Microbial interactions in the atopic march

Summary

The human body is populated by a large number of microorganisms and exist in symbiosis with these immensely diverse communities, which are suggested to influence health and disease. The microbiota plays an essential role in the maturation and function of the immune system. The prevalence of atopic diseases has increased drastically over the past decades, and the co‐occurrence of multiple allergic diseases and allergic sensitization starting in early life has gained a great deal of attention. Immune responses in different organs affected by allergic diseases (e.g. skin, intestine and lung) may be linked to microbial changes in peripheral tissues. In the current review, we provide an overview of the current understanding of microbial interactions in allergic diseases and their potential role in the atopic march.

The prevalence of atopic diseases has increased drastically over the past decades and the co‐occurrence of multiple allergic diseases and allergic sensitization starting in early life is an important area of research in this field. Immune responses in different organs affected by allergic diseases may be linked to microbial changes in peripheral tissues. In the current review, we provide an overview of the current understanding of the microbiome in allergic diseases and its potential role in the atopic march.

Introduction

The prevalence of atopic diseases has increased dramatically during recent decades, especially in industrialized countries 1, 2. The atopic march describes the developmental progression from atopic dermatitis (AD or allergic eczema) and/or food allergy in early infancy to allergic asthma and allergic rhinitis in childhood 3, 4. These diseases are driven by a familial or personal tendency to induce immunoglobulin (Ig)E antibodies and sensitization in response to different stimuli 5. Genetic and environmental factors play a role in atopic diseases 6, 7, 8, 9. Currently, 20% of the population in the western world suffers from AD and 5–8% of patients with AD have co‐occurrence of food allergies 10, 11, 12. Cohort studies investigating the co‐occurrence of atopic diseases observed that approximately 33–43% of infants with AD develop allergic asthma. In addition, 38–45% of these children with AD advance to develop allergic rhinitis during childhood. Moreover, 33% of AD patients have been shown to progress to both of these diseases before adulthood 13, 14, 15.

The increase of atopic diseases has been explained by two different hypotheses: the ‘hygiene hypothesis’ and the ‘diet–microbiome hypothesis’. The hygiene hypothesis states that a rise of the incidence of autoimmune diseases and allergic diseases in affluent countries coincides with better hygiene and reduced exposure to infectious agents during childhood. Consequently, the immune response to antigens has been suggested to be altered 16, 17, 18, 19. Additionally, exposure to farming practices in early life correlates with protection against asthma and allergies in epidemiological studies 17, 20. The diet‐microbiome hypothesis provides an alternative explanation, and underlines that changes in the western diet, i.e. decreased fibre intake and increased fat intake, can change gut microbiome composition, leading to an altered production of immunomodulatory molecules, such as a decrease in short‐chain fatty acids (SCFAs) 21, 22, 23. Alterations in SCFAs can, in turn, affect haematopoiesis and immune cell function and play an important role in the regulation of allergic responses 24, 25, 26.

The human body is populated by a great number of microorganisms, of which the gut alone harbours approximately 100 trillion microbes 27. High‐throughput DNA deep‐sequencing technologies have improved the characterization of microbial communities and allow for a thorough comparison between organs or individuals 28. The human body exists in symbiosis with these immensely diverse communities, and they are suggested to influence health and disease. In this review, we provide an overview of the current understanding of microbial interactions in atopic diseases and their potential role in the atopic march.

Atopic dermatitis

AD is a heterogeneous, inflammatory skin disorder affecting up to 15% of children and adolescents 29, 30; prevalence rates are lower in adults 31. This condition often has an early onset and develops during childhood in approximately 60% of cases (before the age of 5 years) 32, 33. AD is characterized by dry and red skin, pruritic lesions and relapsing flares, which typically occur in antecubital and popliteal regions 34, 35. Risk factors predisposing children to developing AD include loss of function mutations in the filaggrin gene 6, allergic sensitization and parental history of atopic diseases 36. There is increasing evidence suggesting that the skin microbiome can be involved in the development of atopic dermatitis. However, it remains to be determined whether alterations in the microbiome are cause or consequence of atopic dermatitis development.

