens may be useful in evaluating patients with suspected food allergy.

Atkinson et al. assessed the therapeutic potential of dietary elimination based on the presence of IgG antibodies to food in 150 IBS outpatients;85 they were randomized to receive for 12 weeks either an elimination diet or a sham diet. After 12 weeks, the elimination diet resulted in a 10% greater reduction in IBS symptom severity score than the sham diet (P = 0.024). The reduction in severity score was 26% in fully compliant patients (P < 0.001 vs sham diet). Following reintroduction of foods in both groups, more patients in the elimination diet group showed worsening of global rating compared with the sham diet group (P = 0.047). Further controlled studies are needed to confirm these provocative findings that evaluate the role of specific serum IgG in the diagnosis and treatment of IBS patients.

Food Intolerance In IBS

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

A recent population-based study, using a valid self-report questionnaire, reported that IBS symptoms are associated with reporting of many ‘food allergies’, which could not be discriminated from food intolerance.103 The next section critically appraises the studies of adverse food reactions in IBS.

Elimination diets and food challenge in IBS

Eight studies investigated the effect of dietary exclusion followed by food challenge (Table 1).13,75–80,85 In 1982, Jones et al. evaluated the role of specific foods in induction of symptoms of IBS patients.75 A study of 25 consecutive IBS patients tested the effect of a 1-week elimination diet composed of a single meat, a single fruit and distilled or spring water, followed by open challenge with the suspected single food. Two-thirds (14/21) of patients discovered that their symptoms cleared and recurred on food challenge. The foodstuffs commonly implicated were wheat, corn, dairy products, coffee, tea and citrus fruits. Six of the 14 patients were then randomized in a double-blind, challenge study which confirmed food-related symptoms. Mechanistically, rectal PGE2 levels were increased after administration of food. However, other markers for immune activation were not altered, arguing against an immunological cause for these intolerances. Bentley et al. studied 27 patients with IBS.76 Food hypersensitivity was confirmed in three of the 27 patients, and these three patients were atopic. In a separate study of 49 patients suspected of having specific food intolerance, only three proved to have specific food intolerance on double-blind challenge.77 Intolerance is often suspected, but is verifiable only in a minority of such patients. McKee et al. studied 40 patients with IBS; 15% showed evidence of food intolerance. Some patients with diarrhoea-predominant or alternating bowel habit responded to an exclusion diet. In contrast, the constipation-predominant IBS group consistently failed to improve.79 Although serum IgG antibody seems not to be a reliable indicator of food hypersensitivity in IBS,80 a recent controlled study demonstrated that food elimination based on IgG antibodies may be effective in reducing symptoms in IBS patients who had elevated serum IgG to specific food antigens.85 The Oxford, UK group followed for more than 1 year 73 IBS patients who were able to identify individual food intolerance during open challenges. All but one patient had prolonged benefit after exclusion diet.13

In summary, several studies have demonstrated 15–71% response rates to exclusion diets in IBS patients.104 The wide range of response rate can be attributed to the lack of standardized protocols, which may impact on the validity of studies. Double-blind, placebo-controlled challenges identified problem foods in 6–58% of cases, with milk, wheat and eggs being the most commonly implicated foods.75–77 It is important to note that lactose intolerance and celiac disease could be the cause of symptoms because they were not excluded in these studies. Diarrhoea-predominant IBS patients had a higher symptomatic response rate compared to other subgroups.75–77 The symptomatic improvement was shown to persist even at 1-year follow-up.13 However, all studies had major limitations in trial design including inadequate patient selection, poor compliance, duration and appropriateness of exclusion diets and methods of food challenge. These limitations, as well as the potential for macro- and micronutrient deficiencies resulting from elimination diets also may limit their usefulness in IBS patients.

