The incidence of allergic asthma, atopic dermatitis and food allergy started to grow to
epidemic proportions after the 1960s. Peanut and nut allergy are common food allergies.
Peanut allergy affects 1.4 to 3.0% of the children. Peanut and nut allergy are often lifelong
and may be severe. Peanut allergy is the leading cause of (fatal) food anaphylaxis. Once
peanut and nut allergy have developed, there is currently no cure other than adhering to an
avoidance diet and carrying and using intramuscular epinephrine or oral antihistamines in the
case of accidental ingestion. Oral immunotherapy with peanut or nuts is only applied in
research setting, however, it has several drawbacks and is still in its infancy.
Inter- and intra-individual differences in threshold in peanut allergy:
Threshold levels for peanut and nuts, the lowest amount of peanut or nuts causing a reaction,
may largely vary between allergic children, for which there is no clear explanation.
Thresholds can be determined during oral food challenge tests with peanut or nuts in the
hospital. An international multi-center study found that 5% of the children react to a low
threshold of 1.7 mg of peanut protein during the food challenge in the hospital, 7.4 mg of
cashew nut protein and 0.29 mg of hazelnut protein during a food challenge in the hospital.
These are only traces, while 50% react to 67 mg of peanut protein. This is around 1⁄3 of a
peanut, thus also a small amount. These threshold levels demonstrate how careful patients
have to be in their dietary behavior. Patients with a low threshold are very sensitive to
peanut or nuts and are at greater risk to react to traces of allergenic protein which can be
intentionally or unintentionally present in prepacked or unpacked food. Studies have shown
that the lower the threshold, the greater the impact on the health-related quality of life of
the child and their parents. It is poorly understood how these differences in sensitivity
(threshold levels) between individuals can be explained. Sensitization to peanut or nuts, as
demonstrated by levels specific immunoglobulin E (IgE) for peanut by blood testing or the
size of the skin prick test with peanut or nuts cannot explain the difference in threshold
level, because they have a low predictive value for the threshold. Infection diseases
illness, exercise and sleep deprivation significantly reduce the threshold level in allergic
adults. However, these co-factors are not relevant in all patients, specifically not in
children, and cannot explain the large differences in threshold levels observed.
Peanut and nut allergy coincides with other atopic disease:
Peanut and nut allergic children frequently suffer from other food allergies, such as milk
and egg, and other coexisting atopic (allergic) diseases such as atopic dermatitis, allergic
rhinitis (hay fever) and allergic asthma, leading to a substantial allergic burden in
children with peanut and nut allergy. Because of the burden of these allergic conditions, the
quality of life of children with food allergy is decreased, however underestimated. and even
lower compared to chronic diseases, e.g. lower than children with diabetes. All these
coexisting allergic diseases are based on immunologic and chronic inflammatory processes.
Asthma is a systemic inflammatory disorder with a close link between the upper and the lower
airways. The majority of patients with asthma have concomitant rhinosinusitis. The
respiratory system is also under the influence by co-morbid conditions related to the
gastrointestinal tract (food sensitization, bowel inflammation), the skin (eczema, barrier
dysfunction) as well as the nervous system (neuroimmunologic network, cognitive dysfunction).
Defective mucosal barrier function (leaky gut) or increased gut permeability as possible
explanation for high prevalence of allergic disease and differences in threshold to peanut or
nuts:
The steep increase of allergic diseases is attributed to several lifestyle changes due to
urbanization and modernization, caesarean section, use of antibiotics, a westernized
pro-inflammatory diet and obesity. Firstly, according to the generally accepted hypotheses,
i.e. the hygiene hypothesis and the biodiversity hypothesis, all these changes lead to
microbial dysbiosis and loss of microbial diversity in the gut, which are major reasons for
inflammation, inappropriate immune responses and disease development, because there is a
continuous crosstalk between the intestinal microbiome and our immune system through
immunomodulatory signals. Allergic diseases, such as food allergy, asthma and atopic
dermatitis are all characterized by a dysbiosis and reduced diversity of the microbiome.
Secondly, one of the most recent additional explanations for the increased prevalence of
allergic disease is a defective epithelial (=mucosal) barrier in the skin, gut and lungs (the
"extended epithelial barrier hypothesis"). Impaired mucosal barrier function, or "leaky gut"
, which results in increased gut permeability, is caused by epithelial-damaging substances
linked to industrialization, urbanization and modern life, such as household and dishwashing
cleaning agents and the use of (ultra) processed foods through, amongst others, emulsifiers.
An intact mucosal barrier is crucial for the maintenance of tissue homeostasis as this
protects against allergens. An increased gut permeability can result in an enhanced uptake of
allergens where they may activate the immune system leading to severe chronic inflammation.
Thus, it is well possible that an impaired mucosal barrier function may contribute to these
observed differences in threshold to peanut and nuts.
Mucosal barrier dysfunction has been demonstrated in asthma, chronic rhinosinusitis, atopic
dermatitis, and Eosinophilic Esophagitis (EoE) and a number of studies in food allergy. Both
the Lactulose/Mannitol ratio in urine (L/M ratio) as well as the Raffinose/Mannitol ratio in
urine (R/M ratio) are commonly used Sugar Absorption Tests (SAT) for the analysis of small
intestinal permeability. In the Netherlands the R/M ratio has been implemented as sugar
absorption test (SAT) and is provided by Good Manufacturing Practice (GMP) certified
pharmacists. If the mucosal integrity is impaired the urinary excretion of Raffinose will
increase (see methods for more details). In children, for example, increased gut permeability
in milk- and egg allergic children was found as compared to 7 controls. Similar results were
found by Andre et al in children and adults with sensitization to foods, 0,6
In a
study in which the relationship between allergic symptoms and mucosal permeability was
studied, a significant correlation between small intestine permeability and the severity of
allergic symptoms at referral was shown.