The skin microbiome in atopic dermatitis

The skin harbours different microorganisms (bacteria, viruses and fungi) that make up the skin microbiota 37, 38, 39. Skin commensals are important for protection against exogenous exposures and invading pathogens, but are also crucial for immune maturation in early life and skin barrier development 40. Skin microorganisms have shown to be critical in AD pathogenesis, and changes in the skin microbiome composition have been observed during disease progression in paediatric AD patients 41, 42, 43.

Recent studies have demonstrated that there is an inverse correlation between atopic dermatitis score (SCORAD) and cutaneous bacterial diversity, indicating that severe AD is linked to decreased microbial diversity at sites of disease predilection 41, 44. Interestingly, only an increase in Staphylococcus relative abundance, and specifically Staphylococcus aureus, was observed in these studies, which also correlated positively with SCORAD 41, 44, 45. S. aureus is an important pathogen in atopic dermatitis, as it is a dominant member of the cutaneous bacterial composition in most AD patients 44, 46. Although increased S. aureus abundance is strongly linked to AD severity, the role of Staphylococci in the establishment of AD had not been investigated until recently. Kennedy et al. determined the temporal transition of the skin microbiome in early life and the dysbiosis observed in AD patients. They demonstrated that colonization with commensal Staphylococci at 2 months of age could be linked to less atopic dermatitis at 1 year of age 47. An overview of the comparison of healthy skin microbiome and AD skin microbiome can be found in Table 1.

Table 1.

Dominant phyla of the human skin, gut and lung microbiome in the diseases of the atopic march

Condition	Skin microbiome	Intestinal microbiome	Respiratory microbiome
Healthy	Firmicutes (Lactobacillus spp.), Bacteroidetes (Prevotella spp.) and Fusobacteria (Sneathia spp.) 34, 143	Firmicutes (Clostridium spp., Enterococcus spp., Lactobacillus spp. and Ruminococcus spp.) 144	Bacteroidetes (Prevotella spp.) 145 Firmicutes (Streptococcus spp. and Veillonella spp.) 145
		Bacteroidetes (Bacteroides spp. and Prevotella spp.) 144	Some Proteobacteria (Pseudomonas spp., Haemophilus spp. and Neisseria spp.) 145
Atopic dermatitis	Increased abundance of Firmicutes (Gemella spp., S. aureus and S. epidermis) 44, 46, 50	Increased abundance of Firmicutes (C. difficile, Coprobaccilus spp. and Enterococcus spp.) [69,146–149]	No data available
	Decreased abundance of Actinobacteria (Dermacoccus spp.) 50	Decreased abundance of Proteobacteria and Bacteriodetes [146–149]
Food allergy	No data available	Increased abundance of Bacteroidetes 94	No data available
		Decreased abundance of Firmicutes (Ruminococcaceae) 94
Allergic asthma	No data available	Increased relative abundance of Actinobacteria (Bifidobacteria) [150]	Increased abundance of Proteobacteria (H. influenza, M. catarrhalis and Psychrobacter spp.) and Firmicutes (S. pneumoniae) 120
		Decreased relative abundance of Firmicutes (Clostridia spp.) [150]

Host–microbe interactions in atopic dermatitis

Disease flares in lesional skin of AD patients are marked by an increased skin pH and surface lipid deficiency 48, 49. Chng et al. analysed the skin microbiome of AD patients with stable disease and healthy controls for functional capabilities using whole metagenome profiling. They observed an enrichment in nitrogen, proline and arginine metabolism pathways, which are linked to ammonia production, in the skin of AD patients 50. Ammonia is a strong base, and the AD microbiome uses its ammonia to create a less favourable and more basic environment for members of the healthy skin microbiome, thereby establishing ideal living conditions for S. aureus and other pathogens to initiate flares 49, 50. Additionally, other characteristics of AD, such as reduced production of anti‐microbial peptides 51 and decreased filaggrin expression 52, can also facilitate S. aureus colonization 53. Increased S. aureus skin colonization correlates positively with AD severity 41, 44, 45. A potential explanation could be the involvement of S. aureus superantigen (SAg) production, including staphylococcal enterotoxins (SEs) A and B, protein A and α‐toxins. Moreover, a number of studies have directly correlated AD severity with elevated levels of anti‐staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin B (SEB) antibodies 54, 55.