Disodium cromoglycate trials in IBS

Disodium cromoglycate inhibits the release of inflammatory mediators such as histamine, leukotrienes and slow reacting substance of anaphylaxis by inhibiting degranulation of mast cells following contact with an allergen in rats or humans.105,106 Disodium cromoglycate has been used successfully in atopic patients with suspected food-induced exacerbation of symptoms.107–109 In 20 patients with persistent diarrhoea, DSCG was assessed in a double-blinded, placebo-controlled, cross-over design; eight of 20 patients receiving DSCG noted significant improvement in diarrhoea whereas no patients receiving placebo showed significant improvement in diarrhoea.83 In a small double-blind, placebo-controlled study, oral DSCG seemed to be a useful treatment in patients with IBS and proven food intolerance.84 Two uncontrolled, unblinded studies have evaluated the effect of oral cromolyn sodium in patients with IBS.81,82 Stefanini et al. conducted an 8-week trial of oral DSCG, which resulted in significant symptomatic improvement in diarrhoea-predominant IBS patients.81 In a multicentre trial of 428 diarrhoea-predominant IBS patients, 1-month trials of oral DSCG or elimination diet were shown to be equally effective, odds ratio for improvement was 0.7 (95% CI for odds ratio: 0.6–3.5).82

These data suggest that DSCG may be effective in a subgroup of IBS patients, and a positive response to DSCG may help select patients who are likely to benefit from dietary manipulation. However, two early studies included small numbers of patients and the others were not randomized controlled studies. Thus, further controlled studies with long-term follow-up in IBS patients are needed to confirm the beneficial effects of DSCG and to identify characteristics of the IBS patients who are likely to improve.

Proposed Management Algorithm For Food Allergy In IBS

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

From the above review, it appears that food allergy may be associated with development of symptoms in a subgroup of IBS patients who have a history of exacerbation of symptoms on ingesting specific foods or atopy. Assessment of food allergy includes a combination of skin prick test and food specific serum IgE and IgG4 antibodies, which may be useful in isolating the causative food antigen. Exclusion diet based on these tests or a hypoallergenic diet with sequential reintroduction of individual foodstuffs can be used in such IBS patients, but this approach is time-consuming and associated with low compliance, and the development of macro- and micronutrient deficiencies may limit their application in clinical practice.

Zar et al. recently proposed an algorithm for diagnosing and treating food allergy in IBS patients including experimental therapies such as hypoallergenic diet, DSCG or other approaches (Fig. 1).110 While this algorithm appears reasonable, based on the published evidence reviewed above, it is still necessary to demonstrate its effectiveness in practice.

image

Figure 1.  Proposed algorithm for managing food hypersensitivity-induced IBS (adapted from Ref. 110). BE, barium enema; SPT, skin prick test; COLAP, colonoscopic allergen provocation test; H/O, history of; DSCG, disodium cromoglycate

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Conclusions

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References

The pathogenesis of functional bowel disorders remains unclear. Food allergy may be one of the factors contributing to the development of these disorders. There have been no controlled studies on the role of food allergy in FD, and further epidemiological studies (only one published to date) are needed to clarify whether food allergy is related to FD.

Food allergy or intolerance is associated with failure of tolerance mechanisms. The gastrointestinal mucosal immune system may be activated in association with the development of symptoms in a subgroup of IBS patients. Such activation can result from gastrointestinal infections, microbial flora and food antigens. The mechanism by which food activates the mucosal immune system in IBS patients is not known, but an immunologically based reaction has been postulated. Food specific IgE and IgG antibodies can mediate hypersensitivity reactions in IBS patients,111 sensitizing the mucosal mast cells, which in turn secrete several chemical messengers (e.g. transmitters, cytokines) capable of mediating sensorimotor dysfunction of the bowel. Clinical trials with exclusion diets based on immunologic tests, hypoallergic diets or DSCG suggest that they have potential in reducing symptoms in the subgroup of IBS patients who have a clear history of adverse food reactions. Further well designed studies are needed to clarify the mechanisms of food-induced activation of the gut mucosal immune system in IBS, how food intolerance or allergy induces neuroenteric effector systems, and how to identify the subgroup of IBS patients in whom it is beneficial and cost-effective to evaluate and treat for food allergy.

