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Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder. IBS is likely to be a multifactorial condition resulting from a number of different mechanisms such as disordered motility, visceral hypersensitivity, abnormal central processing, psychological factors, genetic factors, gut inflammation, and dietary factors. Many patients with IBS give a history of adverse food reactions, but the foods identified to be relevant have been highly variable. Food hypersensitivity can be mediated by immunoglobulin E–dependent and –independent mechanisms involving mast cells, eosinophils, and other immune cells. Recent clinical and experimental studies suggest that there is a possible role for food hypersensitivity in IBS, with improvement of IBS symptom severity in a subset of patients on elimination diets, but the underlying mechanisms in IBS have yet to be fully understood. This review considers the evidence for the role of food hypersensitivity in IBS, based on the available epidemiologic and pathophysiologic data, and the clinical implications.
Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder, affecting 10–20% of the adults in the United States.1 However, the pathophysiology of IBS remains poorly understood, although it is likely to be a multifactorial condition involving a number of different mechanisms such as disturbed motility, visceral sensitivity, central processing, genetic factors, psychological factors, and inflammation.2-5 Adverse food reaction may also play an important role in IBS, as up to 65% patients with IBS report that their symptoms are related to specific foods.6,7 To evaluate the role of adverse food reactions in IBS is difficult, but there is now increasing interest because dietary elimination and rechallenge studies suggest that symptom response in a subgroup with IBS may depend on immunoglobulin (Ig) status.8-10
The aim of this article is to review the evidence of a role of food hypersensitivity in IBS; we will focus on epidemiologic and pathophysiologic data of clinical relevance to examine this issue.
Adverse food reactions include any abnormal responses to food, and are further classified as food intolerance or food hypersensitivity/allergy.11 The term food intolerance encompasses nonimmunologically mediated adverse reactions to food, which resolve following dietary elimination and are reproduced by food challenge. This includes the direct effects of pharmacologically active constituents of foodstuffs (eg, tyramine in cheese or caffeine in coffee) and enzyme deficiencies (eg, lactose and fructose intolerance). Food allergy/hypersensitivity is used to describe conditions in which an immunological mechanism (IgE-or non–IgE-mediated) may be demonstrable (eg, cow’s milk, peanut, or soybean allergy).12,13
Although the prevalence of perceived adverse food reactions is high, with up to 20% of the general population reporting skin allergy, asthma, intestinal symptoms, headaches, and behavioral changes related to foods, the actual prevalence of true food hypersensitivity or intolerance is estimated to be 5% in the general population.14-16 The prevalence of food hypersensitivities is greatest in the first few years of life, affecting about 6% of infants less than 3 years of age in the United States, but decreases with age.15 The perception of food hypersensitivity in IBS seems to be higher than in the general population, with 20–65% of IBS patients attributing their symptoms to food hypersensitivity. 7,17,18 In fact, patients with IBS often report that specific foods aggravate their symptoms.19 However, there are discrepancies between perceived food hypersensitivity or food intolerance and actual food allergies in patients with IBS. Dainese and colleagues20 reported that more than 50% of IBS patients were found sensitized to some food or inhalant by skin prick test without any typical clinical signs, but patients were unable to identify potentially offending foods.
Food allergy represents an abnormal response of the mucosal immune system to antigens delivered through the oral route. The gastrointestinal mucosal barrier is a complex physical (mucus, epithelial cell tight junctions, acid, and enzymes) and immunologic (natural killer cells, polymorphonuclear leukocytes, macrophages, epithelial cells, toll-like receptors, lymphocytes, Peyer patches, secretory IgA, and cytokines) structure. Despite the complex mucosal barrier, about 2% of ingested food antigens are absorbed and transported throughout the normal mature gut wall.21,22 Even though intact foreign food antigens routinely penetrate the gastrointestinal tract, they infrequently induce clinical symptoms because of the development of oral tolerance to dietary proteins in most individuals.23 Recent studies suggested that antigen-presenting cells, especially intestinal epithelial cells and dendritic cells, and regulatory T cells play a central role in oral tolerance.24,25 However, the underlying immunologic mechanisms involved in oral tolerance induction are not fully understood.
