Alergia Alimentos Manejo 2016

REVIEWS
Food allergy and the gut

Anna Nowak-Wegrzyn1, Hania Szajewska2 and Gideon Lack3
Abstract | Food allergy develops as a consequence of a failure in oral tolerance, which is a default
immune response by the gut-associated lymphoid tissues to ingested antigens that is modified
by the gut microbiota. Food allergy is classified on the basis of the involvement of IgE antibodies
in allergic pathophysiology, either as classic IgE, mixed pathophysiology or non-IgE-mediated
food allergy. Gastrointestinal manifestations of food allergy include emesis, nausea, diarrhoea,
abdominal pain, dysphagia, food impaction, protein-losing enteropathy and failure to thrive.
Childhood food allergy has a generally favourable prognosis, whereas natural history in adults is
not as well known. Elimination of the offending foods from the diet is the current standard of
care; however, future therapies focus on gradual reintroduction of foods via oral, sublingual or
epicutaneous food immunotherapy. Vaccines, modified hypoallergenic foods and modification
of the gut microbiota represent additional approaches to treatment of food allergy.
Food allergy is an adverse reaction to food protein medi- fishand shellfish collectively cause >90% of food allergy
ated by the immune system13. The gastrointestinal tract in children, worldwide7. Most allergies to cows milk,
is the major route of exposure to food allergens. Nausea, egg, soybean and wheat are outgrown, whereas most
vomiting, diarrhoea, abdominal pain, food refusal, early allergies to peanut, tree nuts, seeds and seafood persist
satiety, dysphagia, food impaction, haematochezia and into adulthood8. Presence of IgE sensitization is a risk
dysmotility (regurgitation and constipation) are common factor for more persistent food allergy in infants; infan-
manifestations of allergic reactions to ingested foods. tile non-IgE-mediated gastrointestinal food allergic
The expression of food allergy ranges from immedi- disorders usually resolve by age 13years, whereas in
ate, IgE-mediated anaphylaxis, chronic eosinophilic IgE-mediated food allergy, high levels of IgE antibodies
gastrointestinal disorders to cell-mediated, delayed- to cows milk, egg white, wheat and soy are associated with
onset disorders such as food-protein-induced entero- persistent food allergy 8. In addition to nuts and seafood,
colitis syndrome (FPIES) (TABLE1). Both coeliac disease oral allergy to raw plant foods is common in adults with
1
Jaffe Food Allergy Institute, and dermatitis herpetiformis fulfil the definition of an pollen allergic rhinitis, with an overall estimate of adult
Department of Pediatrics,
Division of Allergy and
adverse reaction to a food protein (in this context, to food allergy of ~4% in developed countries. Peanut allergy
Immunology, Icahn School gluten and related prolamines) by an immune-mediated prevalence has increased considerably over the past two
ofMedicine at Mount Sinai, mechanism. However, both diseases are proven auto- decades, affecting up to 14% of children in societies with
1425 Madison Avenue, immune disorders with an identified autoantigen (tissue westernized lifestyles, such as the USA, UK, Canada and
NewYork, New York 10029,
transglutaminase) that require certain HLA types for Australia9. Food allergy is also on the rise globally, includ-
USA.
2
The Medical University of manifestations. Coeliac disease should be distinguished ing in developing countries5, presumably owing to the
Warsaw, Department of from food allergy, particularly from cell-mediated wheat adoption of a more Western lifestyle in these countries.
Paediatrics, Zwirki i Wigury allergy, and is consequently not included in this Review 3. Food allergy has a high prevalence in patients with certain
63A, 02091 Warsaw, Poland. In addition to the classic food allergic disorders (such as atopic conditions; an estimated 35% of children with
3
Kings College London
Academic Paediatric Allergy
anaphylaxis, acute urticaria and oral allergy syndrome), moderate to severe persistent atopic dermatitis have IgE-
Service, Guys & St Thomas immune reactions to foods can contribute to expres- mediated food allergy1. Among patients with eosinophilic
NHS Foundation Trust sion of GERD, IBS, constipation in young children and oesophagitis (EoE), most have food-responsive disease
Childrens Allergies infantile colic. In this Review we discuss diverse aspects in which symptoms and histological changes improve or
Department, St Thomas
of food allergy, focusing on the gastrointestinaltract. resolve with elimination of the offendingfood10.
Hospital, Westminster Bridge
Road, London SE1 7EH, UK.
Correspondence to A.N.-W.
Epidemiology of food allergy Pathophysiology of food allergy
anna.nowak-wegrzyn@ Food allergy is most common in the first few years of Oral tolerance
mssm.edu life, with an estimated prevalence of ~68% in child- Gut-associated intestinal lymphoid tissue is the largest
doi:10.1038/nrgastro.2016.187 hood46. Cows milk, egg, soybean, wheat, peanut, tree secondary lymphoid organ in the human body. This
Published online 21 Dec 2016 nuts (forexample, almond, cashew, hazelnut and walnut), tissue constantly samples ingested foreign antigens and
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Key points effects on regulatory Tcells17. Limited evidence exists