Certain strains of S. epidermidis have been shown to produce anti‐microbial peptides 56, thereby strengthening the keratinocyte response to pathogens 57 and increasing the expression of tight junctions, which can consequently improve barrier function 58. Moreover, S. epidermidis can selectively prevent S. aureus growth and biofilm formation by production of a serine protease (Esp) 59 and phenol‐soluble modulins 56. However, increased S. epidermis counts are not correlated with the potentially beneficial effects mentioned above, as these properties are strain‐specific and additional research is needed to determine whether these subtypes are present in AD 60.

The intestinal microbiome in atopic dermatitis

In recent years, the importance of microbial interactions in understanding inter‐organ cross‐talk has been increasingly recognized (Fig. 1) 61, 62. Given the multi‐factorial nature of the atopic march and the potential involvement of microbial cross‐talk in the establishment of co‐occurrence of multiple allergic diseases, it is important to be aware of microbial changes in peripheral tissues and their potential implications on immune responses. Several studies have shown that early life perturbations of the gut microbiome are linked to the development of allergic diseases, and that the intestinal microbial composition is altered in AD patients 63, 64, 65, 66, 67. Microbial diversity in the gut of infants at 1 month of age is decreased in patients who develop atopic eczema at 6 months 68 and 2 years of age 69, suggesting that low microbial diversity is associated with increased risk for allergic disease. Abrahamsson and colleagues provided evidence that this decrease in bacterial diversity was due to a decrease in Bacteroidetes phyla and Bacteroides genus at 1 month of age 69. Interestingly, Bacteroides species have anti‐inflammatory potential in the intestine, by aiding the conversion of CD4⁺ T lymphocytes into T regulatory lymphocytes 70, suggesting that a decrease in Bacteroides, as observed in AD, may affect T effector cell responses. Analysis of the gut bacterial composition of 1‐month‐old infants in the KOALA birth cohort study demonstrated that infants colonized with Clostridium difficile were at higher risk for developing atopic dermatitis and other allergic diseases 71. Moreover, a recent study revealed differences in functional genes related to host immune development in the gut microbiome of AD patients compared to healthy controls independent of feeding type 66. These studies indicate that intestinal microbiome composition may be involved in the development of atopic dermatitis in early life. However, studies determining gut–skin interactions are warranted to further dissect the mechanisms underlying these observations. An overview of the comparison of healthy intestinal microbiome to the intestinal microbiome in AD patients is provided in Table 1.

Figure 1.

Cross‐talk in the atopic march. Inter‐organ cross‐talk in the atopic march may be linked by interactions of the microbiota in different tissue compartments such as the skin, intestine and the lung. Atopic dermatitis is generally considered as the ‘starting point’ of the atopic march. Alterations in the skin microbiome have been observed in atopic dermatitis patients compared to healthy controls, with an increased abundance of Staphylococcus aureus as one of the most pronounced changes. Atopic dermatitis has also been associated with changes in the intestinal microbial composition; however, causality has not yet been proven. A reduction in microbial richness of the gut microbiome was observed in infants with food allergies. In addition, dietary composition can alter the gut microbiome and also affect food allergy development. Microbial colonization of the lung in early life has profound effects on pulmonary immune responses and can be a determinant for long‐term lung health and disease. Alterations in the gut microbiome have been linked to changes in allergic airway inflammation via immune modulation. Until now, it remains unclear whether alterations in the local and peripheral microbiomes in allergic diseases can drive the atopic march phenomenon.

