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REVIEW ARTICLE
Anti-acid medication as a risk factor for food allergy
I. Pali-Scho¨ll & E. Jensen-Jarolim
IPA – Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University
Vienna, Vienna, Austria
To cite this article: Pali-Scho¨ll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011; 66: 469–477.
Food allergies and intolerances – the basics
Approximately 1.8–3.3% of the young adult population
(aged 18–39 years) in industrialized countries like Denmark
(1), France (2), or Germany (3) suffer from immunologically
mediated adverse reactions to food, i.e. food allergies. How-
ever, a recent study of the European Community Respiratory
Health Survey (ECRHS) found even higher numbers, with
positive allergen-specific IgE to any of 24 tested food aller-
gens in 7–24% of a young adult population aged from 20 to
39 years in different countries of Western Europe, the USA,
and Australia (4). Furthermore, 6–8% of children younger
than 3 years are affected in the USA (5, 6).
In these patients, sensitization occurs in a ‘silent way’, i.e.
without symptoms, and leads to IgE formation and specific
hypersensitivity against the offending food. There are at least
two possibilities of sensitization: (i) indirectly, when respira-
tory allergens lead to induction of IgE that is cross-reactive
with food proteins, or (ii) directly, when oral sensitization
and IgE induction occur via the gastrointestinal mucosa. As
a consequence, effector cells like mast cells and eosinophils
get armed by IgE, thus ready to release mediators when the
relevant food allergen is ingested subsequently. This may lead
to mild up to severe immediate-type symptoms. For yet
unknown reasons, the same patient may react toward food
allergens to different extents at different time points of life.
Today, consequent avoidance of allergen exposure is the
only option for food-allergic patients because no causative
therapies are available yet. Therefore, much focus is given on
the development of methods to predict allergenicity of
proteins or to trace allergens in food. A multidisciplinary
International Workshop held in May 2007 focused on risk
assessment and safety assessment for allergenic foods and
concluded that three possible approaches should be consid-
ered to protect consumers from potentially hazardous
reactions: (i) safety assessment using no observed adverse
effect level (NOAEL)/lowest observed adverse effect level
(LOAEL) and uncertainty factors; (ii) safety assessment using
Keywords
acid suppression; anti-ulcer drugs; food
allergy; gastric pH; oral sensitization.
Correspondence
Prof. Erika Jensen-Jarolim, MD, IPA –
Institute of Pathophysiology and Allergy
Research, Center of Pathophysiology,
Infectiology and Immunology, Medical
University Vienna, Waehringer Guertel
18-20, 1090 Vienna, Austria.
Tel.: +43 (01) 40400 5110
Fax: +43 (01) 40400 5130
E-mail: erika.jensen-jarolim@
meduniwien.ac.at
Accepted for publication 21 October 2010
DOI:10.1111/j.1398-9995.2010.02511.x
Edited by: Hans-Uwe Simon
Abstract
An important feature for oral allergens is their digestion-resistance during gastroin-
testinal transit. For some oral allergens, digestion stability is an innate feature,
whereas digestion-labile antigens may only persist in times of impairment of the
digestive system. In this review, we collect evidence from mouse and human studies
that besides the inherent molecular characteristics of a food protein, the stomach
function is decisive for the allergenic potential. Gastric acid levels determine the
activation of gastric pepsin and also the release of pancreatic enzymes. When anti-
ulcer drugs inhibit or neutralize gastric acid, they allow persistence of intact food
allergens and protein-bound oral drugs with enhanced capacity to sensitize and elicit
allergic reactions via the oral route. Mouse studies further suggest that maternal
food allergy arising from co-application of a food protein with anti-acid drugs
results in a Th2-biased immune response in the offspring. Especially, anti-ulcer
drugs containing aluminum compounds act as Th2 adjuvants. Proton pump inhibi-
tors act on proton secretion but also on expression of the morphogen Sonic hedge-
hog, which has been related to the development of atrophic gastritis. On the other
hand, atrophic gastritis and resulting hypoacidity have previously been correlated
with enhanced sensitization risk to food allergens in elderly patients. In summary,
impairment of gastric function is a documented risk factor for sensitization against
oral proteins and drugs.