for altered gut microbiota in children with food allergy.
Food allergy affects 68% of children <5years old and 34% of the general population In vitro alterations in gut microflora might change Toll-
in developed countries; incidence of peanut allergy has increased considerably over like receptor signalling and integrity of intestinal epithe-
the past decade lial cells in children with food allergy 18. In a gnotobiotic
Food allergy results from a lack of oral tolerance, a state of systemic unresponsiveness mouse model, selective colonization of the gut with
to ingested soluble antigens mediated mainly by regulatory Tcells in the Clostridia-containing microbiota protects from food
gastrointestinal tract
allergy via activation of innate lymphoid cells, IL-22
Food reactions can have IgE-mediated, non-IgE-mediated or a combination of production and enhancement of intestinal permeabil-
IgE-mediated and non-IgE-mediated pathophysiology involving the skin,
ity 19. Adults from the USA with self-reported nut and
gastrointestinal tract, respiratory tract and/or cardiovascular system
seasonal pollen allergy have low phylogenetic diversity
Double-blind, placebo-controlled food challenge remains the gold standard for
of the gut microbiota, characterized by reduced rela-
diagnosing food allergy
tive abundance of Clostridiales and increased relative
Dietary elimination of offending foods is the current standard of care; future therapies
abundance of Bacteroidales in their gut microbiota20.
focus on specific food immunotherapy via oral, sublingual and epicutaneous routes
Whether supplementation with probiotic bacteria can
Most childhood food allergies resolve with age, with the exception of peanut and tree
correct the underlying alterations in gut flora in children
nut allergies that tend to be lifelong
with food allergy remains to be determined21.
Initial exposure to food through the impaired skin
barrier in infants with atopic dermatitis could pre-
has evolved to discriminate between potentially harmful dispose these individuals to the development of IgE sen-
pathogens and nonharmful antigens to either mount a sitization prior to first ingestion of food. Additionally,
protective immune response or to actively ignore benign early-life exposure to topical creams containing peanut
antigens, such as food or commensal bacteria11. The state oil or to peanut dust in the home environment is a risk
of active systemic unresponsiveness to ingested food factor for peanut allergy, particularly in children with
antigens is referred to as oral tolerance and is the default atopic dermatitis, whereas early introduction of peanuts
immune response in the gut. As an example of this toler- at weaning is associated with a decreased risk of peanut
ance, induction of an IgE-mediated immune response allergy among these high-risk infants with atopy 2226.
in mice is very difficult after parenteral immunization Inmouse models of egg and peanut allergy, skin expo-
with antigens (such as ovalbumin, cows milk proteins sure to these foods promotes development of specific
or peanut) present in the diet 11. Tolerance can be trans- IgE sensitization to ovalbumin and peanut, whereas an
ferred to naive animals through the transfer of regu- oral exposure promotes oral tolerance27,28. Cutaneous
latory Tcells, which are pivotal cells in oral tolerance exposure to food antigens induces thymic stromal
(BOX1). Anergy and deletion of reactive effector Tcells lymphopoietin production, activation of basophils
have been identified as potential additional mechanisms that produce IL-4, production of type2 T-helper-cell
of oral tolerance in animal models12. cytokines and accumulation of mast cells in the gut 29.
Oral tolerance is a phenomenally efficient default Mutations in genes encoding proteins that determine
response to ingested food antigens, as demonstrated by the integrity of the skin barrier, such as FLG encod-
the fact that most humans have no food allergy despite ing filaggrin, are independent risk factors for peanut
ingesting several tonnes of food over an average human allergy 30. FIG.1 illustrates differential immune responses
lifespan. However, when oral tolerance fails, food allergy to food protein in the gut and skin, with oral tolerance
develops. Food allergy is most common in infants and being the default response in thegut.
young children, as a result of the immaturity of the gut An alternative pathway of allergic sensitization to
barrier and the immune system in these age groups12,13. food could occur in the airways. In adults working in
Immune deficienciesincluding selective IgA defi- the food industry and exposed to wheat and egg white
ciency, common variable immunodeficiency and IPEX proteins via inhalation of the food dust, asthmatic
(immunodysregulation polyendocrinopathy entero- responses to the inhaled food allergens can occur
pathy X-linked syndrome)are associated with an (forexample, in bakers asthma); in some individuals this
increased prevalence of food allergy 14. Treatment with response is followed by a breach in the oral tolerance to
PPIs increases the risk of IgE sensitization to food owing the previously tolerated wheat and egg-white protein, as
to increased pH in the stomach and impaired digestion these individuals develop immediate allergic reactions
of proteins15. Additional genetic and environmental risk upon ingestion of these foods31. Additionally, systemic
factors for food allergy can include male sex, African reactions to ingested egg can occur in adults exposed to
ancestry, IL10 and IL13 gene polymorphisms, lack of pet bird dander via inhalation32. Whether primary sen-
microbial exposure (including Helicobacter pylori infec- sitization via the airways occurs in infants (for example,
tion) in early life, Caesarean section, low vitaminD through microaspiration of the gastric content in infants
levels, n-3 polyunsuturated fatty acids and westernized with GERD) is unknown.
diet low in fibre16.
Dietary changes affect the gut microbiota, leading Characteristics of food allergens
to changes in bacterial metabolites (such as short-chain The majority of food allergens are proteins. ClassI
fatty acids) that are pivotal for maintaining mucosal food allergens are 1070 kDa animal or plant glyco-
integrity and promoting oral tolerance by epigenetic proteins that are resistant to processing and enzymatic
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digestion and are capable of inducing IgE sensitization Mixed pathophysiology IgE disorders
via ingestion, such as casein and whey protein in cows Eosinophilic gastrointestinal disorders. The hetero-
milk, ovalbumin and ovomucoid in egg and storage geneous group of diseases known as eosinophilic gastro-
seed proteins in nuts1. ClassII food allergens are pollen- intestinal disorders are chronic inflammatory conditions
homologous proteins that are very unstable when sub- of the gastrointestinal tract that include EoE, eosino-
jected to heating or enzymatic digestion, such as in philic gastritis, eosinophilic gastroenteritis, eosinophilic
apple (Mald1), carrot (Dau c 1) and celery (Api g 1). enteritis and eosinophilic colitis37. Ininfants and young
Owing to their susceptibility to digestion, classII food children with mucosal eosinophilic gastroenteritis, atrial
allergens are considered incapable of inducing primary of an elemental diet for 24weeks can be warranted.
IgE sensitization via ingestion1,33. However, when inhal- Non-IgE-mediated cows milk allergy can be associated
ation of pollen leads to expression of pollen-specific IgE with increased numbers of mucosal eosinophils in the
antibodies in the oropharyngeal mucosa, cross-reactive stomach, small intestine and colon. However, in patients
reactions to foods occur, mainly via a form of contact with evidence of transmural (muscular or serosal)
urticaria known as oral allergy syndrome. Rarely, com- involvement, elimination diets are generally not success-
plex carbohydrates cause food allergy. One example is ful38,39. Transmural involvement usually occurs in adults
galactose--1,3-galactose (also known as alpha-gal), and can present with intestinal pseudo-obstruction or
which can induce delayed anaphylactic reactions after ascites. Treatment relies on systemic corticosteroids and
its ingestion via mammalian meat. In the USA, the lone other immune-modulating agents38,39.
star tick (Amblyomma americanum) bite predisposes EoE predominantly affects white men, with an onset
individuals to generation of IgE antibodies against from school age to midlife and is increasingly seen dur-
alpha-gal34. ing infancy through adolescence40,41. The prevalence of
EoE was estimated as between one and six per 10,000
Gastrointestinal manifestations persons in the USA and Europe in 2014 (REFS42,43). EoE
Immediate IgE-mediated food allergy is found in up to 54% of patients with food impaction41.
Oral allergy syndrome. Pollen-associated food allergy, A personal or family history of atopic disorders (includ-
known as oral allergy syndrome, usually manifests as ing asthma, atopic dermatitis, rhinitis and anaphylactic
transient itching in the oropharynx, sometimes accom- food allergy) is common. Family history of EoE is also
panied by mild to moderate lip swelling or blisters in frequently reported, predominantly in male relatives,
the mouth, within minutes of raw plant-food ingestion suggesting a 2% heritability risk41. Genetic variants in
(such as fruits, vegetables, legumes and nuts) inindivid- thymic stromal lymphopoietin, C-C motif chemokine 26
uals with pollen allergy 35. In rare patients, severe symp- (also known as eotaxin-3), and calpain-14 are associated
toms of dysphagia, nausea and abdominal pain can with an increased risk of EoE4447.
be elicited by ingestion or contact of raw plant foods EoE typically manifests with symptoms resembling
with oral mucosa35. Oral allergy syndrome is generally GERD, intermittent emesis, food refusal, abdominal
mild and self-limiting; cooked or baked forms of plant pain, dysphagia, irritability, sleep disturbance and
foods are well tolerated. Pollen-specific subcutaneous failure to respond to conventional reflux medications.
immunotherapy with a high dose of birch pollen extract Ininfants and young children, symptoms are unspeci-
can ameliorate or resolve oral allergy syndrome symp- fic, with refusal of solid foods and failure to thrive being
toms to apple in a subset of patients35. Oral symptoms most common; in adolescents and adults, abdominal
identical to oral allergy syndrome can also be an initial discomfort, dysphagia, oesophageal strictures and
manifestation of a systemic reaction to non-pollen- food impaction are typical symptoms. Patients can
related foods, such as milk or egg, in patients with food exhibit compensatory behaviours, such as eating slowly,
allergy 1. Oral symptoms in patients with a known sys- chewing carefully, cutting food into small pieces,
temic food allergy must be observed closely and can drinking liquids to dilute foods and avoiding hard
warrant immediate treatment. foods that could cause dysphagia (for example, meats
and breads).
Anaphylaxis. Reaction to an allergen can result in EoE is a food-allergen-responsive disease (meaning
anaphylaxis, an immediate, potentially fatal multisys- that elimination of the offending food resolves inflam-
temic allergic reaction; nausea, vomiting, diarrhoea mation) in both children and adults. The immune
and abdominal cramps start within minutes to 12 h responses to food proteins in EoE are non-IgE-mediated
following food ingestion. Symptoms improve with (driven by eosinophils and mast cells), despite a high
intramuscular adrenaline and/or antihistamines and frequency of associated IgE sensitization to multiple
resolve within minutes to hours. Gastrointestinal symp- foods in these patients48. In children, response rates to
toms are usually accompanied by pruritus, urticaria, dietary management vary from 98% on an amino-acid-
angioedema, flushing, cough, wheezing, shortness based diet to 81% on an empiric six-food elimination
of breath, tachycardia or hypotension. Teenage men diet (which includes cows milk, wheat, egg, soy, nuts
and young athletic adult women (aged2040years) and seafood)49. In adults, response to amino-acid-based
can manifest anaphylactic symptoms if they exercise diet is 88% and to empiric six-food elimination diet is
within 24 h following food ingestion, which is referred 74%50,51. No statistically significant difference exists in
to as food-dependent, exercise-induced anaphylaxis36 response rates to elimination diets between children
(TABLE1). andadults50.
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Eosinophilic gastroenteritis is a rare disease, esti- Non-IgE disorders

