Research Article :
From the beginning of this century, symptomatic
improvements in different disorders with food specific immunoglobulin G
(IgG)-guided exclusion diet have been reported. Most of them belong to
gastrointestinal tract such as irritable bowel syndrome (IBS) and inflammatory
bowel disease (IBD). Although this diet has given a chance of symptomatic
improvement as the main treatment in IBS or adjuvant therapy in IBD, it is
still a matter of debate. Presence of food specific IgG antibodies also in
healthy individuals and the use of IgG4 antibodies, known as protective
antibodies against excessive immune responses in some of these studies are the
main causes of these controversies. Additionally, there is no definite
nomenclature for the reaction mediated by food specific IgG antibodies, the
name of food intolerance is often used and it makes confusion by evoking
non-immune adverse food reactions. Finally, the underlying mechanisms of these
improvements have not been fully elucidated yet. Removal of foods that cause
intensive immune responses or non-IgE-mediated allergic reactions or increased
mast cell activation through IgG-food antigen complexes are among the suggested
mechanisms. The effectiveness of this diet, opposing views and possible
mechanisms to explain symptomatic improvements are focused in this manuscript. Irritable bowel syndrome (IBS)
is one of the common gastrointestinal disorders in the world with
low-grade inflammation of the intestines [1]. Inflammatory bowel disease (IBD)
includes Crohn’s disease (CD) and ulcerative colitis (UC) which are chronic
idiopathic inflammatory disorders with increasing incidence and
prevalence in recent decades [2]. Although IBS is a functional disorder
and IBD is an autoimmune one, there are some similarities between them. For
instance, their etiopathogeneses are unknown, their therapeutic managements are
often unsatisfactory and food-related complaints are frequently observed in
these two diseases [2-4]. Adverse food reactions are perceived in up to 65% of
IBS patients [3] and many patients with IBD often give histories of food related
onset or aggravation of their attacks [2,4]. Some patients with IBS
modify their diet by excluding self-identified foods and a few of them have to
feed themselves with a very limited number of food. In patients with CD,
exclusive enteral nutrition (EEN) usually can induce remission [5], however,
relapse commonly occurs when normal diet is reintroduced [4,6]. The role of
foods in both IBS and CD was demonstrated by Jones and his colleagues with elimination of symptom-forming foods from the diet
[7,8]. These foods were found by adding a single food daily in patients’
diet after making them asymptomatic with some applications e.g., TPN treatment
as in some CD patients. 51 of 77 CD patients remained well for periods of
up to 51 months with diet only [8]. Afterwards, these initial observations,
some studies were achieved in IBS [9] and one study in CD [10]. In the largest
study of patients with IBS, symptomatic improvements were found in 48% of
patients with maintaining for a mean 14.7 months [11]. But in clinical
practice, this procedure has not become prevalent because food selection takes
time (for at least 3 months), needs more effort and is negatively affected
by poor patient compliance [12]. The therapeutic effects of the elimination diet, based on the food
specific IgG antibodies in patients with IBS were first studied by Atkinson and
and his colleagues [16]. They randomly divided patients into true diet (whose
exclude IgG positive foods) and sham diet (whose exclude same number of foods
but not IgG positive) groups. After 12 weeks, the true diet group had in a
10-26% reduction in symptom score (related to their compliance) than the sham
diet group. They concluded that food elimination based on IgG antibodies might
be effective in reducing IBS symptoms and test for IgG antibodies might help
select foods for elimination. In the second study of
patients with IBS, exclusion diet was administered according to food specific
IgG4 antibody results [17]. Significant improvements were reported in severity
and frequency of pain, severity of bloating with satisfaction of bowel habits
and increase in rectal compliance. Then, three studies in patients with IBS
were reported with elimination diet according to IgG antibody positivity. In
the first one, the symptoms relieved completely in 31.4% and remarkably in
34.3% of patients at the end of eight weeks [18]. In the other
study, the 12-week diet was evaluated in patients with diarrhea-dominant
IBS. They obtained significant improvements in abdominal pain and distension,
stool frequency and shape, general feelings of distress and total symptom score
as compared with baseline findings of patients [19]. In the last one, the
improvements were reported not only in IBS symptoms but also in migraine pain
of the patients with both IBS and migraine [20]. The efficacy of this
diet was more investigated in CD than UC. In the first study, the daily stool
frequency in the patients with CD decreased significantly during a true diet in
comparison to sham diet. Their abdominal pain reduced and general well-being
improved [21]. In the second one, foods were eliminated according to IgG4
antibody results. At the end of four weeks, symptomatic improvement with a
significantly reduction in modified CDAI and decreased ESR were obtained [22].