Abbreviations
GERD, gastro-esophageal reflux disease; H2RA, H2-receptor
antagonist; HP, Helicobacter pylori; LOAEL, lowest observed
adverse effect level; NOAEL, no observed adverse effect level;
PPI, proton pump inhibitor.
Allergy
Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 469
Benchmark Dose and Margin of Exposure (MoE); and (iii)
risk assessment using probabilistic models (7).
Regarding the in vitro safety assessment, different food
processing methods have been recognized to result in differ-
ent impacts on stability and/or allergenicity of different foods
[reviewed in (8)]. Some processes were shown to enhance
either the IgE-binding capacity, the digestion stability, or the
skin prick test reactivity to food proteins, for instance roast-
ing of peanuts (9); pasteurization of milk (10); or smoking of
fish (11). However, there are also studies showing that some
treatments of food can reduce its capacity to induce allergic
reactions, for instance the simple addition of vinegar to
extracts of boiled chicken meat, eggs, or lentils decreased
their capacity to induce positive reactions in skin prick test
and oral provocation test, as well as IgE-binding in immuno-
blotting experiments, indicating that some allergens may
already be disarmed by low pH (12). Also, technological
treatment like homogenization of bovine or ovine meat can
reduce the skin prick test reactivity in allergic patients (13).
Additionally, formation of aggregates or multimers may
influence the immunogenicity/allergenicity of antigens (14).
The occurrence of dimers and/or multimers was shown to
enhance immunogenicity as well as allergenicity of aeroaller-
gens (14) and food allergens (10). Multimers can also arise
during cross-linking processes, accomplished for instance by
the enzyme tissue transglutaminase in the gastrointestinal
tract, which gets activated under stress-like conditions like
exercise, inflammation, etc. This cross-linking process involves
glutamine residues, for instance present in gliadins of wheat,
and leads to enhanced IgE-binding and skin prick test reac-
tivity to the high-molecular weight complexes formed (15).
Furthermore, the food matrix might play a role in the determi-
nation of allergenicity, as for instance most allergic patients
tolerate egg and milk, respectively, when heated/baked with
wheat (16, 17). Another factor determining the allergenicity
outcome could be the fat content of the food stuff, as a higher
fat content of the vehicle also led to tolerance of higher aller-
gen amounts in peanut-provoked patients (18). Similarly, the
presence of different plant polysaccharides used in food indus-
try, such as xylan, pectin, and gum arabicum, was shown to
change/reduce the IgE-binding capacity of digested peanut
proteins (19) or heated milk-protein beta-lactoglobulin (20).
The search for common food allergen characteristics is,
however, unsatisfactory yet, even if a limited number of
proteins seem to be relevant for sensitization (21, 22): only
eight foods/foodgroups, namely crustacean, eggs, fish, milk,
peanuts, soybeans, tree nuts, and wheat account for 90% of
food-allergic reactions (23). Accordingly, in the above-men-
tioned ECRHS study of young adults, the most frequent
sensitizers were found to be hazelnut, peach, shrimp, and
wheat (4). Importantly, this top list still remained true when
birch pollen positive patients were excluded, which means
that the high number of reactions to hazelnut and peach
(cross-reactive food allergens to birch pollen) cannot solely
present cross-reactive food intolerance. In contrast, no
wheat-sensitized individuals remained when the group of rye
grass allergic patients was excluded in the Australian cohort
of this study.
Several important questions still remain open: Which are
the first cells responsible for sensitization to oral allergens
and turning on the IgE program? Why are some persons
going to develop allergy, independent of atopic or nonatopic
genetic background, whereas others being exposed toward
the same type of food will not? Which factors determine the
threshold of food allergens leading to symptoms in the same
patient at different time points? Why are some proteins able
to sensitize via the oral route although they are obviously
easily digested by gastric proteases?
Physiological fate of food proteins during digestion
Resistance to gastrointestinal digestion has been proposed as
one dominant feature of food allergens (24). This cognition
led to the development of so-called in vitro digestion assays
using simulated gastric fluid as part of food safety tests (25).
Some working groups have tried to come closer to the in vivo
situation by combining gastric and intestinal digestion in
in vitro models (26, 27); by imitating and comparing the adult
vs the infant digestion situation in vitro (26); or by using
so-called dynamic models of digestion (28), which mimic not
only the influence of digestive enzymes, but also the physical
processes and temporal changes in conditions of the stomach
and the lumen of the small intestine, like hydration, mixing,
shear forces, transport, and delivery [reviewed in (27)].