References

  1. Top of page
  2. Abstract
  3. Introduction: Definition
  4. Methodology Of Systematic Review
  5. Epidemiology
  6. Pathophysiology Of Food Allergy In Adults
  7. Diagnosis Of Food Allergy In Adults
  8. Role Of Food Allergy In Functional Dyspepsia
  9. Role Of Food Allergy In IBS
  10. Relationship Of Food Allergy, Immune Hypersensitivity And IBS
  11. Food Intolerance In IBS
  12. Proposed Management Algorithm For Food Allergy In IBS
  13. Conclusions
  14. Acknowledgments
  15. References
  • 1
    Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2003; 98: 4129.
  • 2
    O'Mahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128: 54151.
  • 3
    Cooke RA, Van der Veer A. Human sensitization. J immunol 1916; 1: 201305.
  • 4
    Loveless MH. Milk allergy: a survey of its incidence: experience with masked ingestion test. J Allergy 1950; 21: 489.
  • 5
    Graham DT, Wolf S, Wolf HG. Changes in tissue sensitivity associated with varying life situations and emotions: their relevance to allergy. J Allergy 1950; 21: 478.
  • 6
    Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 7
    Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 1987; 79: 6838.
  • 8
    Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113: 80519.
  • 9
    Bruijnzeel-Koomen C, Ortolani C, Aas K et al. Adverse reactions to food. Allergy 1995; 50: 62335.
  • 10
    Shanahan F. Food allergy: fact, fiction, and fatality. Gastroenterology 1993; 104: 122931.
  • 11
    Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R. A population study of food intolerance. Lancet 1994; 343: 112730.
  • 12
    Bischoff SC, Herrmann A, Manns MP. Prevalence of adverse reactions to food in patients with gastrointestinal disease. Allergy 1996; 51: 8118.
  • 13
    Nanda R, James R, Smith H, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut 1989; 30: 1099104.
  • 14
    Dainese R, Ce Galliani EA, Lazzari F, Di Leo V, Naccarato R. Discrepancies between reported food intolerance and sensitization test findings in irritable bowel syndrome patients. Am J Gastroenterol 1999; 94: 18927.
    Direct Link:
  • 15
    Bischoff S, Crowe SE. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology 2005; 128: 1089113.
  • 16
    Ciprandi G, Canonica GW. Incidence of digestive diseases in patients with adverse reactions to foods. Ann Allergy 1988; 61: 3346.
  • 17
    Haderstorfer B, Psycholgin D, Whitehead WE, Schuster MM. Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome. Am J Gastroenterol 1989; 84: 3758.
  • 18
    Tolliver BA, Jackson MS, Jackson KL, Barnett ED, Chastang JF, DiPalma JA. Does lactose maldigestion really play a role in the irritable bowel syndrome? J Clin Gastroenterol 1996; 23: 157.
  • 19
    Johannson SG, Dannaeus A, Lilja G. The relevance of antifood antibodies for the diagnosis of food allergy. Ann Allergy 1984; 53: 66570.
  • 20
    Untersmayr E, Scholl I, Swoboda I et al. Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice. J Allergy Clin Immunol 2003; 112: 61623.
  • 21
    Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005; 307: 19205.
  • 22
    Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev immunol 2003; 3: 71020.
  • 23
    Podolsky D. Mucosal immunity and inflammation. Innate mechanisms of mucosal defense and repair: the best offence is a good defense. Am J Physiol 1999; 277: G495G499.
  • 24
    Jackson PG, Lessof MH, Baker RW, Ferrett J, MacDonald DM. Intestinal permeability in patients with eczema and food allergy. Lancet 1981; 13: 12856.
  • 25
    Andre C. Food allergy. Objective diagnosis and test of therapeutic efficacy by measuring intestinal permeability. Presse Med 1986; 25: 1058.
  • 26
    Heyman M, Grasset E, Ducroc R, Desjeux JF. Antigen absorption by the jejunal epithelium of children with cow's milk allergy. Pediatr Res 1988; 24: 197202.
  • 27
    Tatsuno K. Intestinal permeability in children with food allergy. Arerugi 1989; 38: 13118.
  • 28