mated to affect 8.1 in 100,000 people in the USA52. Several gastrointestinal disorders are thought to result
Diagnosis of eosinophilic gastroenteritis is based on from cell-mediated hypersensitivities, such as FPIES,
clinical symptoms (including abdominal pain, diar- food protein-induced proctocolitis (FPIAP) and food
rhoea, eosinophilic ascites, protein-losing enteropathy protein-induced enteropathy (FPE). T-cell-mediated
and nausea and/or vomiting) in combination with gas- pathophysiology has been determined in FPE, how-
tric, small intestinal and/or large intestinal eosinophilia ever, direct evidence is lacking in FPIES and FPIAP
above the normally reported numbers53. (TABLE1).
Table 1 | Classification of gastrointestinal food allergic disorders on the basis of IgE antibody involvement in pathophysiology
Disorder Age groups Food triggers Symptoms Diagnosis Prognosis and natural
history
IgE-mediated food allergic disorders
Oral allergy Any Raw plant foods, fruits, Immediate symptoms on History, positive skin-prick Severity of symptoms
syndrome Most common vegetables, legumes contact of raw food with test with raw fruits or fluctuates with pollen
in young and nuts oral mucosa: pruritus, vegetables season
adults (age Common pollen-food tingling, erythema or Oral food challenge Oral allergy syndrome
2050years) cross-reactivities angioedema of the lips, positive with raw plant can improve in a subset
with pollen include: birch allergy tongue or oropharynx; food, negative with of patients with pollen
allergy (apple, peach, carrot, throat pruritus or cooked food immunotherapy
50% of adults celery, peanut, soy and tightness; and rarely
with birch hazelnut); ragweed nausea, abdominal pain,
pollen allergic allergy (melon, banana rhinorrhea and blisters in
rhinitis report and cucumber); the mouth
oral allergy mugwort allergy
syndrome (cabbage, mustard,
toapple fennel, carrot and celery)
Anaphylaxis Any Any, most common Onset of minutes History, positive skin-prick Favourable in infants
triggers in severe to 2 h, with nausea, test and/or serum food-IgE and young children;
anaphylaxis include abdominal pain, level those with peak lifetime
peanut and tree nuts emesisand diarrhoea Confirmatory physician- food-specific IgE antibody
Typically in supervised oral food levels >50 kUA/l tend to
conjunctionwith challenge have a more persistent
cutaneous and/or food allergy
respiratory symptoms
Food- Any Any, most common Exercise within 24 h History, positive skin-prick Natural history unknown
dependent, Most common triggers are wheat, cows after food ingestion test and/or serum food-IgE Severity can increase
exercise- in teenage milk, celery, fish and yields symptoms of level during or after pollen
induced men and shellfish anaphylaxis Confirmatory oral food season in pollen-allergic
anaphylaxis young athletic Food well tolerated if challenge patients
women (age no exercise
2050years)
Mixed, IgE and cell-mediated gastrointestinal food allergy
Eosinophilic Any Any, most common Infants and Endoscopy and biopsy Chronic, relapsing
oesophagitis triggers are cows milk, children: chronic or >15 eos/hpf) provides course
wheat, egg, soy, seafood intermittent emesis, conclusive diagnosis Uncontrolled
and nuts gastro-oesophageal and information about inflammation yields
reflux, abdominal pain, treatment response a risk of fibrosis and
poor appetite and History, positive skin-prick oesophageal narrowing
failure to thrive test and/or food-IgE level with time
Adolescents and adults: in up to 50%, but poor
chronic intermittent correlation with clinical
dysphagia, food symptoms
impaction, abdominal Elimination diet and oral
pain and early satiety food challenge
Eosinophilic Any Children with mucosal Chronic or intermittent Endoscopy or biopsy Variable, can be transient,
gastroenteritis form of eosinophilic abdominal pain, emesis, provides conclusive persistent or chronic
gastroenteritis: any irritability, poor appetite, diagnosis and information intermittent
food, most commonly failure to thrive, about treatment response
cows milk weight loss, anaemia History, positive skin-prick
Adults, especially and protein-losing test, and/or food-IgE level
those with serosal or gastroenteropathy in up to 50% of patients,
muscular involvement: but poor correlation
the disease is usually not with clinical symptoms,
responsive to dietary elimination diet, and oral
elimination food challenge50,112
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FPIES. Onset of FPIES is usually in the first 6months infants and children. In adults, shellfish sensitivity can
of life, and the syndrome manifests as protracted vomit- provoke a similar syndrome, with symptoms of severe
ing, lethargy, pallor and diarrhoea39. Prevalence of cows nausea, abdominal cramps and protracted vomiting 55,56.
milk FPIES was reported as 0.34% of infants younger
than 12months in an unselected Israeli birth cohort 54. FPIAP. Usually, FPIAP manifests in the first few months
Repetitive vomiting usually occurs 14 h after feeding; of life and is predominantly caused by cows milk or soy.
continued exposure leads to diarrhoea, anaemia, abdom- The majority of cases occur in breastfeeding infants
inal distension and failure to thrive (chronic FPIES). that seem well, have normally formed or loose stools
Cows milk and soy-protein-based formulas are the most and are discovered because of the presence of blood
common triggers in infants; rice, oatmeal, egg, wheat, oat, (gross or occult) mixed with mucus in their stools57,58.
peanut, nuts, chicken, turkey and fish are triggers in older Blood loss is usually minor but occasionally can cause
Table 1 (cont.) | Classification of gastrointestinal food allergic disorders on the basis of IgE antibody involvement in pathophysiology
Disorder Age groups Food triggers Symptoms Diagnosis Prognosis and natural
history
Non-IgE, presumed cell-mediated gastrointestinal food allergy
Food-protein- Majority onset Infants: cows milk, Chronic: emesis, History, response to Avoidance of the
induced in the first soy, rice, oat, egg, fish, diarrhoea, failure dietary restriction offending food in
enterocolitis 12months poultry, fruits and to thrive on chronic Physician-supervised oral thediet
syndrome of life vegetables exposure to cows milk food challenge Most have resolution by
New onset Older children and or soy-infant formula Jejunal biopsies: flattened 35years; rarely persists
rarely occurs adults: fish, shellfish Acute: repetitive villi, oedema, and into adulthood
in older and egg emesis within 14 h increased numbers of
children post food ingestion, lymphocytes, eosinophils
oradults dehydration (15% and mast cells113,114
shock), leukocytosis
and thrombocytosis on
repeat exposure after
elimination period
Food-protein- Young infants Cows milk or soy in infant Blood-streaked or History, prompt response Avoidance of the
induced (<6months formula; cows milk, egg, haeme-positive stools; (resolution of gross offending food in
allergic old) who are wheat or corn in maternal otherwise healthy blood in 48 h) to allergen the maternal diet or
proctocolitis frequently breast milk appearing elimination; biopsy would substitution with a
breastfed be conclusive but is not hypoallergenic formula;
necessary for most patients Most patients able to
Sigmoidoscopy: areas of tolerate cows milk or
patchy mucosal injection soy by 12years of age,
to severe friability with reintroduction of the
small, aphthoid ulcerations offending food at home
and bleeding
Colonic biopsy: prominent
eosinophilic infiltrate in the
surface and crypt epithelia
and the lamina propria;
neutrophils are prominent
in severe lesions with crypt
destruction
Food-protein- Young infants; Cows milk, soy, egg, Osmotic diarrhoea History, endoscopy Avoidance of the
induced incidence has wheat resulting from secondary andbiopsy offending food in the diet
enteropathy decreased lactose intolerance; Response to dietary Most patients have
since the 1970s secretory diarrhoea restriction resolution in 12years
resulting from loss Clinical symptoms resolve Reintroduction of the
of villus surface, within a few weeks offending food at home
fat malabsorption Recovery of villi can take In contrast to coeliac
and protein losing up to 6months disease, wheat food
enteropathy; emesis, protein-induced
failure to thrive and enteropathy is a
anaemia in 40% self-limiting condition;
ofpatients coeliac serology is
negative, genetic
markers are absent and
wheat food-protein-
induced enteropathy is
commonly associated
with additional food
sensitivities
eos/hpf, eosinophils per high power field.
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Box 1 | FOXP3+CD4+ Treg cells are central to the maintenance of immune homeostasis and tolerance
FOXP3+ CD4+ Tregulatory (Treg) cells are present in every organ of the body and constitute ~10% of the total CD4+ Tcell
population. In the intestinal lamina propria, they constitute a much higher proportion: >30% of CD4+ Tcells in the
colonic lamina propria and ~20% in the small intestinal lamina propria105.
Intestinal FOXP3+ Treg cells regulate mucosal immune responses at multiple cellular levels through various molecular
mechanisms. They constitutively express CTLA4, inducible Tcell co-stimulator (ICOS), IL-10, TGF and IL-35, and inhibit
bystander Tcells to maintain immune tolerance to dietary components and intestinal microbiota.
A subset of Treg cells controlls expansion of T follicular helper cell populations.
Treg cells suppress immunopathology mediated by effector Tcells. Mice with low numbers or reduced suppressive
activity of colonic Treg cells have an increased susceptiblity to infection and mucosal injury.
FOXP3+ induced Tregcells are required for oral tolerance and their depletion results in defective oral tolerance in mice106,107.
Consequence of FOXP3+ Tcell deficiency
Lack of FOXP3+ Tcells leads to enteropathy, eczema and elevated IgE in both mice and humans (immunodysregulation
polyendocrinopathy enteropathy X-linked syndrome). Severe food allergy occurs as one manifestation of FOXP3
mutations in humans108.
Role of FOXP3+ Tcells in resolution of food allergy
Natural development of oral tolerance on food-allergic children is associated with increased FOXP3+ Tcells.
Resolution of cows milk allergy in children is associated with an increased frequency of peripheral blood CD4+ CD25+
Treg cells after an oral milk challenge and reduced proliferation of milk-specific Tcells109,110. Depletion of CD4+ CD25+ Treg
cells restores the invitro proliferative response in milk-tolerant individuals109.
In children with egg and peanut tolerance, stimulation of the peripheral mononuclear cells with the relevant allergen
resulted in markedly increased numbers of IL-10-expressing CD25+ CD127lo cells (type1 Treg cells), FOXP3+ cells and
CD4+ cells compared with children who have persistent egg and peanut allergies111.
anaemia. However, in many breast-fed infants with Diagnosis of food allergy