However, resistance to gastrointestinal digestion is not an
innate characteristic to all food proteins, and some authors
have even concluded that missing stability to digestion may
speak for a minor importance of proteins as allergens. Exam-
ples are glycinin and Ara h 3 from soybean and peanut,
respectively, of which the authors concluded that due to their
sensitivity to peptic digestion, they may not be such impor-
tant food allergens (29), although these proteins were previ-
ously described as major allergens in these legumes (30, 31).
The hindrance of normal digestion of these allergens because
of some external influence factors, however, has not been
implicated in their allergenicity.
From a physiological point of view, the gastric digestive
system uses pH shifts to control the activity state of proteases
and as a means to protect the mucosa against autodigestion.
Gastric propepsin is activated to become pepsin by cleavage
of a peptide, which is produced exclusively at low pH (32,
33). Hunger, appetite, or ingestion enhance gastric acid
production from parietal cells in the stomach and lead to
propepsin release from gastric chief cells, protease activation,
and finally peptic protein digestion. Further transit of the
acidic chymus to the duodenum leads to stimulation of the
pancreas to release alkaline secrets containing the classical
pancreas proteases trypsin, chymotrypsin, and carboxypeptid-
ases. However, this releasing process is dependent on the acti-
vation of secretin, a hormone detected in 1902 by Bayliss and
Starling (34). This substance is synthesized in cytoplasmic
secretory granules of S-cells, especially present in the mucosa
of the duodenum and less numerous in the first portion of
the jejunum (35). Importantly, the release of secretin into
plasma and/or the lumen of the intestine is dependent on low
duodenal pH (between 4 and 4.5) (36, 37). This low pH
Anti-acid medication as a risk factor for food allergy Pali-Scho¨ll and Jensen-Jarolim
470 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
usually stems from the acidic chyme of the stomach (38),
although digested products of fat and protein, bile acids, and
some herbal extracts have also been shown to release secretin
(39). There has been some controversy on this dependency of
secretin release on low pH in early times after secretin detec-
tion (40); however, according to more recent work, actually
the acid in the duodenum appears to be the major stimulant
of secretin release (39, 41).
This means that low gastric acid pH is crucial for activa-
tion and liberation of gastric and pancreatic proteases. In
concert, these enzymes degrade proteins to small nutritionally
valuable peptones and peptides, which optimally are ignored
by the immune system or lead to tolerance. This implicates
that the functional acidic stomach has a protective function
against many digestion-labile proteins, which otherwise could
present antigens or even allergens.
The low pH in the gastrointestinal tract is also important
to minimize the risk of intestinal infections (42, 43). In line
with this, it has been observed that bactericidal activity in the
stomach is given when the pH is below 3.0, in contrast, bac-
terial overgrowth (e.g. Clostridium difficile, Campylobacter
jejuni, Salmonella spp.) occurs during hypochlorhydria at pH
above 4.0 (43–45). The consequence of this colonization due
to breakdown of the ‘gastric bactericidal barrier’ (42, 45) is
diarrhea, and actually this symptom was found to be associ-
ated with the usage of proton pump inhibitor (PPI) as the
second-most important reason after the usage of antibiotics
(46). Vice versa, babies aged between 1–12 months with
chronic diarrhea presented with increased gastric pH (mean
pH above 4.0 in about 57%) (47). However, to complete the
picture, one has to mention that also breast-fed babies were
shown to have an increased gastric pH (mean pH around
4.0), but there was no bacterial overgrowth of gram-negative
bacilli and no diarrhea, an observation that may be related
to the transfer of protective factors (e.g. lysozyme, lacto-
ferrin, IgA antibodies) by the mother’s milk. Underlining the
bactericidal barrier function of the stomach, in young gastro-
esophageal reflux disease (GERD)-affected children, aged
4–36 months, who were treated either with ranitidine [H2-
receptor antagonist (H2RA)] or omeprazole (PPI) for
8 weeks, an enhanced risk for acute gastroenteritis and
community-acquired pneumonia was detected, although chil-
dren were healthy otherwise (42). These risks even sustained
after ending the therapy.