A body of evidence shows that host–microbe interactions not only exert effects locally, e.g. between the intestinal microbiome and the gut itself, but also influence immune responses in the periphery; for example, the skin or lungs 72. Based on different diet–microbiome hypotheses, it is suggested that lifestyle factors, such as alterations in dietary composition and intake, play an important role in the increased prevalence of atopic diseases in industrialized countries 73, 74, 75. A recent study by Roduit and colleagues demonstrated that infants in the PASTURE birth cohort study with high levels of SCFA in faecal content at 1 year of age were less likely to be atopic at 6 years of age 76. In addition, the authors observed a trend towards a decreased incidence of AD in children with the highest levels of butyrate. A number of mechanisms of SCFAs producing bacteria to prevent or delay allergic disease have been studied. Allergic eczema patients have an impaired intestinal barrier function 77 and SCFAs have been shown to up‐regulate the expression of tight junctions, thereby improving intestinal barrier function. Furthermore, SCFAs can inhibit inflammatory pathways, such as the nuclear factor kappa B (NF‐κB) pathway, and these molecules can regulate proliferation and activation of regulatory T cells 78, 79. Faecalibacterium prausnitzii is a poor butyrate producer and the abundance of its subspecies are highly altered in the AD microbiome 80. Dysbiosis of F. prausnitzii in atopic dermatitis leads to a reduction of faecal butyrate and propionate levels, causing an increase in abundance of pathobionts and opportunistic auxotrophs. This can induce damage of the intestinal mucosa, causing nutrients such as fucose and N‐Acetylgalactosamine (GalNAc) and toxins to enter the circulation. Consequently, a cutaneous T helper type 2 (Th2) immune response is mounted against these circulating components, which can result in enhanced skin inflammation and damage 80. Furthermore, Proteobacteria, which are less abundant in paediatric AD, contain lipopolysaccharides (LPS) in their cell wall, and LPS is known to induce a Th1 response through boosting interleukin (IL)‐12 production by monocytes and dendritic cells (DCs) 81. These protective actions may explain the decrease of this phylum in paediatric AD.

Food allergies

Food allergy is an allergic reaction to food allergens, such as cow’s milk or peanuts, among others, and approximately 1–5% of the population in developed countries suffer from this disease 74. Food allergy often continues into adulthood, resulting in a significant economic burden and reduction of the quality of life among all ages 82, 83. The occurrence of food allergy is due to the loss of oral tolerance, which means that the immune system initiates an immune response against food antigens 84. The clinical response consists of mast cell and basophil degranulation as a result of allergen cross‐linking of IgE bound to Fc_εRI. Consequently, this leads to increased IgE levels and inappropriate Th2 activation to a food allergen 85. The symptoms of food allergy can vary from mild oral allergy to severe anaphylaxis 86, 87.

Risk factors for the development of food allergy include hereditary ones, such as having a sibling or parent with peanut allergy 88 or gene polymorphisms, e.g. IL‐10 89, filaggrin 90 and signal transducer and activator of transcription 6 (STAT6) 91. In addition, increased vitamin D intake 92, earlier atopy, antibiotic usage and obesity can be risk factors for the development of food allergy 93. Moreover, increasing evidence suggests that the intestinal microbiome can be involved in the development of this disease.

The intestinal microbiome in food allergies

In recent years, several studies have reported alterations in the gut microbiome in early life in children who developed sensitization to food allergens. When interpreting these studies it is important to keep in mind whether or not the observed alterations are due to food allergy‐related changes in the diet, which can consequently affect the gut microbiome, and are potentially independent of sensitization status. Analysis of the microbial composition of infants at 3 and 12 months of age enrolled into the CHILD cohort demonstrated that children who had a positive skin prick test for food sensitization at 12 months of age had lower microbial richness at 3 months 94. The investigators reported that for each quartile increase in gut microbial richness at 3 months of age there was a 55% reduction in the risk to develop food sensitization at 1 year. Furthermore, sensitized infants were shown to have an over‐representation of Enterobacteriaceae and a reduction of Bacteroidaceae abundance at both 3 and 12 months after birth. The changes observed in this study were independent of antibiotic intake, delivery method and breastfeeding 94. These results suggest that early dysbiosis in the gut can contribute to the development of food allergy. However, whether microbial alterations in the intestine are drivers of food allergy development in early life remains to be determined.