proctocolitis, the resolution of bloody stools occurs Diagnosis of food allergy is based on clinical features,
spontaneously over few weeks, without maternal dietary physical examination and the results of supportive lab-
foodelimination57,58. oratory tests13 (FIG.2). The initial assessment should
include details about the specific signs and symptoms,
FPE. Manifestation of FPE usually takes place in the the timing of symptom onset from food ingestion,
first several months of life, with protracted diarrhoea, and the presence of potential co-factors that might
vomiting, failure to thrive, malabsorption, anaemia increase reaction severity (such as exercise, alcohol,
(40%) and/or protein loss. Cows milk is the most fre- NSAIDs or histamine H2 receptor blockers). Medical
quent cause of FPE, but other causes include soy, egg, history and physical examination guide the selection
wheat, rice, chicken and fish. In contrast to coeliac dis- of the laboratory tests. History can be useful in diag-
ease, wheat-FPE is mostly not a life-long condition and nosing food allergy in acute events such as systemic
autoantibodies specific for coeliac disease are negative. anaphylaxis after isolated ingestion of peanut, but alone
Additionally, wheat-FPE can be associated with allergies should never be used to make a definitive diagnosis,
to otherfoods. as <50% of reported food-allergic reactions could be
verified by double-blinded, placebo-controlled food
Other gastrointestinal disorders challenges1. Inchronic disorders (for example, atopic
Food allergy can contribute to the dysmotility under- dermatitis, EoE and non-IgE-mediated gastrointestinal
lying the pathophysiology of GERD (especially in the food allergy) the history is often an unreliable indica-
infants with severe and persistent regurgitations, food tor of the offending allergen1. Although history alone
aversions, failure to thrive and atopic dermatitis), infan- is insufficient, it is critical when combined with other
tile colic, IBS and constipation in a subset of patients. assessments for establishing whether reported symp-
The exact pathomechanism of dysmotility induced by toms are consistent with an IgE-mediated (for exam-
food allergens remains poorly understood5961. Adirect ple, urticaria or anaphylaxis within minutes to 12 h)
interaction between the enteric nervous system and or non-IgE-mediated immune mechanism (for exam-
inflammatory cells (such as mast cells and eosino- ple, bloating and abdominal discomfort after drink-
phils) and pro-inflammatory cytokine secretion is ing milk in a patient who tolerates small amounts of
possible6267. Stimulation of afferent nerve circuits via dairy and cheese, suggestive of lactose intolerance).
the brainstem during allergic reaction might influ- When history suggests that an immune mechanism is
ence sphincter tone and trigger gastrointestinal symp- unlikely, testing for food allergy is discouraged because
toms68. Large and well-designed studies are needed for it could yield false-positive results, lead to unneces-
a better understanding of the role of food proteins and sary dietary restrictions and delay accurate diagnosis.
to delineate the immunological mechanisms at work in The differential diagnosis of food allergy is extensive,
thesedisorders. assummarized in TABLES2&3.
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a Gut b Skin
High dose Low dose exposure peanut from skin contact
ingested peanut (e.g. kissing, touching, household dust)
Low pH digestive enzymes No digestion

Intact peanut proteins
Partially degraded proteins
Peptides of lower allergenity Atopic dermatitis skin Healthy skin
S. aureus SEB25
Commensal Gut
probiotic bacteria microbiota
TSLP Intact skin
Filaggrin barrer
Dietary SCFA Butyrate CD86 Lipids
bre GPR109A
IL-22
IL-4
Langerhans IL-31 No
DC penetration
IL-13 of peanut
proteins
DC Dermal
CD4+ IL-10 IL-4 DC
T cell IL-13
IL-6
TGF Treg Mesenteric No immune
IL-2 lymph node response
TH2
B cell
IL-4
B cell
Peanut
IgE
allergy
IgG IgA Skin
Oral tolerance to peanut lymph node
Figure 1 | Differential immune responses in the gut (oral tolerance) and skin (IgE sensitization and food allergy)
using peanut allergy as an example. Oral ingestion of peanut has an increased likelihood of inducing oral tolerance in
the majority of children at a high-risk of peanut allergy with atopic dermatitis, compared with epicutaneous exposure to
peanut protein in children with atopic dermatitis and impaired skin barrier, which has an increased likelihood of allergic
IgE sensitization. a | In the induction of oral tolerance, dietary fibre is digested by probiotic bacteria to release short-chain
fatty acids (SCFA; for example butyrate, which acts via GPR109A) that then stimulate dendritic cells (DC) to produce IL10
and to induce regulatory Tcells (Treg). b | Conversely, S.aureus and its toxins (for example, staphylococcal enterotoxin B;
SEB25) can lead to inflammation by inducing Tcellindependent expansion of Bcells, which initiates the production of
thymic stromal lymphopoietin (TSLP) from keratinocytes, and stimulates mast cell degranulation, resulting in type2
Thelper cell (TH2) skewing. S.aureus also disrupts proteolytic balance in the skin by inducing multiple metalloproteases
indermal fibroblasts. DCs secrete IL4, IL13 and IL6 that stimulate generation of TH2 skewed effector Tcells. TH2
CD4+Tcells secrete IL4 that induces IgE production by Bcells. Failure to develop oral tolerance can be influenced by
lackof ingestion of regular doses of peanut, combined with intermittent exposure to trace amounts in the diet,
inflammation in the gastrointestinal tract, high gastric pH, low levels of digestive enzymes, gut dysbiosis and
increasedintestinal permeability or immune defects resulting in deficiency of FOXP3 (immunodysregulation
polyendocrinopathy enteropathyXlinked syndrome; see BOX1) or IgA (selective IgA deficiency, common variable
deficiency). TGF,transforming growth factor .
Diet diaries can be used as an adjunct to history; of cows milk and dairy products will also improve
patients keep a chronological record of all foods ingested symptoms of primary and secondary lactose intoler-
and any symptoms experienced over a specified period. ance. Although avoidance of suspected food allergens is
Diet diaries should be recorded prospectively to minim- recommended before oral food challenge, results from
ize recall bias and provide very detailed information elimination diets alone are rarely diagnostic of food
about foods eaten (such as amount, specific foods and allergy, especially in chronic disorders such as atopic
food brands) and temporal association with symptoms. dermatitis, EoE and non-IgE-mediated gastrointestinal
Additionally, elimination diets are commonly used in food allergy. A trial of diagnostic elimination diet that
the diagnosis of food allergy. Suspected foods are com- resulted in resolution or improvement of symptoms
pletely eliminated from the diet for ~2weeks in atopic should be followed by a rechallenge. In IgE-mediated
dermatitis and up to 48weeks in EoE and chronic food allergy and in FPIES, the oral food challenge
non-IgE-mediated gastrointestinal food allergy 13. The should be conducted under physician supervision
resolution of symptoms with an elimination diet sup- owing to risks of a severe reaction. Double-blinded,
ports the diagnosis of food allergy; however, elimination placebo-controlled food challenge remains the gold
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standard in the diagnosis of IgE-mediated food allergy; Laboratory tests for food allergy
however, open oral food challenge is considered a useful Diagnosis of IgE-mediated food allergy. Skin-prick
screening tool. A positive oral food challenge with mild tests are an inexpensive, reproducible method that
objective or subjective symptoms should be confirmed can be used to screen patients for IgE-mediated food
by a double-blinded, placebo-controlled food challenge. allergy 69. Glycerinated food extracts and appropriate
In non-IgE mediated gastrointestinal food allergy, such positive histamine and negative saline controls are
as EoE, FPIAP or FPE, challenge to the suspected food applied by the prick or puncture technique. Results
can be done at home and symptoms recorded with a are available within 1015 min. A positive skin-
symptomdiary. prick test (indicated by wheal and flare) indicates the
History and physical History

examination Type and amount of food ingested
Timing of symptoms to food ingestion
Symptoms and signs
Treatment
Co-factors (e.g. exercise, alcohol,
anti-acid therapy, NSAIDs)
Most recent reaction
Most severe reaction
Personal and family history of atopy:
Suspected mixed or food allergy, asthma, atopic dermatitis,
cell-mediated food allergy atopic rhinitis
EoE, FPIES, FPIAP and FPE
Suspected IgE-mediated Suspected non-immune

Biopsy food allergy (anaphylaxis adverse food reaction
and atopic dermatitis) Testing for food allergy not indicated
Peripheral eosinophils
Hgb, Hct, albumin and total protein
EoE, FPIES
Faecal occult blood
Screen for food-IgE Consider testing for non-immune