Physiological situations and pathophysiological events
leading to impaired digestion
One population group who often presents with enhanced
gastric pH (pH > 4.0 for 80–90% of time) are preterm born
infants, the acidity in these children only rising with age (48).
In full-term infants, the acidity in the stomach changes
during the first hours and days of life: starting with a median
pH of about 6.1, it decreases to a median pH of 2.2 after 6 h
of age (49). However, after this initial low pH, there occurs a
loss of acidity for 10 day (pH increases), and thereafter pH
only slightly goes down again (50). Adult values of gastric
pH, as well as the full digestive capacity and the complete
mucosal barrier function, are reached at an age of approxi-
mately 2 years only [reviewed in (51)]. For example, the
output of pepsin/kilogram body weight per hour was found to
be 1/15 of the adult levels on the first day of life (52) andwould only be roughly comparable to that of adults in the
second year of life (53). Similarly, the mean acid output in
21-month-old children after histamine stimulation was found
to be only 50% of that observed in adults and is roughly
similar to adult levels only by the end of the second year of
life (54, 55). Therefore, peptic digestion may not be complete
during early life, and protein remnants of the diet could act
as allergens. Together, these facts may contribute to the
higher incidences of food allergies in children.
Food allergies in adults have been observed at any age,
and thus novel sensitization principally may occur at any
point of time. There are different scenarios when the stom-
ach’s acid and pepsin production and thus protective func-
tion could be disturbed in adults. Hypochlorhydria or
achlorhydria can be due to chronic atrophic gastritis. Inter-
estingly, the other way round, it was shown that the loss of
parietal cell function is preceding the development of gastric
atrophy. Owing to parietal cell loss, hydrochloric acid is
missing, and this results in the negative fate of other cell
lineages in the stomach leading to atrophic gastritis (56). In
parallel, the expression of the morphogen called Sonic hedge-
hog (Shh) correlated with atrophic gastritis and metaplasia in
the intestine (57). It was further shown that Shh expression
and signaling depends on gastrin levels and gastric acidity, as
the omeprazole-induced hypoacidity inhibited the cleavage
of the precursor protein of Shh. This cleavage is mediated by
the protease pepsin A, which is acid-dependent (58). Omepra-
zole furthermore reduced the expression of Shh mRNA
(59). Loss of Shh expression, however, is not the outcome of
loss of glandular cells but is preceding it, although not neces-
sarily being causative for parietal cell loss. Nevertheless, loss
of Shh may be involved in hypochlorhydria and hyperg-
astrinemia with subsequent morphological changes and loss
of sensitivity to histamine-regulated acid secretion (60). Sum-
ming up these recent data, Shh is responsible for parietal cell
function, the loss of it leads to hypochlorhydria and hyperg-
astrinemia, resulting in atrophic gastritis (61). The circle
closes as Shh is acid-dependent and therefore could be
reduced/inhibited by acid-suppressing drugs. Based on these
facts, we hypothesize that the treatment for atrophic gastritis
with acid-suppressing drugs (see below) may in fact accelerate
the disease. Actually, studies have shown that all patients on
long-term treatment with PPIs develop hypergastrinemia (as
is the case during any situation with lowered gastric acid
secretion) (62); however, other authors have attributed the
main reason for atrophic gastritis to Helicobacter pylori (HP)
infection and dismissed the contribution of PPIs (63).
Achlorhydria may be frequently found in older people
(32.4% in subjects aged 74–80 years) (64); in context with
chronic alcohol consumption (65); or during acute (66, 67);
or chronic gastric infection (68). In addition, low gastric acid-
ity, for instance due to atrophic gastritis, represents an
enhanced risk for oral infection e.g. elderly people are more
likely to be infected with HP (69). Other diseases with
Pali-Scho¨ll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy
Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 471
reduced acid production are chronic renal failure (70) and
gastric ulcer (in contrast to duodenal ulcer), where patients
may present with decreased basal and stimulated acid pro-
duction (71). Also, resections and bypasses of the stomach,
including bariatric surgery, cause achlorhydria (72).