In a double-blinded randomized sham-controlled study with IgG4 guided
four-week exclusion diet, improvement in quality of life and symptoms were
shown [23]. In another study, IgG-guided exclusion diet also found to be useful
in maintaining remission [4]. Patients in remission after EEN were divided
as with or without (control group) diet intervention. Disease
relapsed in 12.5% of the exclusion group compared with 25% of the control
group. Moreover, more remarkable increasing in CDAI and ESR in the control
group than in diet intervention group was obtained [4]. To date, there is
only one study, investigating the effect of IgG positive food exclusion diet in
patients with UC. Patients were randomly divided into an intervention
(whose exclude IgG positive foods) and a control (whose eat healthy diet as
normal) groups. At the end of six months, stool frequency and Mayo score
decreased, rectal bleeding, mucosal characteristics, and quality of life improved
significantly in the intervention group than in the control group. Moreover,
the number of patients with extraintestinal manifestations also decreased in
the exclusion diet group [24]. There is no definite
nomenclature for the reaction, mediated by increased food specific IgG
antibodies. “Food intolerance” is often used term for this reaction [30,31]. In
fact, food intolerance includes non‑immune‑mediated adverse reactions to foods,
related to enzyme deficiencies (e.g., lactose intolerance), pharmacologically
active constituents of foodstuffs (e.g., tyramine in cheese) and unclear
causes, such as certain irritants [3,32,33]. Food tolerance is the
specific suppression of immune responses to food antigens and considered
to play a central role in immune homeostasis. This physiological
mechanism prevents unnecessary immune reactions to innocuous dietary antigens
[34]. Food intolerance term may be preferred to explain the breakdown of
this mechanism for some foods. “IgG-based food intolerance” or
“IgG-mediated food intolerance” are the other terms, given for this reaction
[24,35,36]. On the other hand,
immunologically mediated adverse food reactions are known as food
allergy/hypersensitivity [3,32,33]. Food allergy is classified as IgE-mediated
(type I or immediate) and non-IgE-mediated (delayed) immune reactions [3,33].
Non‑IgE‑mediated reactions were postulated as to be type III hypersensitivity
(IgG or IgM immune complex reactions) or type IV hypersensitivity (delayed‑type
or cell‑mediated reactions) [33]. 40-50% of children who are allergic to cow’s
milk have non-IgE-mediated e.g., delayed-type immune reactions may be caused by
effector T cells or IgG antibodies [33]. “IgG-mediated food hypersensitiviy” is
another name, preferred for this reaction [3]. Although the general acceptance
takes time, this term seems to be the most suitable one for this reaction. For
now, it seems more appropriate to use one of the initial names, food
sensitivity [16,37], instead of food intolerance. There are some
laboratory findings as an objective marker that suggest the relationship
between IgG positive foods and CD. While decreased ESR was reported in two
studies with elimination diet [4,22], we demonstrated significantly increased
highly sensitive CRP levels and white blood cells counts with IgG positive food
(6 days) and additive (added last 3 days) provocations in a pilot study [38].