(prick skin test andor reaction (e.g. hydrogen breath test
Trial of diagnostic elimination diet serum foodspeci c IgE) for lactose intolerance)
Foods selected based on experience
and results of screening tests
If foodspeci c IgE is detectable
physician-supervised OFC might be
warranted for food reintroduction Positive Negative
Convincing history of
allergic reaction and Reintroduction of food into diet
evidence of foodspeci c IgE If convincing history of anaphylaxis
Resolution Positive PST or serum IgE consider further evaluation and OFC
No Yes
Yes No
Review diet
Reconsider foods Strict dietary food avoidance
Correct diagnosis? Nutritional support
Anaphylaxis treatment plan Periodic re-assessments

Adrenaline auto-injector Consider OFC and
If foodspeci c IgE is detectable
Medical jewelry reintroduction of food
reintroduction should be done as OFC
Figure 2 | Approach to diagnosis and management of food allergy. In eosinophilic oesophagitis (EoE) and food
Nature Reviews | Gastroenterology & Hepatology
proteininduced enterocolitis syndrome (FPIES) foodspecific IgE can be detectable in a subset of patients. In EoE, patients
with detectable food-specific IgE could be at risk of immediate, anaphylactic-type reactions to foods upon reintroduction
following a period of elimination. Consequently, evaluation of food-specific IgE is recommended before food
reintroductionin EoE; if positive, supervised oral food challenge (OFC) might be warranted; if negative, food reintroduction
can be done at home. In FPIES, especially as a result of cows milk, ~25% of patients develop detectable cows-milk-specific
IgE (a condition known as atypical FPIES) over time. Of these patients, ~1 in 3 can progress to immediatetype symptoms,
including anaphylaxis. In FPIES, the offending food reintroduction should be done during a supervised OFC (not at home)
regardless of IgE positivity, owing to the risk of severe reactions with hypotension. Whenfoodspecific IgE is detected,
OFCprotocol is modified to account for the possibility of anaphylaxis. FPE, food proteininduced enteropathy; FPIAP, food
protein-induced allergic proctocolitis; Hct, haematocrit; Hgb, haemoglobin; PST, prick skin test.
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Table 2 | Differential diagnosis of food allergy

Condition Pathomechanism Symptoms
Enzyme deficiencies
Lactose intolerance Lactase deficiency can be primary (congenital Bloating, abdominal pain, diarrhoea (dosedependent) and borborygmi
and hypolactasia) or secondary (coeliac
disease,infectiousenteritis, radiation, graft
versushost diseaseor enteropathy resulting from
other causes)
Hereditary fructose Hereditary deficiency of fructose aldolase B; Emesis, poor feeding, hypoglycaemia, seizures, jaundice and chronic
intolerance uncommon liver disease with hepatomegaly
Sucrase-isomaltase Sucrase-isomaltase deficiency The majority of infants present in the first year of life with severe
deficiency Can be congenital, resulting from genetic diarrhoea, abdominal bloating, perianal excoriation and growth failure
mutations: both parents must carry the mutated after the introduction of sucrose and starch-containing foods
gene for the child to have the disease
Alcohol intolerance Polymorphism of the gene encoding aldehyde Nasal congestion, flushing and vomiting within minutes of ingesting
dehydrogenase causing deficiency of the alcohol
enzyme, which metabolizes alcohol in the liver
Common in people of Asian descent
Exocrine pancreatic Deficiency of pancreatic enzymes, which can be Diarrhoea and/or steatorrhoea with weight loss and/or growth failure
insufficiency acquired or congenital (such as in cystic fibrosis Other symptoms can be caused by deficiencies in fat-soluble vitamins
and ShwachmanDiamond syndrome)
Chronic liver disease Deficiency of bile acids Diarrhoea and/or steatorrhoea with weight loss and/or growth failure
or cholestasis Other symptoms can be caused by deficiencies in fat-soluble vitamins
Gastrointestinal disorders
Veryearlyonset IBD 25% of patients have underlying Increased probability of manifestation as colitis compared with
immunodeficiency patients with lateonset IBD, with blood and mucus in the stool
Can be caused by mutations in IL10, IL10R, NCF2, Onset younger than 6years; infantile IBDonset younger than 2years
XIAP, LRBA or TTC7 Patients frequently resistant to IBD therapies
Associated with a very strong family history of IBD
(at least one 1st degree family member with IBD)
Fructose Deficiency of fructose carrier GLUT5 in the small Bloating, abdominal pain, diarrhoea (dosedependent)
malabsorption intestine enterocytes
Prevalence 10% in Asia, up to 30% in Western
Europe and Africa
GERD Symptoms related to erosive or nonerosive Nausea, emesis, heartburn, refusal to feed, acid regurgitation, dysphagia
oesophagitis by acid GERD and failure to thrive
Peptic ulcer disease Ulcer of the gastrointestinal tract Abdominal pain, anorexia, nausea, weight loss and
(commonly duodenum) melaena
Pylorus hypertrophy Hypertrophy of the pylorus muscle Severe, projectile nonbilious vomiting in the first 3months of life;
rarecase reports described eosinophilic infiltrates in pylorus and
reported resolution of muscle hypertrophy with hypoallergenic formula
or steroids
Hirschsprung Failure of the neural crest cells to migrate Delayed passage of meconium, severe constipation and/or inability to
disease completely during fetal development of the pass bowel movement spontaneously (distal obstruction syndrome),
intestine resulting in agangliosis, usually affecting ileus, emesis and abdominal distension
the short segment of the distal colon
Tracheo- Congenital: failed fusion of the Prominent salivation, choking, coughing, vomiting, and cyanosis
oesophageal fistula tracheosophageal ridges during the third week associated with the onset of feeding in newborn babies and young
of embryological development infants, recurrent pneumonia, if not recognized and treated
Acquired: a surgical complication for example,
laryngectomy
Gastrointestinal infections
Viral, bacterial or Virus (for example, norovirus, rotavirus, enteric Pain, fever, nausea, emesis and diarrhoea
parasitic enteritis adenovirus), bacteria (for example, Salmonella
spp, Campylobacter spp, Shigella spp, Yersinia
spp), or parasites (for example, Giardia intestinalis,
Cryptosporidium parvum)
Neurologic disorders
Gustatory rhinitis Neurogenic reflex Profuse watery rhinorrhoea associated with spicy foods
Frey syndrome Neurogenic reflex, can be associated with Facial flush in trigeminal nerve distribution associated with spicy foods
(auriculo-temporal traumatic delivery and injury to trigeminal nerve
syndrome) (for example, forceps delivery)
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Table 2 (cont.) | Differential diagnosis of food allergy

