IgG and Gastrointestinal Disorders

Dr Anton Emmanuel, consultant gastroenterologist and senior lecturer in neuro-gastroenterology at University College Hospital, London, outlines some of his recent work. Additions in italics in brackets are intended to help our less medically literate readers to understand Dr Emmanuel - they might also be helped by reading our article on allergy testing.

The possible role of food hypersensitivity in causing gastrointestinal disease was first suggested in 1950. While there is good evidence of the clinical importance of food allergy in certain gut diseases (eosinophilic enteritis, coeliac disease), the role of gastrointestinal hypersensitivity (allergic) reactions in other gut disorders remains controversial.

Food allergy and intolerance in IBD (Irritable Bowel Disease)

While there is no evidence that specific immune-mediated (allergic) reactions to food play a role in most patients with either Crohn’s disease or ulcerative colitis (UC), it is common for patients with gastrointestinal (GI) disorders to believe that something in their diet has caused their condition. Some studies have claimed that food sensitivities are common in Crohn’s and have found that when food intolerances are detected, patients on an exclusion diet maintain remission significantly longer than those on an unrestricted diet. However, when these patients are subjected to double-blind food challenges only 15% show a positive response.

In contrast UC does not seem to respond to bowel rest or elemental diets (totally allergen-free formula food made solely from nutrients so there is no waste to be eliminated via the bowel). However, when patients with UC were surveyed regarding the frequency and pattern of food intolerance there existed no significant difference in findings between UC and Crohn’s disease. Food intolerance was reported at a significantly higher rate in patients with IBD than in normal controls.

Potential mechanisms for food allergy in IBD

While the bowel mucosa (lining) acts as a physical barrier to dietary and microbial antigens (substances which the immune system recognises as harmful), even under normal physiological conditions intact food antigens can penetrate the mucosal barrier via transcellular or para-cellular routes. The integrity of the GI mucosa is further compromised by inflammatory conditions such as infectious gastroenteritis or IBD. This increased permeability exposes the immune components of the GI tract, principally resident in the lamina propria and Peyer’s patches (parts of the mucosal lining of the gut), to the potentially antigenic components of the luminal contents (the food moving through the intestines).

IgE mediated food hypersensitivity
Immediate phase reaction

Previously sensitised mast cells are induced to release inflammatory mediators by IgE in the immediate phase reaction (see IgE reactions). These mediators result in increased vascular permeability, smooth muscle contraction and the classical wheal and flare (allergic) response. There is evidence that similar mechanisms may operate in mucosal (gut lining) hypersensitivity reactions. Certainly food antigen induced mast cell degranulation (the process by which histamine etc is released when the IgE antibody ‘binds’ to the antigen) has been demonstrated in the rat intestine. In addition degranulating mast cells have been found in the gut mucosa of patients with Crohn’s disease.

Delayed phase reaction

The immunomodulators and pro-inflammatory agents released by mast cell degranulation result in granulocyte, lymphocyte and monocyte/ macrophage (all white blood cells involved in an immune response) migration and activation. This results in a more protracted hypersensitivity (allergic) response. The role of this delayed phase reaction in asthma and atopic eczema is well demonstrated. It has also been suggested that a similar mechanism may play a role in food allergy. However a clear role in IBD has not been demonstrated.

IgG mediated food hypersensitivity

Whilst raised IgG levels are seen in patients with asthma, hayfever, eczema and atopic dermatitis, the published data regarding IgG mediated immune reactions in food hypersensitivity (allergy) is contradictory. In fact it has been suggested that IgG production may be a normal immunological response to dietary antigens. However, increased levels of food-specific IgG and IgG4 antibodies have been demonstrated in atopic eczema and respiratory allergy. In food allergy the immunological response may be heterogenous with a predominance of one type of antibody response in different patients.