    Laudat A, Arnaud P, Napoly A, Brion F. The intestinal permeability test applied to the diagnosis of food allergy in paediatrics. West Ind Med J 1994; 43: 878.
  • 29
    Kohout P, Ettlerova K, Bratova M, Zadak Z. Intestinal permeability in patients with food allergy. Vnitr Lek 1998; 44: 2635.
  • 30
    Husby S, Forged N, Host A, Svehag SE. Passage of dietary antigens into the blood of children with celiac disease: quantification and size distribution of absorbed antigens. Gut 1987; 28: 106272.
  • 31
    Reinhardt MC. Macromolecular absorption of food antigens in health and disease. Ann Allergy 1984; 53: 597601.
  • 32
    Chase MW. Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol 1946; 61: 257259.
  • 33
    Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol 2005; 115: 312.
  • 34
    Zeiger R. Breast-feeding and dietary avoidance. In: De WeckA, SampsonH, eds. Intestinal Immunology and Food Allergy, New York: Raven Press, 1995: 20322.
  • 35
    Jarvinen KM, Suomalainen H. Development of cow's milk allergy in breast-fed infants. Clin Exp Allergy 2001; 31: 97887.
  • 36
    Kaplan MS, Solli NJ. Immunoglobulin E to cow's-milk protein in breast-fed atopic children. J Allergy Clin Immunol 1979; 64: 1226.
  • 37
    Taylor B, Wadsworth J, Golding J, Butler N. Breast feeding, eczema, asthma, and hayfever. J Epidemiol Community Health 1983; 37: 959.
  • 38
    Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997; 159: 173945.
  • 39
    Bischoff S, Crowe SE. Food allergy and the gastrointestinal tract. Curr Opin Gastroenterol 2004; 20: 15661.
  • 40
    Steinke JW, Borish L, Rosenwasser LJ. Genetics of hypersensitivity. J Allergy Clin Immunol 2003; 111: S495S501.
  • 41
    Howard TD, Meyers DA, Bleecker ER. Mapping susceptibility genes for allergic diseases. Chest 2003; 123: 363S368S.
  • 42
    Breiteneder H, Ebner C. Molecular and biochemical classification of plant-derived food allergens. J Allergy Clin Immunol 2001; 31: 10315.
  • 43
    Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999; 103: 71728.
  • 44
    Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002; 97: 111326.
    Direct Link:
  • 45
    Di Stefano M, Miceli E, Malservisi S, Missanelli A, Strocchi A, Corazza GR. Mixing of the intestinal content and variations of fermentation capacity do not affect the results of hydrogen breath test. Am J Gastroenterol 2003; 98: 15847.
  • 46
    Bruijnzeel-Koomen C, Ortolani C, Aas K et al. Adverse reactions to food. European Academy of Allergology and Clinical Immunology Subcommittee. Allergy 1995; 50: 62335.
  • 47
    Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. American Gastroenterological Association. Gastroenterology 2001; 120: 102640.
  • 48
    Sicherer SH. Food allergy. Lancet 2002; 360: 70110.
  • 49
    Bischoff SC, Mayer JH, Manns MP. Allergy and gut. Int Arch Allergy Immunol 2000; 121: 27083.
  • 50
    Bischoff SC, Mayer J, Wedemeyer J et al. Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. Gut 1997; 40: 74553.
  • 51
    Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GN. Functional gastroduodenal disorders. Gut 1999; 45: II37II42.
  • 52
    Read NW. Food and hypersensitivity in functional dyspepsia. Gut 2002; 51 (Suppl. 1): i503.
  • 53
    Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther 2004; 20 (Suppl. 2): 19.
  • 54
    Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology 2003; 124: 166271.
  • 55
    Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med 1962; 31: 30722.
  • 56
    McKendrick MW, Read NW. Irritable bowel syndrome–post salmonella infection. J Infect 1994; 29: 13.
  • 57
    Gwee KA, Graham JC, McKendrick MW et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347: 1503.
  • 58
    Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ 1997; 314: 77982.
  • 59
    Gwee KA, Leong YL, Graham C et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999; 44: 4006.
  • 60
    Rodriguez LA, Ruigomez A. Increased risk of irritable bowel syndrome after bacterial gastroenteritis: cohort study. BMJ 1999; 318: 5656.