Condition Pathomechanism Symptoms
Psychiatric disorders
Panic disorder An anxiety disorder in children and adults; Subjective reactions, fainting upon smelling or seeing the food,
usually leads to extensive medical testing; can be tachycardia, perspiration, dyspnoea, shivers and uncontrollable fear
controlled with medication (fear of dying)
Anorexia nervosa Psychiatric disorder, predominantly affecting Extreme dietary restrictions, distorted body image, untreated can lead
young women (age 2040years) to death owing to electrolyte abnormalities and bradycardia
Bulimia Psychiatric disorder Binge eating followed by vomiting, weight fluctuations, enamel erosions
possibility of a symptomatic IgE-mediated food allergy, Cor a 9 and/or 14 are at high risk of systemic reactions72.
whereas negative results confirm the absence of IgE- Basophil activation tests rely on detection of the expres-
mediated food allergy (negative predictive accuracy sion of surface markers (CD63) on basophils during
95%) if good-quality food extracts are used from a degranulation in an allergic reaction, measured by flow
reliable source13. In oral allergy syndrome, fresh foods cytometry. Inone study, basophil activation was more
can be used. The skin-prick test can be an excellent accurate than food-specific IgE detection for diagnosis
means of excluding IgE-mediated food allergy but it of symptomatic peanut allergy in children73.
can only suggest the presence of clinical food allergy.
The skin-prick test is of limited or no utility in EoE and Diagnosis of mixed or non-IgE mediated food allergy.
other cell-mediated food allergic disorders1. No reliable laboratory tests exist for mixed and
Intradermal skin testing is a more sensitive and non-IgE-mediated food allergy, as food-specific IgE
less specific diagnostic method than the skin-prick are either not detected or, as in the case of EoE, have
test, but increases the risk of a systemic reaction com- poor diagnostic accuracy in identifying the triggering
pared with skin-prick testing; therefore, this test is not foods. Peripheral blood eosinophilia, increased intesti-
recommended for diagnosis of food allergy 1. Atopy nal permeability, faecal presence of eosinophil-derived
patch tests have also been evaluated for the diagnosis of neurotoxin, presence of faecal reducing substances or
food allergic disorders with proven or suspected Tcell presence of blood, mucus and/or leukocytes in stool
involvement, such as atopic dermatitis, EoE or FPIES, smear support the diagnosis of food allergy but are
with conflicting results. However, the lack of standard- non-specific and can be present in many other diseases.
ized reagents limits the utility of this approach; there- Diagnosis of EoE is based on a constellation of clin-
fore, atopy patch tests are not recommended for routine ical symptoms and supporting findings on endoscopy
diagnosis of foodallergy 1,2. and in biopsy samples. Endoscopy can show white
The quantitative measurement of serum food-specific specks (eosinophilic exudates), linear furrows, mucosal
IgE antibodies (using an enzyme immunoassay) is more oedema, oesophageal rings and strictures. With few
predictive of symptomatic IgE-mediated food allergy exceptions, 15 eosinophils per high-power field (peak
than other methods1,3. Food-specific IgE levels exceed- value) in one biopsy specimen are considered a min-
ing the diagnostic values indicate >95% likelihood of an imum threshold for a diagnosis of EoE40,74,75. Patients
allergic reaction following food ingestion: for example, with suspected EoE should be treated with high-dose
serum peanut-IgE levels >14 kUA/l (allergen-specific PPIs for 8weeks to exclude GERD or PPI-responsive
units of IgE per litre)70. Food-specific IgE levels can be oesophageal eosinophilia, with the responses assessed
monitored, and if they fall to serum levels <2 kUA/l for clinically and by repeat biopsy 40,76. A trial of a diagnostic
egg, milk, or peanut, patients without severe reactions in elimination diet followed by an oral food challenge is
the past 12years should be rechallenged to evaluate for utilized to identify the offending foods in EoE and other
resolution of IgE-mediated foodallergy 71. cell-mediated food allergy 1,2,77(FIG.2).
Molecular diagnosis is based on purified individual In FPIES, after an acute reaction, a prominent
natural or recombinant allergens and potentially offers increase in the number of peripheral blood neutrophils
superior specificity owing to the purity of the allergens occurs, peaking at 46 h from the onset of symptoms78,79.
compared with whole food extracts. Molecular diag- Stools often contain occult blood, neutrophils, eosino-
nosis is particularly useful in diagnosis of peanut and phils and CharcotLeyden crystals. Skin-prick test
hazelnut allergy in patients with birch pollen allergy, as results for the suspected foods are usually negative, but
these nuts are the most studied and are cross-reactive a small subset of patients can develop IgE sensitization
with birch pollen. Patients with IgE antibodies directed to the FPIES food (known as atypical FPIES), which is
exclusively against birch Bet v 1 cross-reactive aller- associated with a protracted reactioncourse.
gens in peanut (Ara h 8) and hazelnut (Cor a 1) are at Diagnosis can be established when elimination of
low risk of systemic reaction to peanut and hazelnut 13. the responsible allergen leads to resolution of vomiting
Many individuals can ingest these nuts without any within several hours (although diarrhoea can persist up
allergic symptoms and consequently such patients are to 72 h) and oral food challenge induces symptoms of
excellent candidates for supervised oral food challenge. repetitive vomiting within 14 h. Because ~50% of oral
By contrast, patients with IgE directed against Ara h 2 or food challenges lead to profuse vomiting, dehydration
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and hypotension, these tests must be performed under Histological improvement usually occurs within
medical supervision1. FPIES is a clinical diagnosis that 46weeks of allergen avoidance, but complete resolu-
is based on a constellation of symptoms, and oral food tion of the intestinal lesions can require 618months
challenges are usually not necessary for an initial diag- in a subset of patients81. Unlike coeliac disease, loss
nosis of FPIES in infants with repeated reactions to the of clinical reactivity frequently occurs in FPE, but
same food, episodes of hypotension and resolution of the natural history of this disorder has not been
symptoms with food elimination. Oral food challenges wellstudied39.
are routinely performed to monitor for resolution of
FPIES, usually at 1218month intervals1. Unproven diagnostic tests. No controlled trials cur-
The diagnosis of FPIAP can be established when rently support the diagnostic value of current com-
food elimination leads to resolution of gross blood mercially marketed tests for food-specific IgG or IgG4
or haemato chezia, usually with dramatic improve- antibody levels, food antigenantibody complexes, evi-
ment observed within 72 h; complete clearance and dence of lymphocyte activation (for example, uptake of
resolution of mucosal lesions can take up to 1month. 3H-tagged food protein, IL-2 production or leukocyte
Reintroduction of the allergen leads to recurrence of inhibitory factor production), or sublingual or intra-
symptoms within several hours to days. Lesions are cutaneous provocation in IgE-mediated and non-IgE-
usually confined to the distal large bowel. Cows milk mediated food allergy 1,2. Use of the IgG and IgG4-based
and soy FPIAP usually resolve within 6months to tests, for example, could result in considerable over-
2years of allergen avoidance, but occasional refractory diagnosis of allergy, as they mostly reflect exposure to a
casesexist 39. given food in the diet.
Diagnosis of FPE requires the identification and
elimination of the responsible allergen from the diet, Management
with resolution of symptoms within days to weeks. Management of IgE-mediated food allergy relies on
Onendoscopy, a patchy villous atrophy is found; biopsy dietary avoidance, prompt recognition and treatment
samples exhibit a prominent mononuclear cell infiltrate of acute reactions, attention to the nutritional risksof
and a small number of eosinophils in the lamina pro- elimination diets and potential feeding difficulties in
pria, which are similar to, but less extensive than, those infants 13,77. In mixed and non-IgE-mediated food
observed in coeliac disease80. allergy, empirical dietary elimination is common
Table 3 | Physiological effects of the active substances in foods

Substance Source Symptoms
Tyramine A natural monoamine derived from tyrosine that acts as Migraine
a catecholamine-releasing agent; found in pickled, aged,
smoked, fermented or marinated foods; e.g. tofu, sauerkraut,
hard cheeses and fava beans
Histamine Naturally occurring in fermented foods and beverages; e.g. Flushing, headache and nausea
fish and sauerkraut owing to a conversion from histidine to
histamine performed by fermenting bacteria or yeasts
Sake contains histamine in the 2040 mg/l range; wines
contain it in the 210 mg/l range
Serotonin A neurotransmitter derived from tryptophan found in nuts, Flushing, palpitations, diarrhoea
mushrooms, fruits and vegetables
The highest values of 25400 mg/kg have been found in nuts
of the walnut and hickory genera
Concentrations of 330 mg/kg have been found in plantain,
pineapple, banana, kiwi, plums and tomatoes
Theobromine Bitter alkaloid in cocoa bean and tea leaves Anxiety, tremors, restlessness,
sleeplessness, increased urination,
loss of appetite, nausea and vomiting
Caffeine Xanthine alkaloid (natural pesticide in plants) that acts as a Tremors, cramps and diarrhoea
stimulant drug
Found in coffee, tea and drinks containing products derived
from the kola nut, yerba mate, guarana berries and guayusa
Sodium Antioxidant and preservative in food, E223 Rare reports of bronchospasm in
metabisulfite sensitive individuals
Monosodium Naturally occurring non-essential amino acid, flavour So-called Chinese restaurant
glutamate enhancer; double-blinded, placebo-controlled food syndrome begins 1520minutes
(MSG) challenges confirmed objective reactions to MSG in 2 of 130 after the meal and lasts ~2 h
(1.65%) selfreported MSGreactive adults Symptoms: numbness at the back
of the neck, gradually radiating to
both arms and the back, general
weakness and palpitations
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Table 4 | Management of food allergy