The influence of nutrition on gut permeability:
Nutrition is one of the important external factors contributing to the maintenance of an
intact mucosal barrier function of the gut. In contrast, unhealthy nutrition or nutrition
containing barrier-damaging agents contributes to the disruption of the mucosal barrier
through the following processes:
1. Direct effects of foods and nutrients on the maintenance or disruption of the mucosal
integrity in the gut.
Vitamin A plays a critical role in the differentiation of cells towards mucosal barrier
function. Zinc and iron have an essential role in the maintenance of intestinal
epithelial tight junction barrier via the regulation of claudin-3 and occluding
expression. Short chain fatty acids produced through the microbial fermentation of
dietary fiber, maintain mucosal integrity by processes including mucus production,
tissue repair and up- regulation of the expression of tight junction proteins.
In a small study in adult patients with eosinophilic esophagitis, it was shown that the
intake of sunflower oil and/or stir fry oil, as well as the total amount of added fat,
was negatively (i.e., unfavorably) related to in vitro values of permeability, while the
consumption of buttermilk/yoghurt drink with Lactobacillus rhamnosus, dairy and vitamin
A were favorably related to mucosal permeability of the esophagus.
In contrast nutrition may also may have deleterious effects on the mucosal barrier
function. Emulsifiers in highly processed foods are surfactants that behave like
detergents, and even trace amounts of these agents markedly increase bacterial
translocation in mouse models. Advanced Glycation End products (AGE) formation and
additives commonly used by the food industry in highly processed foods play a role.
Thus, our diet may be one of the key factors in the maintenance or impairment of our
epithelial barrier function, and may as such contribute to the prevention and treatment
of chronic immune disorders.
2. Our diet is an important source for the composition of our microbiome and regulation of
the mucosal barrier function.
Healthy dietary constituents feed our gut microbiota by providing substrates for a large
variety of intestinal microbial species, leading to a diverse and anti-inflammatory
microbiome. Dietary fiber, vegetables, legumes, grains, nuts, fish, plant-based foods,
fermented dairy (e.g. buttermilk and yoghurt), omega-3 polyunsaturated fatty acids n-3
and polyphenols have anti-inflammatory capacity through modulation of our gut microbiota
composition with a protective effect on our mucosal barrier function by regulation of
tight junction barriers. Higher intake of animal foods, saturated fat, processed foods,
alcohol and sugar induce pro-inflammatory processes by the reduction of the total
abundance and reduction of specific species of bacteria in our gut and subsequent
negative impact on our mucosal barrier function. Plant-based proteins and n-3
polyunsaturated fatty acids induce the opposite effect alongside increased abundance of
anti-inflammatory species.
3. Nutrition provides nutrients which are essential for the functioning of the innate and
adaptive immune system, which in turn regulate the mucosal barrier function. T cells,
type 2 innate lymphoid cells (IL2) and interleukine 13 (IL13)play major roles. According
to very strict criteria several nutrients are recognized by European Food Safety
Authority (EFSA) for their immunomodulatory properties. These are copper, folate, iron,
selenium, vitamin A, B6, B12, C, D and zinc.
4. Our diet can induce either pro-inflammatory or anti-inflammatory effects in the gut and
our body. Diet is established among the most important influences on health in modern
societies. Poor diet is among the leading causes of chronic disease. The composition of
our diet may importantly enhance or reduce inflammation and may therefore influence
inflammatory disease such as asthma and atopic dermatitis, This cannot be contributed to
single foods, instead, the total dietary pattern is important. A Western diet which is
characterized by a high consumption of meat, highly processed foods, ready-to-use foods
and meals, refined grains, sugar, omega-6 fatty acids and saturated fatty acids, and a
low consumption of dietary fiber, omega 3 fatty acids, anti-oxidants, fruits, vegetables
and plant-based foods. Such a diet induces a pro-inflammatory state of our immune system
and increased intestinal permeability.
In contrast, dietary patterns such as a traditional Mediterranean diet, with high contents of
monounsaturated (MUFA), ω-3 polyunsaturated fatty acid, home-made meals, fruits, vegetables,
legumes, and grains, has shown anti-inflammatory effects when compared with typical North
American and Northern European dietary patterns. With regards to allergic disease
specifically, the use of organic dairy and unprocessed milk is associated with lower
prevalence of allergic diseases, as was shown in the KOALA birth cohort study and studies on
children on farms.
Taken together, for peanut and nut allergy there is yet no cure and threshold levels to
peanut or nuts differ widely for reasons unknown. Peanut and nut allergy often present in
patients with coexisting atopic diseases such as atopic dermatitis and atopic asthma, which
are based on inflammatory processes. An impaired mucosal barrier may contribute to the
observed differences in thresholds to peanut and nuts. Nutrition can either positively or
negatively influence our immune function, gut microbiota composition and gut permeability,
and therefore may influence threshold levels to peanut and nuts, as well as severity of
coexistent symptoms such as atopic dermatitis and asthma.
Thus, a study on dietary intervention as proposed in this protocol will yield lacking
knowledge on the effect of a healthful diet on gut permeability and clinical symptoms in
allergic disease.
The study will be performed in children as peanut and nut allergy are often lifelong, may be
severe, cannot yet be cured and has a significant impact on quality of life which is
underestimated by parents. The risk of inadvertent allergic reactions specifically holds for
children with a low threshold to peanut. With a higher threshold level fewer products need to
be avoided which will improve quality of life. In addition, comorbidity in allergic disease
such as eczema is most prominent in children. Therefore, children will most benefit from our
study results if we can show immune-supportive diet improves gut barrier function and
alleviates allergic symptoms.
