Hot Topic in Allergy: Allergy and Irritable Bowel Syndrome

Mast cells (MC) release potent mediators which alter enteric nerve and smooth muscle function and may play a role in the pathogenesis of the irritable bowel syndrome (IBS). Mast cell volume density was significantly higher in IBS than normal controls in the caecum but not at other sites. Apart from MC, there was no evidence of increased cellular infiltrate in the IBS group. MC were significantly increased in the caecum of IBS patients compared to controls. The multiple effects of the intestinal mast cell alone, or as a participant of a persistent inflammatory response, may be fundamental to the pathogenesis of IBS.

Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder – that is the presence of symptoms in the absence of demonstrable pathological abnormalities. The notion of food allergy in irritable bowel syndrome (IBS) resurfaces in scientific thinking in this issue of Gut on the basis of a solid randomised placebo controlled trial conducted by Atkinson and colleagues. Determination of serum IgG antibodies against foods was used to guide the construction of elimination diets.
The presence of specific IgG class antibodies is often accepted as uncommitted or protective “altered reactivity”, unlike those of the IgE class. Detection of antigen specific IgE is invariably taken as an attribute of causality, a condition called “IgE mediated disease” and, more specifically, of “allergy”.

IBS appears to result from an interplay between susceptibility genes and impaired gut barrier functions, immunological dysregulation, together with bacterial and viral infections and other environmental factors

Empirical data are accumulating to suggest that transient increases in antigen specific IgE antibodies prevail in most healthy asymptomatic children during the first five years of life. Generation of these antibodies (sensitisation) on antigen exposure may not necessarily induce clinical disease especially atopic disease. Reducing the risk of atopic disease does not necessitate reduction of sensitisation6–8 and, finally, resolution or aggravation of clinical disease is not invariably associated with a corresponding alteration in antibody concentration. Bearing these limitations in mind, however, the clinician may successfully profit from determination of specific IgE to complete the clinical history in an attempt to identify potential offending antigens in a symptomatic patient’s diet for the explicit diagnostic elimination-challenge procedure.9 This is precisely what Atkinson et al did, with specific IgG antibodies.

Low grade inflammatory infiltrates in both the small and large bowel of some patients with IBS – often rich in mast cells, along with serological markers of low grade inflammation have focussed attention on IBS as an inflammatory disease. The observation that mast cells often lie in close association to enteric neurons, and in-vitro and in-vivo animal studies demonstrating that mast cell mediators may influence enteric motility provides a biologically plausible causal mechanism in IBS. Pilot studies on patients with IBS using the mast cell stabiliser sodium cromoglycate (‘proof of concept’) have been encouraging. The essential question remains why mast cells infiltrate the bowel of IBS patients.

The function of mast cells in allergic inflammatory reactions is well documented in the literature. Mast cells also play an important role in the regulation of gastrointestinal visceral sensitivity and vascular permeability. Several studies have noted an increased number of mast cells in the mucosa of patients with gastrointestinal diseases such as irritable bowel syndrome, mastocytic enterocolitis, and systemic mastocytosis. The role of mast cells in the symptomatology of these and other diseases has only recently been fully appreciated and could provide avenues for new therapeutic opportunities. T

A disturbance of the ‘brain-gut axis’ is the current favoured hypothesis, whereby childhood stress or psychiatric comorbidity act via neuro-immune mechanisms to modulate low grade inflammation. An alternative hypothesis is that food allergy may be responsible. Serum specific IgE, and skin prick tests are not elevated in IBS patients, suggesting type 1 IgE mediated food allergy is not the cause. However questionnaire based studies indicate IBS patients have higher rates of atopic disease, and increased bronchial reactivity to methacholine has been demonstrated. The potential role of mast cells in IBS, and current and future research directions into this intriguing condition.

They identified a significant reduction in IBS symptom severity in patients on elimination diets, provided that dietary elimination was based on foods against which the individual had raised IgG antibodies; fully compliant patients showed the best clinical improvement. The reverse pattern was observed after reintroduction of the respective foods.

Terminal ileal MMCC are significantly elevated in a majority of patients with IBS. The mast cell may be responsible for the altered visceral perception found in the gastrointestinal tract in patients with IBS. The poor correlation of the MMCC to the clinical features of IBS may be the result of the dynamic state of the mast cell.

In common with allergic disease, IBS appears to result from an interplay between susceptibility genes and impaired gut barrier functions, immunological dysregulation, together with bacterial and viral infections and other environmental factors. It is no easy matter to describe succinctly “gut barrier function”. In the gastrointestinal tract, the external and internal environments are in close proximity. The dilemma of the mucosal surface of the intestine is to fend off the constant challenge from antigens, such as microorganisms, in mounting a brisk response to pathogens, and to enable assimilation of innocuous antigens derived from food. In order to perform these opposing functions, the intestine is in a state of continuous immune responsiveness, and a delicate balance is generated and maintained between concomitant facilitation and suppression of inflammatory responses. Gut barrier function consists of physiological and immunological factors which exclude and degrade antigens and restrict their adherence, penetration, and transfer. Antigen presenting cells, and more precisely dendritic cells, are pivotal in directing mucosal immune responses. Three dendritic cell derived signals are required for pan effective T cell response.