More importantly, inhibition or neutralization of gastric
acid with so-called anti-ulcer drugs is performed when treat-
ing gastritis and peptic ulcers. The therapy goal is to reach
gastric pH levels above 4.5 (73), also for children (74), or
even above 6.0 for treating bleeding peptic ulcers (75). Avoid-
ance of acid is needed in these therapies to stop autodigestive
processes and support mucosal healing in the extreme
environment of the gastric lumen. Long-term treatments with
steroidal and nonsteroidal anti-inflammatory drugs are
associated with gastric mucosal damage for various pharma-
cological reasons. Therefore, anti-ulcer drugs are also co-pre-
scribed during these treatments to protect the gastric mucosa.
Several classes of medications are available for these pur-
poses: PPIs already mentioned above; H2RA; sucralfate; and
acid neutralizers like bismuth compounds. Our in vitro diges-
tion assays have indicated that already at pH 2.75–3.0 pepsin
is no longer fully activated (76, 77). The work of Tanaka and
colleagues also underlines this observation, as the activation
of pepsins optimally occurs at pH 1.0–3.5 and at higher pH
drops significantly (78, 79). As a consequence, peptic diges-
tion is significantly hampered. This implies that during
medications with anti-ulcer drugs, when pH values even get
much higher (80), also digestion-labile food proteins might
acquire allergenic potency (Fig. 1).
From a case of caviar allergy to a novel mouse model
of food allergy
Our work was originally triggered by a case of Beluga caviar
allergy (81) occurring in a patient suffering from chronic
ulcer and constantly taking PPIs during years. The patient
noted specific sensitization several years after the first caviar
consumption when experiencing anaphylactic episodes. As
caviar consumption usually is a rare event, he remembered
that the first time eating caviar happened during treatments
with PPIs.
We imitated this case in an animal study and fed mice with
caviar (82). Only those groups that were additionally treated
with sucralfate, H2 receptor blockers, or PPIs developed an
allergic phenotype consisting of specific IgE and positive
immediate-type skin tests. Subsequently, we repeated the
experiments with other types of allergens, like parvalbumin
from fish (82), hazelnut (83), and recently ovalbumin (84)
and peanut (unpublished). In these novel animal models of
food allergy, we also found dense infiltration with eosinophils
in the gastric mucosa (85), which may support IgE produc-
tion via IL-4 secretion. Furthermore, the morphology and
immunologic setting of the gastrointestinal tract was altered
in animals that received sucralfate along with the allergen, as
Pathophysiology
Digestion-resistant antigens
Prototype: Ara h 2 from peanut
Stomach: acidic pH 
=> Pepsin activated
=> Protein resists I.
Duodenum: 
=> Acidic chyme 
=> Secretin release 
=> Release of pancreatic enzymes 
=> Protein resists II.
Immune response:
*sensitization
*allergic symptoms at 
low threshold levels
Physiology
Digestion-susceptible antigens
Prototype: Bet v 1-homologues in edible plants
Stomach: acidic pH 
=> Pepsin activated 
=> Protein digestion I.
Duodenum: 
=> Acidic chyme 
=> Secretin release 
=> Release of pancreatic enzymes 
=> Protein digestion II.
Immune response:
tolerance/ignorance
Pathophysiology
Digestion-susceptible antigens
Prototype: parvalbumin from fish
Immune response:
*sensitization
*allergic symptoms at
low threshold levels
Stomach: non-acidic pH 
=> Pepsin not activated 
=> Protein persists I. 
Duodenum: 
=> Alkaline chyme 
=> No secretin release 
=> No release of pancreatic enzymes 
=> Protein persists II.
B CA
Figure 1 The fate of a food protein depends on its intrinsic stabil-
ity and/or the gastric acidity level at the time point of ingestion. (A)
Proteins homologous to Bet v 1 from birch pollen are easily
degraded. They cause oral, but rarely systemic reactions because
in degraded formthey are ignored or tolerated by the immune sys-
tem. (B) Digestion-labile proteins, like parvalbumin from codfish,
may become allergenic when digestion is inhibited. This may occur
in conditions where the gastric pH is elevated, resulting in dimin-
ished activation of pepsin. The elevated pH of the chyme subse-
quently prevents the release of duodenal secretin resulting in
impaired pancreatic digestive function. Persisting protein remnants
are then able to induce an (allergic) immune response. (C) Sensiti-
zation against digestion-stable food proteins/oral antigens like Ara h
2 occurs independently of the gastric acid condition because of
specific molecular features causing stable tertiary or quaternary
structures of these proteins.