Dietary composition in early life is an important determinant of the gut microbial composition, and can affect immune responses and the development of food allergies in early life. Grimshaw and colleagues set out to determine the influence of the dietary pattern in infants during the first year of life on the development of food allergy in infancy. They observed that children diagnosed with food allergies by the age of 2 years were fed a diet characterized by lower fruit and vegetable intake and fewer home‐prepared meals (after switching to solid foods) compared to non‐allergic controls 95. These data provide a first insight into the importance of a healthy diet during the first year of life as a measure to prevent food allergy development. However, whether there is a role for the gut microbiome in this process remains to be further investigated.

Host–microbe interactions in food allergy

Studies investigating the effects of environmental and exogenous exposures on the development of food allergy among children have gained increased interest. Different environmental factors, including early life feeding practices, antibiotic usage and earlier atopy, may contribute to dysbiosis in the intestine, which can consequently affect food allergy development. However, whether microbial dysbiosis is cause or consequence for food allergy development remains to be determined. Efforts have been made to assess the importance of the gut microbiome composition in the development of food allergy in experimental murine models.

Ovalbumin (OVA)‐sensitization of a food allergy‐prone mouse model with a gain‐of‐function mutation in the IL‐4 receptor α‐chain (Il4raF709) indicated that these mice exhibit a specific microbiota signature characterized by changes in the abundance of taxa of several bacterial families, including Lachnospiraceae, Lactobacillaceae, Rikenellaceae and Porphyromonadaceae, when compared to wild‐type mice. Interestingly, transfer of the intestinal microbiome of OVA‐sensitized Il4raF709 mice to germ‐free mice led to the development of anaphylaxis and Th2 skewing of the immune response upon OVA stimulation in the recipient germ‐free mice. This suggests that the microbiome can transmit the susceptibility to food allergy sensitization 96.

Microbial colonization was found to be important in protection against the development of peanut allergy 97. Germ‐free mice exposed to peanut allergen with the adjuvant cholera toxin (PN/CT) exhibited increased PN‐specific IgE levels and had a reduced core body temperature, which is indicative of an anaphylactic response. Colonization of germ‐free mice with Clostridia reversed the observed anaphylactic response, suggesting that Clostridia has a protective effect against sensitization to food allergens by regulating innate lymphoid cell function and intestinal epithelial permeability.

Obesity and western diet consumption have been associated with increases in allergy. A recent study by Hussain and colleagues reports that high‐fat diet (HFD) consumption in mice is associated with intestinal dysbiosis 98. In addition, the observed that an HFD‐specific microbiota signature was correlated with clinical signs of experimental food allergy. Co‐housing of germ‐free mice with HFD‐fed obese mice revealed that the microbiome from obese mice can transmit susceptibility to food allergies independently of obesity, suggesting that high dietary fat intake has disease‐promoting properties by acting on the intestinal microbiome.

Interestingly, several recent studies have gained mechanistic insight into inter‐organ cross‐talk between the skin and the intestine. Allergen penetration through a disrupted skin barrier in patients with and without atopic dermatitis can elicit both a Th2‐dominated systemic and local immune response 99. Consequently, systemic levels of total and allergen‐specific IgE are increased. Co‐occurrence of atopic dermatitis with food allergy is often seen in early life 100. Bartnikas and colleagues first reported a link between mechanical skin injury and intestinal mast cell expansion 101. Recently, this mechanism was shown to be mediated by increased IL‐33 and IL‐25 release by keratinocytes and tuft cells, respectively, which consequently induced expansion of intestinal type‐2 innate lymphoid cells (ILC2). Mast cell expansion in the intestine was consequently induced by ILC2‐derived IL‐4 and IL‐13 102, 103. It remains to be determined whether there is a role for the microbiome in this inter‐organ cross‐talk linking atopic dermatitis and food allergy.