Moreover, the increased fecal calprotectin levels in most of the
patients on the following day of first provocation suggested the
relationship between intestinal inflammation and IgG positive foods. The
development of intestinal inflammation due to food antigens was shown in an
experimental study, using a mouse model of colitis [39]. In this study, the
inflammation via CD4(+) T cell hyperactivation was induced by food antigens
associated with high serum IgG levels. Additionally this inflammation
ameliorated by the elimination of food antigens. On the other hand,
clinical improvements in CD patients with decreased CDAIs [4,22,23]
and the lower endoscopic score in the food exclusion group compared
with the sham diet group of patients with UC [24] are the other
objective findings that support the relationship between IgG positive
foods and IBD. The exact mechanism of IgG-mediated food reaction has not
been fully elucidated yet. In the definition of food specific IgG test
kits, it is suggested that IgG positive food exclusion diet prevents type
III hypersensitivity reaction. Prevention of food allergy with IgG
positive food elimination also has been considered by some authors
[3,15,28]. Some authors
have suggested that the existence of intensive immune responses to food
antigens in patients with CD and explained these improvements
by excluding the moderately and strongly immune-reactive foods
[4]. They observed longer remission periods in CD patients with IgG
positive food restriction and have also explained this condition due
to stabilizing the decreased microbial diversity, provided by prior
EEN treatment [4]. Reduction in microbial diversity with EEN was
reported in some studies [40,41]. Besides, it was shown that elimination of the
food antigens ameliorated the inflammation in mice without altering the
composition of their intestinal microbiota [39]. Another explanation for
the improvements with IgG-guided exclusion diet has been based on decreased
mast cell activation [29,42]. Although mast cells have long been
recognized as only central players in IgE-mediated allergic reactions,
recently it has been understood that they are multifunctional immune cells
which are effective in several health and disease status [43,44]. Between
several activating factors of mast cells, there are IgG-antigen immune
complexes [45-48]. Food and food additive antigens often stimulate mast
cells mediated by IgG antibodies [49]. While mast cells involve in
physiological processes of the intestine such as regulating permeability,
secretion, peristalsis and host defence to pathogens [43,44], increased
mast cell activation have been suggested as a common feature
in the pathogenesis of IBS [1,50,51] and IBD [52-54]. The
relationship between increased mast
cell mediators and pathophysiologic factors of IBS such as
increased excitability of senso-secreto-motor neurons and visceral
hypersensitivity [55,56], disturbed motility [57], and increased permeability
[58,59] were shown in several studies. Increased IgG-food antigen
complexes due to increased food specific IgG antibodies can cause more mast
cell activation. Elimination of their specific antigens from diet
may reduce mast cell activation by decreasing immune complexes because of
lack of the food antigen part of them [29]. IgG-guided exclusion
diet has also been suggested to help restoration and maintenance of gut barrier
by decreasing the local inflammation [4]. On the other hand, mast cell tryptase
has been considered as a key factor, disrupting the intestinal barrier in
patients with IBS [1,50]. The reduced junctional adhesion molecule-A
expression due to mast cell tryptase in patients with IBS was shown
[59]. Increased intestinal permeability may be due to increased mast cell
activation, mediated by IgG-food antigen complexes, as well. Removal of IgG
positive food antigens has been considered to reduce intestinal permeability
and bacteria, food and additive antigen absorption by decreasing mast cell
activation [29]. Elevated IgG levels for
some foods may also be related to breakdown of oral tolerance to them
[28,34,62]. Antibiotic treatment induced bacterial dysbiosis may affect oral tolerance
[34,62]. Other suggested factors that might cause disrupted oral
tolerance are injury, shock, trauma, surgery, drugs, blood transfusion and
environmental triggers [62]. Mast cell
activation related suppression of regulatory T (Treg) cell
functions [63-65] may be another factor. Treg
cells play a central role in oral tolerance [34]. Xenoestrogens activate mast