The nature of signal 1 depends on the antigen in question and its processing; necessary costimulatory molecules create the second signal and the pericellular cytokine milieu is the basis of the third. On antigen recognition, maturation of dendritic cells and secretion of cytokines and chemokines occur. These secretions direct the polarisation of a naïve T helper cell to type 1, type 2, or a regulatory T cell and thus regulate other adaptive immune responses, such as B cell derived immunoglobulin production. Tolerance to lumenal dietary and microbial antigens is likely to be achieved through those dendritic cells which induce production of regulatory T cells secreting interleukin 10 and transforming growth factor β. These cytokines promote gut barrier function by suppressing the production of both T helper 1 and 2 cytokines, overexpression of which is associated with increased gut permeability. Moreover, the anergic T cells induced by interleukin 10 exposed dendritic cells appear to be able to suppress other T cells in an antigen specific manner. Transforming growth factor β downregulates both T helper 1 and 2 responses directly and indirectly by modulating the activity of antigen presenting cells and favouring the development of regulatory T cells. After intestinal priming, these cells migrate to the periphery, thus mediating peripheral tolerance on reactivation. In addition to its effects on T cell function, transforming growth factor β is a key factor in IgA production21 and thus contributes to maintenance of gut barrier function and to immune responses at other mucosal surfaces also. Taken together, “gut barrier function” strongly depends on antigen processing and presentation and the cytokine milieu in the mucosal immune system, and determines the nature of the immune response (that is, tolerance or inflammation) elicited to a particular antigen.
“Inflammation can cause profound alterations in the function of smooth muscle and enteric nerves as well as in deeper neuromuscular layers”
In certain circumstances, such as metabolic stress, the peaceful coexistence across the barrier is disturbed and an inflammatory response ensues. Abrogated barrier function of the gut mucosa leads to greater antigen transfer when the routes of transport are also altered, thereby evoking aberrant immune responses and release of proinflammatory cytokines with further impairment of barrier function. Inflammation can cause profound alterations in the function of smooth muscle and enteric nerves as well as in deeper neuromuscular layers. Indeed, a subtle inflammatory response and exaggerated sensitivity to that type of response has been suggested to be causative in IBS. In view of recently reported alterations in the immunological defence in IBS, the trigger(s) of the vicious circle can be depicted among the intraluminal antigens.

Atkinson describe IgG antibody responses to dietary antigens of clinical significance and an apparent causal relation to symptoms in IBS, in a fashion resembling the elimination-challenge procedure in food allergy. To broaden this concept, it is intriguing to speculate that IBS may perhaps also be associated with IgG antibodies against other intraluminal antigens such as those from the indigenous microbiota, partially analogously to loss of tolerance to gut microbiota in inflammatory bowel disease.

The human gastrointestinal tract harbours a complex collection of microorganisms which form the individual microbiota typical for each person. Defence is facilitated by peristalsis, secretion of mucus and antimicrobial peptides such as defensins and cathelicidins, and commensal induced IgA.

Intestinal epithelial cells further contribute to the homeostasis of gut barrier function by a scarcity of both pattern recognition receptors (PRRs; for example, toll-like receptors and nucleotide binding oligomerisation domain proteins) and their coreceptors, expression of active negative regulators of PRR signalling, and secretion of the suppressive cytokines interleukin 10 and transforming growth factor β. All of these characteristics assist in preventing unnecessary and even hazardous systemic immunity to commensals while allowing local protective mucosal immune responses. In addition, some specific strains of non-pathogenic bacteria have been shown to attenuate intestinal inflammation by selective inhibition of intracellular signalling pathways elicited by diverse potentially deleterious stimuli. A healthy gut microbiota is thus an indispensable component of “gut barrier function”. “A healthy gut microbiota is thus an indispensable component of gut barrier function”

The findings of Atkinson and colleagues should encourage studies dissecting the mechanisms responsible for IgG production against dietary antigens and their putative role in IBS. This may serve not only IBS research but also that into allergy and allergic diseases. In the perspectives of both normal gut barrier function and the vague findings in a few studies of probiotic supplementation in IBS.

The possible role of the gut microbiota in the pathogenesis of IBS may deserve closer attention. If the host-microbe cross talk is misinterpreted in IBS, a working target for novel therapeutic interventions beyond elimination diets could be provided in modulating the composition and/or activity of the gut microbiota and promoting gut immune defence. Research interest in the science of nutrition is directed towards improvement of defined physiological functions beyond the nutritional impact of food. The search for active non-nutritive compounds is also a focus for research in the treatment and prevention of allergic diseases.