Allergic asthma

Atopic dermatitis and food allergy often co‐occur with the development of allergic asthma in early childhood 104, 105. Allergic asthma is a chronic, heterogeneous, inflammatory disease affecting the conducting airways 106. Approximately 50% of the asthmatic adults and most asthmatic children suffer from allergic asthma 107. This disease is preceded by allergic sensitization, and first diagnosis often takes place around school age (5–7 years of age) 108, 109. Allergic asthma symptoms include bronchial hyperreactivity (BHR), mucus over‐production and airway narrowing 110. Allergic asthma is initiated when allergens are captured by antigen‐presenting cells (APCs), such as DCs, which are recruited to the airway epithelium by epithelium‐derived factors, including IL‐33 and thymic stromal lymphopoietin (TSLP) 111, 112. Antigen presentation on DCs can consequently activate naive T lymphocytes and prime them towards a Th2‐dominant response.

A variety of endogenous and exogenous factors can predispose an individual to developing atopic asthma 113, 114, 115; for example, a history of other atopic diseases and consequent allergic sensitization 2. Furthermore, allergic asthma is a genetically complex disease and more than 100 genes have been implicated in the disease pathogenesis, including genes associated with epithelial‐derived cytokines and variation at the asthma locus that encode ORMDL3 and GSDML 116, 117. Moreover, the airway and intestinal microbiome have been demonstrated to play a role in the development and progression of allergic asthma.

The role of the airway microbiome in allergic asthma

Until recently, the human airways were considered to be sterile; however, during recent years it has become evident that the airways harbour a microbiome, and that microbial diversity and loads changes from upper to lower airways 118, 119. The lower respiratory tract microbiota forms within the first 2 months of life 120. In addition, the colonization of the lung in early life is a highly dynamic process that can be influenced by endogenous and environmental exposures 120, 121, which consequently can increase the susceptibility for developing lung disease in early life.

Bisgaard and colleagues studied nasopharyngeal aspirates from high‐asthma‐risk neonates (born to mothers with asthma) using culture‐based methods. They found that colonization with Haemophilus influenzae, M. catarrhalis or Staphylococcus pneumoniae or a combination of these species was associated with elevated levels of IgE and an increased risk of allergic asthma development by 5 years of age 122, 123. However, this association was no longer detected at 12 months of age, which indicates that early life, i.e. at least the first month of life, is crucial in the development of the microbiome 124. Furthermore, Escherichia coli and Psychrobacter were found to be over‐represented in nasal samples of children with allergic asthma compared to healthy age‐matched subjects 125.

Childhood asthma can be influenced by seasonal changes, and a recent study investigated nasal lavage of 58 children (age 6–8 years) for 5 weeks during the cold season. It was demonstrated that children with allergic asthma experienced more frequent and more severe viral illness, which increased the morbidity of respiratory disease in these children 126. To further analyse this line of thought, Kloepfer et al. examined nasal samples of 308 children (age 4–12 years) with or without atopic asthma for rhinoviruses, and observed a similar association between allergic asthma and Proteobacteria and Firmicutes. However, the detection of these bacteria increased in conjunction with rhinovirus, which exacerbated both cold and allergic asthma symptoms 127. Furthermore, Neisseria subflava was shown to increase after rhinovirus infections 128. Although some studies did not observe significant seasonal differences in microbial diversity, they demonstrated that the nasopharyngeal microbiome differed between children (both atopic and non‐atopic) and over time 129, 130.