Disorder Dietary food allergen avoidance Emergency management of Comments
acute reactions
IgE-mediated food allergy
Anaphylaxis Strict dietary avoidance, as well as avoidance of Educate patients on how to Dietitian consultation recommended
skin or mucosal contact (e.g. kissing) and inhalation recognize and treat anaphylaxis for patients with anaphylaxis to
(e.g.steaming milk or boiling fish) exposures Provide written emergency trace amounts of foods or multiple
Annual allergy re-testing and periodic oral treatment plan foodallergy
foodchallenges are recommended to evaluate Prescribe adrenaline
forresolution auto-injector device
Milder forms Majority of children with milder cows milk and egg Educate patients on how Children reactive to baked cows milk
of systemic allergy tolerate extensively heated (baked) products to recognize and treat have higher risk of anaphylaxis and
immediate with cows milk and egg anaphylaxis more persistent cows milk allergy
milk and egg Baked cows milk and egg diet seems to accelerate Provide written emergency than individuals tolerant of baked
allergy115 development of tolerance to regular non-baked cows treatment plan cows milk
milk and egg Prescribe adrenaline
Annual allergy re-testing and periodic oral food auto-injector device
challenges are recommended to evaluate for resolution
Food- Avoid exercise for 24 h after ingestion of the offending Educate patients how to In some patients ingestion of any
dependent, food recognize and treat anaphylaxis food can trigger allergic reactions
exercise- and not exercise alone iffollowed by exercise
induced Provide written emergency Exercise transiently increases
anaphylaxis treatment plan intestinal permeability and
Prescribe adrenalin inflammation
auto-injector device Natural history is unknown
OAS Strictness of avoidance of the triggering raw food Prescribe adrenaline OAS usually develops following major
depends on the severity of the objective symptoms auto-injector device for patients pollen allergy to raw plant foods that
Strict avoidance is recommended for patients with pharyngeal swelling and have been previously well tolerated
reporting throat discomfort or worsening symptoms discomfort Pollen immunotherapy can improve
Patients with mild oral symptoms can eat raw foods OAS symptoms in some patients
as tolerated Severity of OAS fluctuates and
Baked, cooked, microwaved or pasteurized foods are usually increases during or following
usually well tolerated pollen season
Mixed pathophysiology gastrointestinal food allergic disorders
Eosinophilic Elemental (aminoacidbased formula) or For patients with evidence of Longterm adherence to diet is
oesophagitis* oligoallergenic diet can be used with strict avoidance IgE-sensitization to foods and suboptimal
of all forms of the eliminated foods with risk factors for anaphylaxis: Dietitian consultation is
A subset of patients can tolerate baked milk educate how to recognize and recommended for all patients to
With regular ingestion of food allergens, acute treat anaphylaxis, provide a educate about the principles of
symptoms are uncommon but following several written emergency treatment food avoidance and to compose
weeks of food avoidance, anaphylactic reactions plan and prescribe an adrenaline a nutritionally adequate and tasty
can ensue in patients with IgE-sensitization to foods; auto-injector device elimination diet
therefore, reintroduction of the suspected foods
should be done under physician supervision
Eosinophilic Rare published reports of avoidance of cows milk or For patients with evidence of Longterm adherence to diet is
gastroenteritis elemental diet IgE sensitization to foods and suboptimal
Improvement with elimination diet within 68weeks risk factors for anaphylaxis: Dietitian consultation is
educate how to recognize and recommended for all patients to
treat anaphylaxis, provide a educate about the principles of
written emergency treatment food avoidance and to compose
plan and prescribe an adrenaline a nutritionally adequate and tasty
auto-injector device elimination diet
Most effective treatment is oral
steroids
Cell-mediated disorders
FPIES Majority of patients react to a single food, usually Provide emergency treatment Children with multiple food FPIES
cows milk, soy or rice plan in writing emphasizing or those exclusively breastfed are
Strict avoidance of the offending food in the patient intravenous rehydration in at risk of deficiencies of calories,
diet is recommended severe reactions; in milder vitaminD and iron
Breastfeeding infants are usually asymptomatic and reactions oral rehydration Delayed introduction of solids is
maternal dietary restrictions are not indicated unless cansuffice a risk factor for food refusal and
acute of chronic symptoms occur Intravenous or intramuscular feeding difficulties
Periodic oral food challenges are recommended to ondansetron can be useful to
evaluate for resolution manage vomiting
In cows milk FPIES, testing for cows milk IgE is A single dose of intravenous
recommended; ~25% develop cows milk IgE positivity methylprednisolone can
over time and of those, 33% can shift to immediate beused
IgE cows milk allergy
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Table 4 (cont.) | Management of food allergy

Disorder Dietary food allergen avoidance Emergency management of Comments
acute reactions
Cell-mediated disorders (cont.)
Food-protein- Usually strict avoidance of cows milk and soy formula No risk of acute reactions Natural history is favourable,
induced or proteins in maternal breast milk is necessary for resolution occurs by age 12years;
allergic symptom resolution reintroduction of the offending food
proctocolitis isdone gradually at home
Food-protein- Strict avoidance of the offending foods, usually cows No risk of acute reactions Natural history is favourable,
induced milk, soy wheat, egg resolution occurs by age 23years;
enteropathy reintroduction of the offending food
isdone gradually at home
*Management of eosinophilic oesophagitis is discussed in more detail in TABLE5. FPIES, food protein-induced enterocolitis syndrome; OAS, oral allergy syndrome.
as noreliable invitro testing is currently available. Prevention

Fordiagnostic purposes, this dietary elimination must Infants with at least one first degree relative (parent
be strict to draw correct conclusions. In children, or sibling) with an atopic condition are considered at
nutritional management by an experienced dietitian risk of atopy. In infants who are at risk and who cannot
and close monitoring of growth parameters are essen- be exclusively breastfed during the first 46months
tial. The principles of food allergy management are of life, hypoallergenic formulas (such as extensively
presented in TABLE4. hydrolyzed casein and partially or extensively hydro-
Management of EoE includes elimination diet (with lyzed whey) were shown to protect against develop-
targeted, empiric or amino-acid-based formula), med- ment of atopic dermatitis at 1, 6, 10 and 15years,
ications and dilatation41,82 (TABLE5). Although EoE is compared with conventional cows milk formula8588.
driven by food allergens, implementation of amino- A meta-analysis published in 2016 questioned the
acid-based formula is limited by its high cost, poor use of hydrolyzed formula to prevent allergic disease
adherence by patients to hypoallergenic formulas in infants at a high-risk of atopy 89. Currently, official
(owing to bitter taste) and negative effects on quality guidelines recommend substituting hypoallergenic
of life (if a patient is unable to eat normal foods and formulas in infants who are at risk of atopy and who
must drink hypoallergenic formulas). Pollen exposure cannot be breastfed9092.
in the sensitized individuals can trigger seasonal EoE Solid foods should be introduced between 4 and
flares. Food elimination can shift the chronic food 6months of age, usually starting from oatmeal or
allergy phenotype to anaphylaxis in patients with food rice cereal, fruits and vegetables, followed by grad-
IgE sensitization; allergy evaluation and supervised ual introduction of all food groups, without delaying
oral food challenge can be necessary prior to food the introduction of so-called high-risk foods such
reintroduction1. A number of cases reported resolution as peanut, egg, milk or wheat 9092. The results of a
of eosinophilic gastroenteritis with empirical milk elim- large randomized clinical trial (the Learning Early
ination; alimited trial of amino-acid-based or elimin- About Peanut allergy (LEAP) trial) in infants at risk
ation diet can also be considered, but oral corticosteroids of peanut allergy who have severe atopic dermatitis
are considered the mainstay oftherapy 83,84. and/or eggallergyindicate that early introduction of
dietary peanut has a strong protective effect against
Natural history peanut allergy at 60months in infants with disrupted
Natural history of food allergy varies by food, age of skin barrier 25,93 (BOX 2). Another large randomized
onset and pathophysiology. Infantile IgE-mediated clinical trial (EAT) including an unselected general
food allergy to cows milk, egg, soy and wheat usually population suggested that early introduction of pea-
resolves by school age; peak food-specific, lifetime nut and egg (with consumption of at least 2 g per week)
serum IgE antibody concentrations exceeding 50 kUA/l into the diet of a breast-fed infant could be protective
are associated with the persistence of food allergy into against IgE-mediated peanut and egg allergy at age
adolescence8. Allergy to peanut, tree nuts and seafood 13years26. Infants aged 612months who have known
tends to be lifelong. EoE is a chronic relapsing disease, IgE-mediated food allergy should be tested for specific
but infantile forms of EoE can have a more favourable IgEto other high-risk foods and, if positive, these foods
prognosis. Regarding non-IgE gastrointestinal food should be introduced under medical supervision.
allergy, resolution of FPIAP usually occurs by age
12months, and FPE by age 13years. FPIES usually Future therapies
resolves be age 35years; however, development of IgE No proven therapies currently exist that accelerate the
to the offending food is associated with a protracted development of oral tolerance or provide reliable protec-
allergy course39. The natural history of adult-onset tion from accidental exposures94. Ongoing active clinical
foodallergy is not well known, which is due in part to investigations involve food-allergen-specific immuno-
the lower frequency of food allergy in adults compared therapy via oral, sublingual and epicutaneous routes;
with infantile food allergy. hypoallergenic vaccines based on the modified major
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peanut allergens with and without adjuvants are under tolerated doses96. Nevertheless, the patients are pro-
preparation95. To date, clinical trials have reported high tected from unintentional exposures. How long and
rates (>50%) of desensitization with food oral immuno- at what dose food immunotherapy should be given to
therapy but no permanent tolerance. Desensitization is achieve permanent tolerance is currently unclear. Two
a temporary state of an increased threshold for allergic studies have suggested that long-term daily dosing could
reactions that requires daily intake of the immunotherapy be necessary 97,98. At this time, oral immunotherapy has
doses. Interruption of dosing, concurrent febrile illness, been most extensively studied; compared with sublingual
exercise, dosing on an empty stomach or menstrual and epicutaneous immunotherapy, oral immunotherapy
period might cause allergic reactions to the previously seems to have superior efficacy but an inferior safety
Table 5 | Principles of EoE management