  • 61
    Parry SD, Stansfield R, Jelley D et al. Does bacterial gastroenteritis predispose people to functional gastrointestinal disorders? A prospective, community-based, case-control study. Am J Gastroenterol 2003; 98: 19705.
  • 62
    Ji S, Park H, Lee D, Song YK, Choi JP, Lee SI. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol 2005; 20: 3816.
  • 63
    Ilnyckyj A, Balachandra B, Elliott L, Choudhri S, Duerksen DR. Post-traveler's diarrhoea irritable bowel syndrome: a prospective study. Am J Gastroenterol 2003; 98: 5969.
    Direct Link:
  • 64
    Hiatt RB, Katz L. Mast cells in inflammatory conditions of the gastrointestinal tract. Am J Gastroenterol 1962; 37: 5415.
  • 65
    Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig Dis Sci 1993; 38: 15905.
  • 66
    O'Sullivan M, Clayton N, Breslin NP et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000; 12: 44957.
  • 67
    Barbara G, Stanghellini V, De Giorgio R et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126: 693702.
  • 68
    O'Sullivan MA, Clayton N, Wong T, Bountra C, Buckley MM, O'Morain CA. Increased inos and nitrotyrosine expression in irritable bowel syndrome (IBS). Gastroenterology 2000; 118: A702.
  • 69
    Tornblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 2002; 123: 19729.
  • 70
    Spiller RC, Jenkins D, Thornley JP et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000; 47: 80411.
  • 71
    Chadwick VS, Chen W, Shu D et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002; 122: 177883.
  • 72
    Liu S, Hu HZ, Gao N et al. Neuroimmune interactions in guinea pig stomach and small intestine. Am J Physiol Gastrointest Liver Physiol 2003; 284: G15464.
  • 73
    Schemann M, Michel K, Ceregrzyn M, Zeller F, Seidl S, Bischoff SC. Human mast cell mediator cocktail excites neurons in human and guinea-pig enteric nervous system. Neurogastroenterol Motil 2005; 17: 2819.
  • 74
    Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science 2005; 25: 19205.
  • 75
    Jones VA, McLaughlan P, Shorthouse M, Workman E, Hunter JO. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982; 2: 11157.
  • 76
    Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel syndrome. Lancet 1983; 2: 2957.
  • 77
    Farah DA, Calder I, Benson L, MacKenzie JF. Specific food intolerance: its place as a cause of gastrointestinal symptoms. Gut 1985; 26: 1648.
  • 78
    Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food. Ann Allergy 1985; 54: 53840.
  • 79
    McKee AM, Prior A, Whorwell PJ. Exclusion diets in irritable bowel syndrome: are they worthwhile? J Clin Gastroenterol 1987; 9: 5268.
  • 80
    Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food hypersensitivity. Ann Allergy 1988; 61: 479.
  • 81
    Stefanini GF, Prati E, Albini MC et al. Oral disodium cromoglycate treatment on irritable bowel syndrome: an open study on 101 subjects with diarrheic type. Am J Gastroenterol 1992; 87: 557.
  • 82
    Stefanini GF, Saggioro A, Alvisi V et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol 1995; 30: 53541.
  • 83
    Bolin TD. Use of oral sodium cromoglycate in persistent diarrhoea. Gut 1980; 21: 84850.
  • 84
    Lunardi C, Bambara LM, Biasi D et al. Double-blind cross-over trial of oral sodium cromoglycate in patients with irritable bowel syndrome due to food intolerance. Clin Exp Allergy 1991; 21: 56972.
  • 85
    Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 145964.
  • 86
    Stefanini GF, Bazzocchi G, Prati E, Lanfranchi GA, Gasbarrini G. Efficacy of oral disodium cromoglycate in patients with irritable bowel syndrome and positive skin prick tests to foods. Lancet 1986; 1: 2078.
  • 87
    White AM, Stevens WH, Upton AR, O'Byrne PM, Collins SM. Airway responsiveness to inhaled methacholine in patients with irritable bowel syndrome. Gastroenterology 1991; 100: 6874.
  • 88
    Roussos A, Koursarakos P, Patsopoulos D, Gerogianni I, Philippou N. Increased prevalence of irritable bowel syndrome in patients with bronchial asthma. Respir Med 2003; 97: 759.