cells [66] and excess
xenoestrogen exposure as pesticide residues may be the common factors influencing oral tolerance
because of their wide existence in the environment. The first opposing point
of view has been related to the presence of IgG antibodies against to food
antigens in both normal adults and children. Some authors have considered that they
might be the result of physiological response of the immune system,
thereby reflecting exposure or tolerance to foods without a pathologic
condition [37,67,68]. Actually, food specific IgG antibodies in healthy
individuals usually exist but the levels are rather low [13,14] and mainly
in IgG4 subclass [14]. Low levels of food specific IgG antibodies may be result
of food tolerance. However increased levels for some foods may be due to
the loss of tolerance to them and recognizing these food antigens as
foreign ones with occurrence of B cell responses [28,34,62]. In
addition, small amounts of immune complexes generate from low-level IgG
antibodies and their food antigens may be one of the factors, stimulating mast
cells for physiological functions in healthy individuals [29]. The second one has
focused on food specific IgG4 antibody testing [32,67]. Two different IgG
antibody tests were used in these studies. IgG4 test measures only the amount
of IgG4, a subclass of IgG antibody. IgG test measures the sum of the amount of
four subclasses of IgG antibodies including IgG1, IgG2, IgG3, and IgG4. IgG4
antibodies are usually accepted as “blocking antibodies” especially in the
context of allergies [69,70]. They can usually prevent excessive immune
responses against sterile antigens and may compete with IgE for allergen
binding [69,70]. Immunotherapy studies also support the protective role of
food-specific IgG4 antibodies in patients with food allergy
[71]. Nevertheless, there were three studies which chose excluded foods to
the IgG4 positivity and all obtained good results in patients with IBS [17] and
Crohn’s disease [22,23]. This situation may be explained by co-elevation of IgG
and IgG4 antibodies for same foods especially in frequently consumed ones such
as gluten, yeast, chicken egg, cow’s milk and products. Elimination of IgG4
positive foods may decrease symptoms because of also elimination the IgG
positive ones [29]. On the other hand, some
foods with increased IgG antibody levels may not cause symptoms [68,72] and
this may be the subject of discussion. This situation can be explained by the
binding of some IgG-antigen complexes to the inhibitory receptors of mast cells
[29]. Inhibitory receptors FcγRIIB do not trigger any intracellular signal
and even trigger negative signals when they are co-aggregated with activating
receptors by immune complexes [46]. Provocation for each IgG positive food
after the patient becomes symptomless with elimination diet, may be
necessary to rule out this possibility [42]. Additionally IgG
positivity detected for some foods which not even been tasted beforehand. This
may be due to antigenic similarity. An ideal food specific
IgG testing contains as much as food antigens based on the dietary
characteristics of each country. In addition, it may contain antigens for
alternative foods against the possibility of positivity of the ones frequently
eaten. It is better to add the antigens such as maize, rice, buckwheat, quinoa
or egg white, yolk and quail egg for gluten and chicken egg positivities. Some
applications, related preparing milk and products e.g., boiling or fermentation
will alter the antigenic structures. Hence boiled milk, yoghurt, cheese, and
kefir antigens should be checked separately. In addition, bread and brewer's
yeast must be examined. The type of test is
especially important. Qualitative testing with fingertip blood cannot measure
the level of antibodies, so cannot detect the antibodies very close to the
upper limit. This is important in IBD patients who are under the
immunosuppressive treatment. Even, anti-TNF therapy was shown to reduce the
amount of IgG antibodies to food [28]. It is better to choose a quantitative
testing. According to my personal
data, most of the food additives especially thickening ones also cause
elevation of IgG antibodies against themselves. It is not possible to examine
all of them because of their large number. To get good results when applying
IgG-guided exclusion diet, adding an empirically additive free diet seems
to be logic. Additionally, to reduce
symptoms due to mast cell mediators may increase the success of the diet.