Intervention Mechanism Efficacy Pros Cons
Dietary food protein elimination
Elemental diet Amino-acid-based After 68weeks complete Prompt control Utilization of elemental diet is limited by
formula is not resolution of eosinophilic of eosinophilic high cost, poor adherence owing to taste
recognizable as antigen inflammation in >90% of inflammation and no and negative effects on QOL
by immune system children and adults116 adverse effects Must be maintained long-term,
reintroduction of foods is gradual, repeated
endoscopies and biopsies are required
Recommended consultation with a dietitian
to assist with reintroduction of foods
Oligoantigenic Elimination of the six Symptomatic and histologic No adverse effects High cost, risk of nutritional deficiencies,
diet (empiric) most common food response rate 5382% in of medical therapies, negative effect on QOL
allergens: cows milk, adults and children49,51,117 possible to maintain Must be maintained long-term,
wheat, egg, soy, nuts asatisfying diet reintroduction of foods is gradual, repeated
and seafood endoscopies and biopsies are required
Recommended consultation with a dietitian
to assist with proper dietary elimination and
designing a nutritious alternative diet
Oligoantigenic Allergy evaluation 77% histological No adverse effects High cost, risk of nutritional deficiencies,
diet based combination of skin success118,119 of medical therapies, negative effect on quality of life
on allergy prick and patch testing; possible to maintain Must be maintained long-term,
testing and cows milk is the single asatisfying diet reintroduction of foods is gradual, repeated
elimination of most common food endoscopies and biopsies are required
cows milk allergen in EoE at Recommended consultation with a
allages dietitian to assist with proper dietary
elimination and designing a nutritious
alternative diet
Pharmacotherapy
Oral Decreased inflammation Almost 100% symptomatic Prompt improvement, High relapse rate upon discontinuation of
corticosteroids and fibrosis through and histologic improvement inexpensive, regular diet oral corticosteroids, long-term treatment
the reduction of within few weeks is maintained limited by major systemic adverse effects:
inflammatory cells and adrenal axis suppression, Cushing syndrome,
IL13 (REF.120) immunosuppression, osteoporosis
Topical Decreased Clinical and histological Prompt improvement of Potential adverse effects include
swallowed inflammation and efficacy of topical symptoms, preservation local Candida infection, adrenal axis
corticosteroids fibrosis through swallowed corticosteroids of an unrestricted diet suppression, bone demineralization and
such as the reduction of ranges from 5395% diminished growth
fluticasone or inflammatory cells and after 212weeks of Swallowed topical glucocorticoids undergo
viscous liquid IL13 (REF.120) treatment121,122 first-pass metabolism; therefore, such
budesonide Topical glucocorticoids can adverse effects are uncommon
also reduce the frequency
of food impactions
PPIs Decrease in acid Supportive treatment in Have a role in the Effective in a smaller subset of patients
secretion; decrease coexistent GERD and EoE in diagnostic evaluation compared with diet or corticosteroids
in cytokine secretion a subset of patients of PPI-responsive
from the oesophageal oesophageal
epithelium eosinophilia, inexpensive,
usually well tolerated
Mechanical or surgical approaches
Oesophageal Series of endoscopic Symptomatic relief of Immediate relief of Requires a series of procedures, does not
dilation dilations over multiple luminal narrowing oesophageal strictures, address the underlying inflammation,
sessions to gradually food impactions risk of oesophageal perforation ~1%,
diminish narrowing post-procedure chest pain in 75%
EoE, eosinophilic oesophagitis; QOL, quality of life.
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Box 2 | LEAP Study sustained unresponsiveness; however, the trial did not
include placebo arm for peanut oral immunotherapy 103.
Study design and results Children with cows milk allergies fed with exten-
640 children at high-risk of peanut allergy were enrolled at age 411months sively hydrolyzed casein formula containing LGG had
Each child was randomly assigned to an avoidance group (complete avoidance of increased rates of cows milk tolerance acquisition at
peanut-containing foods) or a consumption group (consume a peanut snack three 12months, compared with extensively hydrolyzed casein
times a week; 6 g of peanut protein per week) formula without LGG, soy formula, hydrolyzed rice for-
Among the 530 children in the intention-to-treat population who initially had mula or amino-acid formula104. LGG-supplemented
negative results on the skin-prick test to peanut, the prevalence of peanut allergy at formula expanded butyrate-producing bacterial strains
60months of age was 13.7% in the avoidance group and 1.9% in the consumption in cows milk-allergic infants21. These results suggest that
group (P <0.001) targeting gut microbiota could be an effective strategy for
Among the 98 participants in the intention-to-treat population who initially had treatment of food allergy. However, at present these data
positive skin prick test results, the prevalence of peanut allergy was 35.3% in the have only been shown in patients from Italy and should
avoidance group and 10.6% in the consumption group (P = 0.004)
be confirmed in different patient populations.
Clinical implications
Health-care providers should recommend introducing peanut-containing products Conclusions
into the diets of infants at a high-risk of peanut allergy early on in life (411months of The gut serves as a major portal of entry for food aller-
age) in countries where peanut allergy is prevalent, because delaying the introduction gens. Food allergy develops when oral tolerance, the
of peanut can be associated with an increased risk of peanut allergy93 dominant physiological immune response to ingested
LEAP, Learning Early About Peanut allergy (www.leapstudy.co.uk)25. food allergens, is not acquired or is breached. Early intro-
duction of peanut is protective against peanut sensitiza-
tion via disrupted skin barrier in infants at a high-risk for
profile. Although severe anaphylactic reactions during peanut allergy with severe atopic dermatitis or egg allergy.
oral immunotherapy are uncommon (usually <0.01% Early introduction of peanut and egg into the diet of
of oral immunotherapy doses), mild symptoms are fre- breast-fed infants from the beginning of the fifth month
quent and chronic gastrointestinal manifestations such as of age could have a protective effect against IgE-mediated
abdominal pain, vomiting and diarrhoea are associated peanut and egg allergy. Childhood food allergy generally
with up to 30% of the doses and are the most common has a favourable prognosis, whereas natural history in
reason for discontinuation of oral immunotherapy. EoE adults is largely unknown. Elimination of the offending
has been reported in up to 2% of patients treated with foods is the current standard of care; however, future
food oral immunotherapy 99. Oral immunotherapy can therapies for IgE-mediated food allergy focus on gradual
be combined with monoclonal anti-IgE antibody to reintroduction of foods via specific food immunotherapy.
improve safety of the dose escalation phase100,101. Multi- Further research is needed to elucidate the pathophysio-
food oral immunotherapy has a similar safety profile logy of various IgE and non-IgE food allergic disorders
to single food oral immunotherapy 102. A randomized to develop specific non-invasive biomarkers for initial
clinical trial suggested that co-administration of pro- diagnosis and monitoring for resolution. The role of
biotic (Lactobacillus rhamnosus GG, LGG) and peanut gut microbiota and strategies for modification of gut
oral immunotherapy could enhance development of microbiota in food allergy require assessment.
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aprospective multicenter study. J.Pediatr. 163, Clin. Immunol. 103, 11951201 (1999). suspensioninpediatric patients with eosinophilic
771777 (2013). 114. Chung,H.L., Hwang,J.B., Park,J.J. & Kim,S.G. esophagitis. Clin. Gastroenterol. Hepatol. 13, 6676
105. Tanoue,T., Atarashi,K. & Honda,K. Development and Expression of transforming growth factor beta1, (2015).
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Immunol. 16, 295309 (2016). andTNF-alpha in the mucosa of the small intestine Acknowledgements
106. Hadis,U. etal. Intestinal tolerance requires gut ininfants with food protein-induced enterocolitis The authors thank S. Koletzko, Division of Paediatric
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REVIEWS

Food allergy and the gut

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 1

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Key points effects on regulatory Tcells17. Limited evidence exists

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Eosinophilic gastroenteritis is a rare disease, esti- Non-IgE disorders

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anaemia. However, in many breast-fed infants with Diagnosis of food allergy

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Low pH digestive enzymes No digestion

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History and physical History

Suspected IgE-mediated Suspected non-immune

Screen for food-IgE Consider testing for non-immune

Anaphylaxis treatment plan Periodic re-assessments

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Table 2 | Differential diagnosis of food allergy

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Table 2 (cont.) | Differential diagnosis of food allergy

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Table 3 | Physiological effects of the active substances in foods

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Table 4 | Management of food allergy

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Table 4 (cont.) | Management of food allergy

as noreliable invitro testing is currently available. Prevention

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Table 5 | Principles of EoE management

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