Anti-acid medication as a risk factor for food allergy Pali-Scho¨ll and Jensen-Jarolim
472 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
this treatment induced changes in the structure of epithelium
and villi, and an increase in eosinophils and mucus-producing
cells in the intestine (86).
Anti-ulcer medications are relevant in human patients
To evaluate the impact of our observations for human
patients, we designed an observational study of 150 gastroen-
terological patients who were treated during 3 months with
anti-ulcer drugs. The data showed that anti-ulcer drugs
indeed supported IgE induction and de novo sensitization
against food proteins from the average daily diet (87). The
sensitization was clinically relevant and long lasting, as skin
prick tests toward specific food allergens remained mostly
positive even 5 months after discontinuation of anti-ulcer
therapy. As the patients were around 65 years of age, the
results indicated that oral sensitization may occur also in
elderly persons. Moreover, we concluded that by the oral
route also established tolerance toward previously well-
tolerated food can be broken.
Another important target group for anti-ulcer drugs are
pregnant women. During pregnancy, anti-ulcer drugs are
consumed because of heartburn/gastro-esophageal reflux (88),
which is caused by hormonal changes leading to reduced
esophageal sphincter pressure (89), and by increasing abdom-
inal volume. Whereas in the past modifications of life-style
and short-term treatments with acid neutralizers were pre-
ferred (88), also this patient group is treated with highly effi-
cient PPIs today (90). We hypothesized that in this setting,
sensitization of the mother could predispose the child for
Th2 immune responses. When we fed pregnant mice with fish
protein in context with anti-ulcer medication, we observed
not only allergy induced in the mother animal but also a Th2
bias in the offspring (91). This prompted us to suggest that
these treatments in pregnancy might contribute to the
increased numbers of atopic predisposition in babies (92).
Interestingly, when Dehlink et al. investigated three data sets
from a Swedish birth registry and correlated the allergy/
asthma incidences of babies with anti-ulcer drug consumption
of the mothers, they could confirm our prediction in the
human setting (93).
Sucralfate with an aluminum compound acts as
immunostimulant
In immunology, aluminum compounds such as Al(OH)3 are
classically used as Th2 adjuvants. Sucralfate is a hydrous
basic aluminum salt of sucrose octasulfate. Indeed, its adju-
vant effect could be recently demonstrated in a mouse model
(94, 95), where ovalbumin as a less degradable protein was
used as a model allergen and applied together with sucralfate.
The induced allergen-specific IgE-antibodies as well as IL-4
and IL-5 cytokines indicated a Th2 shift when sucralfate was
co-applied. Therefore, whereas other antacids and the dietary
supplement base powder bind and reduce acid only (76),
sucralfate additionally acts as immune stimulant (94). It was
further confirmed in a recent study by another working
group that aluminum does also impact the human immune
response, as the addition of aluminum hydroxide to the
model antigen keyhole limpet hemocyanin (KLH) resulted in
a clear Th2-response (96) compared with studies where KLH
was used without an adjuvant (97).
Impaired digestion lowers threshold levels of food
allergens
In the sensitization phase of allergy, IgE-antibodies are obvi-
ously formed against conformational epitopes but not against
smaller peptides, except in persistent allergy. Does this also
apply for the effector phase when IgE is already formed and
fixed to effector cells? We hypothesized that conformationally
intact allergens would trigger mediator release much easier,
whereas peptide leftovers should no longer be able to cross-
link IgE, which would have implications in clinics. Indeed,
when in a clinical study, fish allergic patients were orally
exposed to native or in vitro predigested fish, the native pro-
tein expressed much higher capacity to elicit clinical reactivity
and positive type I skin test reactions (98). Moreover, in his-
tamine release test, the dose of native allergen eliciting posi-
tive reactivity was 10 000 times lower than with predigested
allergen (77). This implies that in settings of impaired diges-
tion, lower levels of allergens may be able to induce hyper-
sensitivity reactions. These data might finally also explain
why some food-allergic patients develop symptoms of differ-
ent intensity at different time points: their actual symptom
intensity may depend on the current functional capacity of
the digestive system. We consider this observation being
clinically important and suggest that a question clarifying
anti-ulcer drug consumption should be regularly included in
allergologic anamnesis.