Xenoestrogens such as pesticides and bisphenol A are common triggers for mast
cells. The frequent sources of pesticides are contaminated water and
foods [66]. To decrease their entrance into the body, spring waters
instead of tap water should be used both for drinking and cooking. Bisphenol A,
a polymer that can be released by polycarbonated plastics and by the linings of
metal cans that are used for food and beverages. Therefore, avoiding storage of
foods in these cans, plastic boxes and bottles will decrease bisphenol A
contamination. Moreover, one of the
mast cell stimuli is the corticotropin-releasing hormone (CRH) induced by
psychological stress [73]. Even, stress-induced mast cell degranulation was
shown experimentally [58]. It will be beneficial for patients to get away from
stressful life. In the near future,
after solving the IgG-IgG4 complexity, quantitative testing with allergen
panels, prepared with the participation of as many but necessary foods as possible, seems to be more promising
treatment results. Hulya
Uzunismail, Internist and Gastroenterologist, Retired from İstanbul University,
Cerrahpaşa Medical School, Turkey, E-mail: hulyauzunismail@gmail.com Inflammatory bowel disease, Irritable bowel
syndrome, Food-specific IgGs, Food exclusion.Evaluation of Food Specific Immunoglobulin G (IgG)-Guided Exclusion Diet in the Treatment of Irritable Bowel Syndrome and Inflammatory Bowel disease
Abstract
Full-Text
Introduction
Elimination of foods which have increased specific IgG antibodies seems as
another successful diet for both IBS and IBD. Normally, healthy
individuals have low levels of IgG antibodies against food antigens [13,14]. In
IgG-guided exclusion diet, foods which have increased IgG levels above the cut-off
value of healthy individuals are excluded and these foods can be
briefly called “IgG-positive″. In the year 2000, symptomatic improvements with
this diet were first reported in patients having treatment resistant delayed
food allergy [15]. Then similar results have been published for different
disorders such as IBS [16-20], CD [4,21-23], UC [24], migraine
[20,25,26] and asthma [27]. In three of these studies, increased IgG4
antibody values were used for excluding foods [17,22,23]. Symptomatic improvements
with IgG-guided exclusion diets suggest that there may be a relationship
between IgG positive foods and these disorders. However it is really
difficult to explain how these foods may be at least one of the
important pathogenetic factors for different disorders in different
systems or even of the same system such as IBS and IBD; one is functional
and the other one is autoimmune. Despite the increasing number of these
studies, the role of exclusion diet, guided food specific IgG antibody testing
in the treatment have been contradictory. Removal of foods causing non-IgE
mediated hypersensitivity reactions [3,15,28] or intensive immune
responses [4] or increased mast cell activation by IgG-food antigen
complexes [29] and stabilizing intestinal flora after EEN [4]
have been suggested to be as pathogenetic mechanisms. In this review,
the efficacy of this diet, possible mechanisms and opposing views are discussed.IgG-guided exclusion diet results in patients with IBS and IBD
Terminology
Complexity
Possible mechanisms of
improvements with IgG-based food exclusion diet
Possible causes of
food-related IgG antibody elevation
The reasons why IgG
antibodies for some foods are elevated have not been exactly known. Increased
intestinal permeability related more easily food antigen presentation to the
gut immune system is one of the suggested opinions [24]. But this could not be
explained by increased generalized intestinal permeability; in this case, IgG
antibodies would be expected to rise against all eaten foods [60,61].
Differential permeability of the gut mucosa to different foods may be the other
thought [60,61]. Different antigenicity of various foods [28,60], the impact of
protein structure modifications during digestive processes [28], disturbance of
the process concerning antigen load presented to the immune cells [28] are the
other hypotheses, proposed. It has been also thought that different foods may
lead to different modification of the gut immune responses [28,61]. However,
some authors have suggested that hereditary and immunological factors might be
effective [24].
Opinions against IgG
test
How the ideal IgG
testing should be?
What are the other
additional factors to be considered in application of the IgG antibody-guided
exclusion diet?
My another personal experience is that genetically modified crops can affect
the success of IgG-guided exclusion diet. These foods contain new antigens and
toxins. For example, transgenic plants, resisting insects contain significant
amounts of Cry toxins (Cry proteins e.g., Cry1Ab, Cry1Ac) of
Bacillus thuringiensis [74,75]. While Cry1Ab protein was shown in human
sera [75], high immunogenicity of Cry1Ac with inducing antibody responses,
including IgG was shown experimentally [74] e.g., food specific IgG antibodies.
Therefore, it is better to use organic foods in which IgG-guided exclusion diet
is not successful.
Conclusion and Future
Expectations
Increased food specific IgG antibodies can be considered as a reliable
indicator in finding most of the foods for exclusion and also management
of IBS and IBD. In many of the patients with IBS, IgG based exclusion diet
gives a treatment chance. In patients with IBD it will increase the success of
medical treatment, shorten the course of active disease and prolongation of
remission with reducing the economic burden of these diseases.Conflict of Interest
The author declares that there is no conflict of interest regarding the
publication of this paper.References
*Corresponding author:
Citation:
Uzunismail H. Evaluation of food specific immunoglobulin G (igG)-guided exclusion
diet in the treatment of irritable bowel syndrome and inflammatory bowel
disease (2019) Edel J Biomed Res Rev 2: 14-19.
Keywords
