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.
