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