During recent years it has become evident that early life respiratory virus infections can also predispose infants to the development of asthma 131, 132. Children who suffered from early life acute respiratory infections were shown to have decreased forced expiratory volume in 1 s (FEV₁) and an increased risk for asthma development at school age 133. Interestingly, these effects were shown to be independent of antibiotic use. Moreover, an increased frequency, severity and mean duration of acute respiratory infections during the first 23 months of life increased the risk of asthma 134. Recent studies suggest that changes in the lung microbiome following respiratory infections in early life are potentially linked to allergic sensitization 135. However, additional mechanistic studies are required to determine whether early life respiratory infection‐induced lung dysbiosis can increase the risk for asthma development.

Host–microbe interactions in allergic asthma

The airway microbiome develops within the first days of life in both mice 136 and humans 120, and microbial presence has been implicated as a key player in asthma development. Herbst and colleagues demonstrated that a lack of microbial colonization, using germ‐free mice, before allergen exposure could increase allergic airway inflammation and that re‐colonization of these animals rescued this phenotype 137. In addition, airway exposure of neonatal mice to bacteria strains isolated from the airways led to protection against or enhanced susceptibility to develop airway inflammation 138. Microbial colonization in the airways is also important for differentiation and maturation of alveolar macrophages in early life 139. Moreover, formation of the airway microbiome in early life has been shown to promote induction of regulatory T cells via expression of programmed cell death ligand‐1 (PD‐L1) on DCs 136. Taken together, these data suggest that microbial exposure in early life has profound effects on pulmonary immune responses and can be a determinant for long‐term lung health or disease.

The role of the intestinal microbiome in allergic asthma

Respiratory diseases are often accompanied by a component of intestinal disease manifestation 140, 141, 142. It has been suggested that a high diversity of the intestinal microbiome is more important than the predominance of specific taxa to educate the immune system 122. The intestinal immune system responds to antigen exposure and repeated exposure is thought to stimulate the development of immune regulation 143. Low gut microbial diversity during the first month of life is associated with increased risk of allergic asthma at school age when compared to non‐allergic controls. This association was restricted to infants who developed atopic dermatitis at the age of 2 years, which is in line with the sequence of events described in the atopic march 143.

It was shown that infants with low gut microbial exposure also exhibited low microbial exposure through the respiratory mucosa, and maturation of the immune system depends in part on bacterial colonization of the lower airways 144. Clostridia strains have been shown to enhance T regulatory cell numbers and induce IL‐10 and IL‐22 expression 145. Bacteroides fragilis has been shown to prevent the onset of asthma by producing polysaccharide A which, in turn, induces the production of regulatory T lymphocytes in the intestine and consequently inhibition of Th1/Th2 responses 146. Furthermore, high‐fibre diet feeding of mice increases intestinal Bifidobacteriaceaea abundance. This family of bacteria produces SCFAs, which have several effects throughout the body, including increased haematopoiesis of DC precursors, leading to a damping of the pulmonary Th2 response 24

Outlook

The overall diversity and taxonomic units of human microbiomes in atopic diseases are both altered compared to the healthy situation. Moreover, within the atopic march the changes in the microbiome are most often initiated during atopic dermatitis and worsen with the occurrence of other allergic diseases. This raises the question of whether outcomes of studies that focus on allergic asthma are due solely to allergic asthma or if the co‐occurrence of other allergic conditions in these individuals may have already induced a dysbiosis. Furthermore, despite the clear involvement of the microbiome in atopic disease, it remains to be determined whether microbial alterations are a cause or a consequence of the disease 147. Trends are observed most commonly in clinical trials studying allergic diseases; however, they cannot be fully supported, as the number of participants is generally limited. In addition, clinical studies on the intestinal microbiome can be confounded by the dominant diet of the country where the study was performed. In future, more longitudinal studies should be performed to establish the role of the microbiome in the co‐occurrence of allergic diseases.

Disclosures

The authors declare no conflicts of interest.

Author contributions

B. N. and N. D. J. U. wrote the manuscript.