A large epidemiologic study has identified infectious gastroenteritis as the most significant environmental risk factor for the development of IBS,26 suggesting that previous infection and persistent low-grade inflammation may play an important role in the pathogenesis of functional gut diseases. This may be because of impairment of the complex immune response of the gastrointestinal mucosa, which results in a breakdown of oral tolerance.
In 1982, Jones and colleagues27 demonstrated a symptomatic response to a 1-week elimination diet in IBS patients. Since then, several studies have reproduced these findings, demonstrating a benefit from exclusion diets in up to two thirds of IBS patients, with the diarrhea-predominant subgroup showing the highest response rate.20,28,29 Niec and coworkers19 performed a systematic review of clinical trials that used dietary exclusion followed by food challenge. Milk, wheat, and eggs were most frequently identified to cause symptom exacerbation, and a possible common factor was salicylate or amine content. However, all studies had methodologic limitations, including inadequate patient selection, appropriateness of and duration of exclusion diets, and methods of food challenge. Double-blind placebo-controlled trials of exclusion diets are considered the gold standard, but they are technically difficult to perform. Most of the studies have used an open dietary elimination and challenge design, and thus could not exclude the role of psychological factors or placebo response.
Food allergy can involve many different organ systems including the oral cavity, digestive tract, skin, and respiratory tract.30-33 Whereas dermatologic, respiratory, and systemic manifestations of food allergy are well recognized, those reactions manifesting primarily in the digestive tract can be difficult to recognize, diagnose, and treat.
Food allergy can be categorized into IgE-dependent (type I or immediate) and IgE-independent (delayed or cell-mediated) immune reactions. An immune-mediated food hypersensitivity response has been suggested as the underlying mechanism in a proportion of patients with IBS.18,28,29
Acute-phase IgE-mediated food allergic reactions typically start within minutes to 1 hour, and may affect the skin (urticaria, angioedema, flushing, pruritus), the respiratory tract (sneezing, rhinorrhea, congestion, cough, wheezing, difficulty breathing), and the gastrointestinal tract (nausea, vomiting, diarrhea, cramping, abdominal pain).34-36 This acute phase causes activation of mast cells and basophils with release of histamine, leukotrienes, and other mediators known to be responsible for a number of effects in the gastrointestinal tract.37 However, there is little evidence of a relationship between acute-phase IgE-mediated food allergy and symptoms in IBS.
Delayed reactions following immediate IgE-mediated hypersensitivity start within 2–24 hours after allergen challenge and are characterized by a cellular infiltration of the tissue with granulocytes (basophils, eosinophils) and lymphocytes (mainly Th2 cells).38,39 These immune reactions to food antigens are believed to play a role in milk and soy protein enteropathies and celiac disease.40
Several studies have tried to establish a relationship between IgE level and food allergy in IBS using total serum IgE, food-specific IgE (radioallergosorbent test [RAST]), and IgE-mediated skin prick as markers of food hypersensitivity.41,42 Petitpierre and associates evaluated total serum IgE titers in 12 atopic and 12 nonatopic patients with IBS who were defined by a personal and family history, atopic symptoms, positive immediate skin test, and RAST.29 All patients were given an exclusion diet for 3 weeks with subsequent food provocation. The level of serum IgE was elevated in 9 of 12 atopic and 0 of 12 nonatopic subjects; 14 out of 24 specific offending foods were found and confirmed by blind challenges. Barau and colleagues46 observed enhanced intestinal permeability induced by food ingestion in 9 of 17 children with symptoms of IBS with a personal and/or family history of allergy and/or raised total IgE. These studies suggest that IgE-mediated food allergies may be important in the subgroup of patients with atopy, although food allergy is unlikely to explain symptoms in most patients with IBS. Other uncontrolled studies have reported that the efficacy of oral disodium cromoglycate treatment was almost as good as diet restriction in IBS patients with diarrheal symptoms and a positive prick test for certain foods.44,45
A number of investigators have performed the gastrointestinal equivalent of skin testing for assessing mucosal evidence of food hypersensitivity. The technique involves injecting the gastrointestinal mucosa (gastric, duodenal, or colon) with a panel of antigens and looking endoscopically for a wheal-and-flare response.46,47 Bischoff and associates46 reported a positive colonoscopic allergen provocation test in 54 of 70 patients with abdominal symptoms suspected to be related to food allergy, whereas no reaction in response to antigen was found in 5 healthy volunteers. This positive reaction was correlated with intestinal mast cell and eosinophil activation, as well as with the patient’s history of adverse reactions to food, but not with serum concentrations of total or specific IgE or with skin test results.