  • 89
    Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity: basic mechanisms of pathophysiology. Gastroenterology 1992; 103: 107595.
  • 90
    Barau E, Dupont C. Modifications of intestinal permeability during food provocation procedures in pediatric irritable bowel syndrome. J Pediatr Gastroenterol Nutr 1990; 11: 727.
  • 91
    Andre F, Andre C, Colin L, Cavagna S. IgE in stools as indicator of food sensitization. Allergy 1995; 50: 32833.
  • 92
    Bischoff SC, Mayer J, Meier PN, Zeck-Kapp G, Manns MP. Clinical significance of the colonoscopic allergen provocation test. Int Arch Allergy Immunol 1997; 113: 34851.
  • 93
    Merrett J, Burr ML, Merrett TG. A community survey of IgG4 antibody levels. Clin Allergy 1983; 13: 397407.
  • 94
    Barnes RM, Barton PG, Doig JE, Finn R, Harvey MM, Johnson PM. Distribution of serum antibodies to wheat gliadin and bovine milk in atopic and non-atopic healthy adults. J Clin Lab Immunol 1983; 12: 1758.
  • 95
    Husby S, Oxelius VA, Teisner B, Jensenius JC, Svehag SE. Humoral immunity to dietary antigens in healthy adults. Occurrence, isotype and IgG subclass distribution of serum antibodies to protein antigens. Int Arch Allergy Appl Immunol 1985; 77: 41622.
  • 96
    Johansson SG, Dannaeus A, Lilja G. The relevance of anti-food antibodies for the diagnosis of food allergy. Ann Allergy 1984; 53: 66572.
  • 97
    Finn R, Smith MA, Youngs GR, Chew D, Johnson PM, Barnes RM. Immunological hypersensitivity to environmental antigens in the irritable bowel syndrome. Br J Clin Pract 1987; 41: 10413.
  • 98
    El Rafei A, Peters SM, Harris N, Bellanti JA. Diagnostic value of IgG4 measurements in patients with food allergy. Ann Allergy 1989; 62: 949.
  • 99
    Miyamoto T, Koya N, Suzuki S et al. Clinical significance of specific IgG4 antibody in serum. Arerugi 1991; 40: 21523.
  • 100
    Zar S, Benson MJ, Kumar D. Serum IgG4 antibodies to common food antigens are elevated in irritable bowel syndrome. Gut 2002; 50 (Suppl. 11): A25.
  • 101
    Nakagawa T, De Weck AL. Membrane receptors for the IgG4 subclass on human basophils and mast cells. Clin Rev Allergy 1983; 1: 197206.
  • 102
    Nakagawa T, Okano Y, Iwasaki E et al. Clinical significance of IgG4 antibody determination in children against egg white, milk, soybean and Dermatophagoides farinae. Arerugi 1992; 41: 1694704.
  • 103
    Locke GR III, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ. Risk factors for irritable bowel syndrome: role of analgesics and food sensitivities. Am J Gastroenterol 2000; 95: 15765.
    Direct Link:
  • 104
    Niec AM, Frankum B, Talley NJ. Are adverse food reactions linked to irritable bowel syndrome? Am J Gastroenterol 1998; 93: 218490.
    Direct Link:
  • 105
    Shin HY, Kim JS, An NH, Park RK, Kim HM. Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions. Life Sci 2004; 74: 287787.
  • 106
    Okayama Y, Benyon RC, Rees PH, Lowman MA, Hillier K, Church MK. Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine. Clin Exp Allergy 1992; 22: 4019.
  • 107
    Brostoff J, Carini C, Wraith DG, Johns P. Production of IgE complexes by allergen challenge in atopic patients and the effect of sodium cromoglycate. Lancet 1979; 1: 126870.
  • 108
    Ortolani C, Pastorello E, Zanussi C. Prophylaxis of adverse reactions to foods. A double-blind study of oral sodium cromoglycate for the prophylaxis of adverse reactions to foods and additives. Ann Allergy 1983; 50: 1059.
  • 109
    Businco L, Benincori N, Nini G, Businco E, Cantani A, De Angelis M. Double-blind crossover trial with oral sodium cromoglycate in children with atopic dermatitis due to food allergy. Ann Allergy 1986; 57: 4338.
  • 110
    Zar S, Kumar D, Kumar D. Role of food hypersensitivity in irritable bowel syndrome. Minerva Med 2002; 93: 40312.
  • 111
    Woolhiser MR, Brockow K, Metcalfe DD. Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a. Clin Immunol 2004; 110: 17280.