Microbiome
The microbiome has been shown to play a key role in the development of
the immune system with microbiome dysbiosis mediating immune
deviation.48 Characterizing the constituents of the
human gastrointestinal, skin, and airway microbiota as well as microbial
peptides and metabolites that influence host immunity and immune
response to allergens in food allergy, atopic dermatitis, and asthma is
the focus of ongoing research.48, 49 Advances in our
understanding of host-microbe interactions have been made possible by
16S rRNA sequencing, which permits precise identification and
quantification of bacteria. 16S ribosomal RNA gene is a highly conserved
locus in the bacteria genome, yet different in sequences among different
bacterial species. Another approach is to sequence the total DNA present
in one ecosystem using whole genome shotgun techniques, and subsequently
map the genes related to microbes, including viruses and
fungi.50 These techniques have enabled us to make
inroads in identifying the species found in a healthy microbiota and
those that cause dysbiosis. In atopic dermatitis, S aureus has
been shown to be clearly correlated with
severity and to decrease during treatment
and to rebound after the end of treatment indicating its use as a
potential diagnostic and prognostic biomarker.51
Studies in mice and humans have shown associations between intestinal
bacteria and allergic response to food. In a murine model, germ-free
mice were colonized with feces from healthy or cow’s milk allergic (CMA)
infants. The healthy and CMA mice showed different transcriptome
signatures in ileal epithelium, and the healthy mice were protected
against anaphylactic responses to cow’s milk allergen. The study
identified a clostridial species that protected against the allergic
response.52 Bifidobacterium breve is a species
commonly isolated from the intestines of healthy breastfed infants and
from human milk and is thought to have a significant impact on the
development of immune tolerance.53 In a longitudinal
study of a Canadian child cohort, it was found that infants at risk of
asthma showed gut microbial changes during the first 100 days of life.
Four bacteria taxa were reduced in high-risk children and this was
accompanied by reduced deregulation of enterohepatic metabolites. To
understand causality, the same study also found that inoculating the
four taxa of bacteria (Lachnospira, Veillonella, Faecalibacterium, and
Rothia) in germ-free mice decreased airway
inflammation.54 Individuals with atopic dermatitis
have reduced skin lipids and increases in Staphylococcus
aureus .55 A study found a correlation between
Staphylococcus species–dominated dysbiosis in the skin
microbiome and dysregulation of the skin barrier transcriptome in
patients with AD, but whether the microbiome dysbiosis is the cause for
or result of the skin barrier defect is unclear.56S. aureus has also been directly correlated with increased
expression of inflammatory cytokines, IL-4, IL-13, IL-22, and TSLP and
with decreased expression of cathelicidin.57 C.
difficile colonization during infancy was associated with a higher risk
of developing allergic diseases during early
childhood.58
A number of factors affect the composition of either the skin or gut
microbiome. Vaginal delivery, breast feeding, presence of older siblings
and exposure to a variety of microorganisms promote healthy microbiota
in infants. In contrast, Caesarean section, formula milk, and exposure
to antibiotics have a negative impact.59 Dietary
factors also play a role in microbiome health. Some of these factors are
discussed below.
DietIn addition to prebiotics and probiotics, other dietary factors that
have been shown to play a role are vitamin D and omega-3 and omega-6
polyunsaturated fatty acids (PUFAs). A study found that higher second
trimester n-6 PUFAs were associated with atopic dermatitis in children
of women with atopy.60 A meta-analysis found that
intake of ω-3 PUFA started during pregnancy may reduce the risk of
sensitization to egg and peanut.61 Levels of ω-3 and
ω-6 were measured in the second trimester and found that higher ω-6
PUFAs were associated with a higher risk of all respiratory outcomes
among children if the mother has asthma, but that male children born to
women with asthma and a higher PUFA ratio had the highest risk for
asthma.62 A meta-analysis of ω-3 consumption suggests
that introduction of fish at 6-9 months and routine consumption once a
week reduces asthma and wheeze in children up to 4.5 years
old.63 The association between vitamin D insufficiency
and increased risk of food allergies have been shown by multiple
studies. While controlling for regional and population characteristics,
places in northern latitudes were found to have more epinephrine
autoinjector prescriptions than those in southern latitudes in both USA
and Australia.64, 65 In another study, food allergies
were found to be more likely in infants with low vitamin
D.66 In children with asthma, vitamin D deficiency was
associated with asthma severity and increased serum IgE
levels.67Farming Environment and Pet Ownership Childhood environments have been shown to play an important role in the
protection against allergies. Individuals living at short distances from
farms had a lower risk of atopy, as measured by IgE, compared with those
living further away. This decrease in atopy risk was even greater for
those who grew up on a farm.68 Children in rural South
African communities with higher exposure to pets and farm animals than
children from urban communities were found to be at lower risk of
allergic disease.69 Marrs et al. reported there was an
association between dog ownership at three months of age and protection
against food allergies.70 However, urban children with
pet exposure in the South African cohort had an increased rate of any
allergy compared to urban children without pets so conflicting data
exists regarding pet ownership in relation to
allergies.69Antibiotics Antibiotic usage has been documented to perturb the gut flora of
individuals, which places them at an increased risk for the development
of allergies and asthma. In mice models of atopic dermatitis, antibiotic
use was associated with significantly aggravated phenotypes, including
clinical score, transepidermal water loss, and histopathology, compared
to those treated with healthy feces or probiotics.71Timing, dose, and frequency of antibiotics in prenatal and infant
populations have also been associated with the development of childhood
allergies and asthma.72, 73 Short chain fatty acids
(SCFAs) which are fermentation end products of insoluble fibers by
intestinal microorganisms have been implicated in the maintenance of
epithelial integrity and IgA production.74Antibiotics-induced dysbiosis of intestinal microbiota has been shown to
increase severity of atopic dermatitis in mice through alterations in
SCFA’s and decreases in the number of Foxp3⁺ T regulatory
cells.71Vaginal versus caesarean section birthsThe composition of gut flora in children born by caesarean section
(C-section) versus vaginal delivery is different and this difference in
gut microbiota colonization may impact the development of the immune
system.75 A vaginal mode of birth exposes the baby to
maternal vaginal and fecal flora.76 Studies indicate
that babies born via C-section have a higher incidence of allergy,
atopy, and asthma, increased susceptibility to infectious
wheezing77 and decreased gut microbiome
diversity.78 In addition, long-term studies show
greater incidence of childhood asthma up to the age of 12
years.79Other factorsIn addition to environmental and lifestyle factors, household
composition has also been shown to affect the risk of allergic diseases.
A study that followed 17,414 British children for 23 years found a
strong association between the birth order of a child and the risk of
hay fever.80 Specifically, contact with older siblings
was hypothesized to increase immunological protection due to an increase
in infections in early childhood through unhygienic contacts with
siblings. A study on 10,834 children enrolled in the Chicago Family
Cohort Food Allergy study found that younger siblings of kids with food
allergies had significantly less prevalence of food sensitization and
clinical food allergy.81Current research shows that psychosocial stress and poor mental health
in mothers increase the risk of allergic diseases in their children.82-88 Stressful life events in childhood, for example
parental divorce, have also been shown to increase the risk for
development of atopic eczema later in life.89Psychosocial stress might trigger or worsen allergic symptoms90 Also, in adults with allergies,
psychoneuroimmunologic mechanisms might play an important role.91 An association of anxiety and depression with
allergies was reported in many studies.92, 93