Table 1 Undesired effects of different acid-suppressing drugs*
Drug/mechanism of drug Side effects
Antacids/neutralize
produced acid
Diarrhea
Constipation
Interference with drug
absorption
Renal, metabolic, and
acid-base disturbances
H2-receptor antagonists/
block histamine receptor 2
and therefore
histamine-induced acid
production
Mental confusion
Interference with drug
absorption
Gynecomastia
Interstitial nephritis
Cytochrome P450
interactions
Proton pump inhibitors/block
H+K+-ATPase and
therefore complete acid
production during their
presence
Hypergastrinemia
Rebound acid
hypersecretion
Malabsorption
Infections
Drug interactions
*Modified from (71) and (101).
Pali-Scho¨ll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy
Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 473
Anti-ulcer drugs as co-medications: role in drug
allergy?
Anti-ulcer drugs are useful co-medications to protect
the mucosa from damage due to steroidal and nonsteroi-
dal drugs. This is especially relevant during long-term
pain- and anti-inflammatory therapies, for instance in
management of rheumatoid arthritis or inflammatory bowel
disease.
A number of these patients develop intolerances to these
drugs. It is apparent that in some incidences, clinical symptoms
are of the immediate-type and mimic antibody-mediated
hypersensitivity. However, serum tests often remain negative
for specific IgE or IgG possibly due to methodological limita-
tions. Moreover, these drugs are haptens and should act as
complete antigens only in context with other proteins. In stud-
ies of the pharmacokinetics of oral drugs, the adsorption to
gastric proteins hindering regular distribution is a well-known
phenomenon. Especially, albumin occurring at high levels in
gastric juice is a preferred binding partner for oral drugs, for
instance for the pain killer diclofenac. Thereby, a complete
antigen is formed as an intermediate product (99). However,
thisproduct is normally digested by pepsin, leading to the
release of the drug. It was tempting to speculate that a problem
might arise when anti-ulcer drugs are co-medicated. Exactly, in
this setting, the intermediate drug-carrier complexes would
possibly be able to persist the transit and sensitize the patient.
Could this be an explanation for antibody-mediated drug
allergy? The answer was found in a BALB/c mouse model
when a drug-albumin conjugate was fed with and without
co-medication of the anti-ulcer drugs sucralfate and PPI (100).
Only the group treated with anti-acid drugs developed IgE and
IgG1 against diclofenac. Clearly, more studies are needed to
confirm this theory in the human setting.
Synopsis
Based on in vitro data as well as mouse and human studies, we
propose that anti-ulcer drugs support clinically relevant sensiti-
zation against oral proteins like food allergens and drugs and
possibly favor eosinophilic gastrointestinal inflammation (101).
The induced Th2 bias is long lasting, clinically relevant and
transmitted to the offspring during pregnancy. Several immu-
nological mechanisms may be causative: (i) anti-ulcer drugs
inhibit peptic digestion and turn harmless food proteins into
allergenic molecules, which are able to perform sensitization
and to elicit allergy at lower threshold levels and (ii) some anti-
ulcer compounds such as sucralfate exhibit additional Th2
adjuvant function. The patient groups affected are those trea-
ted or co-medicated with anti-ulcer drugs to heal or prevent
gastro-esophageal reflux, gastritis, or gastric ulcer. Moreover, a
high number of patients use anti-acid substances, antacids, or
dietary supplements – without a prescription of a physician –
on a more or less daily basis to treat heartburn and stomach
ache. Acid-suppressing drugs are considered safe, with – admit-
tedly rare- side effects [reviewed in (71) and (102)] (Table 1).
However, to this list, we suggest that ‘Increased risk for sen-
sitization against dietary proteins’ and ‘Lowering the food
allergens levels needed to elicit hypersensitivity reactions in
food-allergic patients’ should be added. Therefore, we question
over-the-counter sale of anti-ulcer drugs and suggest prescrib-
ing them according to strict indications during a therapeuti-
cally useful period of time, especially during pregnancy.
Acknowledgments
Financial support has been obtained by the Hertha Firnberg
stipend T283-B13 and grant SFB1808-B13 of the Austrian
Science Fund (FWF).
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