The relation of food allergy and irritable bowel syndrome (IBS) was reported in several study.. However, recent evidence suggests significant reduction in IBS symptom severity in patients on elimination diets, provided that dietary elimination is based on foods against which the individual had raised IgG antibodies. These findings should encourage studies dissecting the mechanisms responsible for IgG production against dietary antigens and their putative role in IBS

Irritable bowel syndrome

Irritable bowel syndrome (IBS, or spastic colon) is a symptom-based diagnosis characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. As a functional bowel disorder, IBS has no known organic cause. Diarrhea or constipation may predominate, or they may alternate (classified as IBS-D, IBS-C or IBS-A, respectively). Historically a diagnosis of exclusion, a diagnosis of IBS can now be made on the basis of symptoms alone, in the absence of alarm features such as age of onset greater than 50 years, weight loss, gross hematochezia, systemic signs of infection or colitis, or family history of inflammatory bowel disease. Onset of IBS is more likely to occur after an infection (post-infectious, IBS-PI), a stressful life event, or onset of maturity.

Although there is no cure for IBS, there are treatments that attempt to relieve symptoms, including dietary adjustments, medication and psychological interventions. Patient education and a good doctor-patient relationship are also important.

Several conditions may present as IBS including coeliac disease, fructose malabsorption, mild infections, parasitic infections like giardiasis, several inflammatory bowel diseases, bile acid malabsorption, functional chronic constipation, and chronic functional abdominal pain. In IBS, routine clinical tests yield no abnormalities, although the bowels may be more sensitive to certain stimuli, such as balloon insufflation testing. The exact cause of IBS is unknown. The most common theory is that IBS is a disorder of the interaction between the brain and the gastrointestinal tract, although there may also be abnormalities in the gut flora or the immune system.

IBS has no effect on life expectancy. However, it is a source of chronic pain, fatigue, and other symptoms and contributes to work absenteeism. The high prevalence of IBS and significant effects on quality of life make IBS a disease with a high social cost.

The primary symptoms of IBS are abdominal pain or discomfort in association with frequent diarrhea or constipation, a change in bowel habits. There may also be urgency for bowel movements, a feeling of incomplete evacuation (tenesmus), bloating or abdominal distention. In some cases, the symptoms are relieved by bowel movements. People with IBS, more commonly than others, have gastroesophageal reflux, symptoms relating to the genitourinary system, chronic fatigue syndrome, fibromyalgia, headache, backache and psychiatric symptoms such as depression and anxiety. Some studies indicate that up to 60% of persons with IBS also have a psychological disorder, typically anxiety or depression

Immune Cell Numbers and Visceral Sensitivity

Repeated exposure to stress leads to mast cell degranulation, microscopic inflammation, and subsequent visceral hypersensitivity in animal models. To what extent this pathophysiological pathway has a role in patients with the irritable bowel syndrome (IBS) has not been properly investigated. Some study observe the relationship between visceral hypersensitivity, microscopic inflammation, and the stress response in IBS. Compared with HV, mast cells, T cells, and macrophages were decreased in IBS patients. Similarly, λ-free light chain (FLC)-positive mast cells were decreased but not immunoglobulin E (IgE)- and IgG-positive mast cells. There were no differences between hypersensitive and normosensitive IBS patients. No relation was found between any of the immune cells studied and the thresholds of discomfort, urge, first sensation, or IBS symptoms (e.g., abdominal pain, stool-related complaints, bloating). Finally, stress-related symptoms and the hypothalamic-pituitary-adrenal-axis response to stress were not correlated with the number of mast cells or the presence of visceral hypersensitivity. Although the number of mast cells, macrophages, T cells, and λFLC-positive mast cells is decreased in IBS compared with HV, this is not associated with the presence of visceral hypersensitivity or abnormal stress response. The role of microscopic inflammation as an underlying mechanism of visceral hypersensitivity, but rather suggest dysregulation of the mucosal immune system in IBS.

References:

E Isolauri, S Rautava, M Kalliomäki.
Food allergy in irritable bowel syndrome: new facts and old fallacies. Gut. 2004 October; 53(10): 1391–1393.
Atkinson W , Sheldon TA, Shaath N, et al. Food elimination based on IgG antibodies in irritable bowel symdrome: a randomised controlled trial. Gut 2004;53:1459–64.
Kulig M , Bergmann R, Klettke U, et al. Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol 1999;103:1173–9. Stagg AJ, Hart AL, Knight SC, et al. The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria. Gut 2003;52:1522–9.
Heyman M , Darmon N, Dupont C, et al. Mononuclear cells from infants allergic to cow’s milk secrete tumor necrosis factor α, altering intestinal function. Gastroenterology 1994;106:1514–23.
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Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritable bowel syndrome. Gut 2001;49:743–5.
Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut 2003;52:91–3.
Duchmann R , Kaiser I, Hermann E, et al. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 1995;102:448–55.
Otte J-M, Kiehne K, Herzig K-H. Antimicrobial peptides in innate immunity of the human intestine. J Gastroenterol 2003;38:717–26. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662–5.
Nobaek S , Johansson M-L, Molin G, et al. Alteration of intestinal microflora is associated with reduction in abnormal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 2000;95:1231–8.
Philpott H, et al. Irritable bowel syndrome – An inflammatory disease involving mast cells. Asia Pac Allergy. 2011 Apr;1(1):36-42.
Braak B, et al. Show all Journal. Mucosal Immune Cell Numbers and Visceral Sensitivity in Patients With Irritable Bowel Syndrome: Is There Any Relationship? Am J Gastroenterol. 2012 Apr 10.

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