Antibody combinations

One study comparing raised levels of IgE, IgG4 and double blind food challenge found that elevation of any one immuno-globulin (Ig) sub-class correlated with a positive history of food hypersensitivity in only 63% of patients, but that the combination of IgE and IgG4 correlated in 91% of patients. These high specificities have been reproduced elsewhere also with IgE and IgG food specific antigens in combination.

IgG, Crohn’s and IBS

Our group has shown that there are increased levels of food specific IgG antibodies in Crohn’s disease compared to controls (in the people in the study with Crohn’s Disease compared to the ‘control’ participants who did not have the disease). There was no significant correlation between food antibodies and patient reported sensitivity, possibly a result of the small number of patients in this study. These results suggest further experiments to investigate whether IgG antibodies can predict foods that provoke disease on double blind, placebo-controlled food challenge and conversely, whether specific food avoidances based on antibody titres (tested levels) might be worthwhile.

In the setting of IBS, an exclusion diet guided by the presence of IgG food-specific antibodies gave greater symptom relief and global rating scores as compared to a sham exclusion diet which did not avoid the foods indicated on IgG testing. Examining the patterns of IgG4 food-specific antibody positivity in patients with IBS compared with controls, it is apparent that subjects with IBS have significantly higher titres (tested levels) of antibodies to wheat, beef, pork and lamb than controls. An exclusion diet based on these IgG4 titres, significantly improves IBS symptoms and rectal sensitivity and compliance.

Challenge to dogma

These findings challenge the dogma that IgG antibodies to food are non-specific and of no relevance to gastroinstestinal (GI) disease. The possibility exists that IgG antibodies to food could be useful in guiding dietary management of other GI disease responsive to dietary manipulation, in particular Crohn’s disease.

IBS is often associated with adverse reactions to food and food allergy might be a mechanism for symptoms in a subgroup of these patients. The observation that faecal IgE levels are increased in a subgroup of patients with IBS but not in healthy subjects lends weight to the concept that allergy might be relevant in at least some patients with IBS.

Research findings

Investigation into the role of food intolerance in IBS dates back to 1982 when Jones et al. evaluated 25 consecutive IBS patients with a one-week elimination diet followed by open challenge with suspected foods. Of patients taking part, 67% had a resolution of symptoms. Wheat, corn, dairy products, coffee, tea and citrus were the most commonly implicated foodstuffs. Since then several studies of dietary exclusion have been reported, with response rates ranging from 15-71%. The most favourable symptomatic response in these studies of dietary manipulation has been in the sub-group with diarrhoea-predominant IBS.

The correlation of a positive dietary challenge with immunological markers of hyper-sensitivity (Type 1, IgE food allergy) has been poor. Three of the above studies examined the association between a positive dietary challenge and skin prick tests and/or radioallergosorbent (RAST) tests. One of these studies demonstrated a positive correlation in those IBS patients with a history of atopy (suffering from allergy) only.

Additional indirect evidence of an association between allergy and IBS takes the form of two small, double blind, placebo-controlled studies of disodium cromoglycate in IBS.

Disodium cromoglycate inhibits the release of inflammatory mediators by inhibiting degranulation of mast cells (prevents the release of histamine etc) following contact with an allergen. Hence, the effect of this drug in IBS may be due to the curtailment of an allergen-mediated response. A larger study of 428 patients comparing disodium cromoglycate and elimination diet demonstrated that disodium cromoglycate was as effective as an elimination diet in improving symptoms.

Further investigation

While there is no clear evidence to suggest that IBS is an infective condition, the observation that 30% of patients develop symptoms after an episode of gastroenteritis raises a question as to possible mechanisms for the association. One possibility is that inflammation of the bowel causes increased mucosal permeability thus increasing exposure of the immune system to dietary and microbial antigens. This might allow ‘priming’ of the mucosal immune system and predispose to hypersensitivity responses. Specific serological data (derived from analysis of the blood) to support this hypothesis do not exist however. Clearly investigation into the mechanism of this association warrants further research.

First published in 2007

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