IgG antibodies to food are detectable in healthy individuals, although usually at rather low levels. Furthermore, studies in healthy children have demonstrated high levels of IgG antibody to milk and egg in the early years of life, which gradually diminish with increasing age.48,49 Although IgG food antibodies are often a normal finding and can vary with age, raised titers of IgG are seen in patients with asthma, hay fever, eczema and atopic dermatitis50,54; IgG4 antibodies levels were higher than normal in patients with eczema and/or asthma.52-54 However, the results of exclusion diets based on IgG food antibodies in food-related disorders have been contradictory.55,56
In a recent, randomized controlled trial, Atkinson and associates8 assessed the therapeutic potential of an elimination diet based on the presence of IgG antibodies to food in patients with IBS. One-hundred-fifty outpatients with IBS were randomized to receive either a diet excluding all foods to which they had elevated IgG antibodies, or a sham diet excluding the same number of foods but not those to which they had antibodies. After 12 weeks, the true diet resulted in a 10–26% greater reduction in symptom score than the sham diet, and this was related to compliance (Figure 1). Global rating scores of symptom relief also significantly improved in the true diet group. On the reintroduction phase of eliminated foods, a significantly greater deterioration was observed in subjects in the true diet group compared with those in the sham group. However, this study had some limitations, including a small effect of the true diet compared to the sham diet, exclusion of significantly different foods, and use of only a symptom assessment to determine the efficacy of the dietary interventions.
Zar and colleagues9,10 also demonstrated that patients with IBS have elevated food-specific IgG4 antibodies to common food antigens. They tested the response to an exclusion diet based on elevated food-specific IgG4 antibodies in 25 patients with IBS for 6 months; symptom assessment and rectal compliance and sensitivity were measured with a barostat. At 3 months, a significant improvement was seen in IBS symptoms, namely pain severity, pain frequency, bloating severity, and satisfaction with bowel habits; this improvement was maintained at the 6-month follow-up for all parameters. Moreover, symptom improvement was associated with changes in objective physiologic data (ie, an increase in rectal compliance as measured by barostat). Limitations included the small sample size and lack of a control group. The authors suggested that serum IgG4 antibody testing may provide an objective and rapid method for selecting an exclusion diet when treating IBS patients. However, IgG4 production may represent a physiologic response of the gut immune system to dietary antigen challenge.57,58 Transient alterations in the permeability of gut mucosa from any insult might theoretically increase the antigenic load presented to the mucosal immune system. An increased IgG4 antibody response may thus be a secondary phenomenon and represent a normal physiologic rather than a pathologic response of the gut immune system. Therefore, further well-controlled double-blind exclusion diet studies based on IgG and IgG subclass are warranted.
The limited understanding of the relevance of food intolerance or allergy in IBS has resulted in a lack of diagnostic or therapeutic options in terms of dietary manipulation for the condition. To try to identify offending food antigens, some studies have evaluated skin prick tests and foods-specific serum IgE and IgG antibodies,8,29,43,44 but the data are not sufficient to change management in IBS. After skin prick tests, introduction of elimination diets or disodium cromoglycate has been reported to improve symptoms in IBS, but the data remain inconclusive.44,59 It is too soon to routinely recommend serum IgE or IgG testing for food hypersensitivity followed by an elimination diet in IBS, as there is not enough evidence or experience.
IBS is a common disorder of the gastrointestinal tract and causes significant morbidity as well as consuming substantial healthcare resources. Patients with IBS frequently complain about an exacerbation of symptoms after food ingestion. This association could be explained by an exaggerated gastrocolonic response, abnormal eating behavior, or psychologic distress rather than food allergy or intolerance. Nevertheless, recent dietary elimination and food challenge studies have demonstrated an improvement in IBS symptomatology in a subgroup with IBS and suggest diet has a role in the pathogenesis.60 The mechanisms by which food may mediate pathophysiologic alterations in IBS remain to be elucidated (Figure 2). Further work into the underlying mechanisms is warranted before management change can be justified.