Impact of local human microbiota on the allergic diseases: Organ–organ interaction

The homogeneous impact of local dysbiosis on the development of allergic diseases in the same organ has been thoroughly studied. However, much less is known about the heterogeneous influence of dysbiosis within one organ on allergic diseases in other organs. A comprehensive analysis of the current scientific literature revealed that most of the relevant publications focus on only three organs: gut, airways, and skin. Moreover, the interactions appear to be mainly unidirectional, that is, dysbiotic conditions of the gut being associated with allergic diseases of the airways and the skin. Similar to homogeneous interactions, early life appears to be not only a crucial period for the formation of the microbiota in one organ but also for the later development of allergic diseases in other organs. In particular, we were able to identify a number of specific bacterial and fungal species/genera in the intestine that were repeatedly associated in the literature with either increased or decreased allergic diseases of the skin, like atopic dermatitis, or the airways, like allergic rhinitis and asthma. The reported studies indicate that in addition to the composition of the microbiome, also the relative abundance of certain microbial species and the overall diversity are associated with allergic diseases of the corresponding organs. As anticipated for human association studies, the underlying mechanisms of the organ–organ crosstalk could not be clearly resolved yet. Thus, further work, in particular experimental animal studies are required to elucidate the mechanisms linking dysbiotic conditions of one organ to allergic diseases in other organs.


| INTRODUC TI ON
It is well known that dysbiotic microbiota contributes to the immunopathogenesis of allergic diseases such as asthma, allergic rhinitis, food allergy, atopic dermatitis, and other clinical manifestations. [1][2][3][4][5][6][7] Recent clinical and experimental studies revealed the association between the microbiome, the immune system, and the progression of clinical manifestations in allergic diseases [8][9][10][11] Many results in the field have been obtained from the gastrointestinal and/or the stool microbiome considering the interaction of the dysbiotic microbiome and local gastrointestinal mucosa inflammatory responses and food allergy. [12][13][14][15][16][17] Similarly, the interaction of the upper and lower respiratory tract microbiome and asthma and/or allergic rhinitis has been reported 2,18-23 as well as the association of the cutaneous microbial disturbances with atopic dermatitis. [24][25][26][27][28] More recent studies demonstrated that microbial changes at one organ site may also affect the inflammatory disease progression at other organs. [8][9][10][11][29][30][31] This concept is very conceivable since the microbiome is highly organspecific. 1 By contrast, the immune system is acting systemically and may thus trigger allergic reactions far from the site of exposure to particular microorganisms. We performed a nonsystemic review of published literature on "Microbiome and Allergy" "Microbiome and asthma" "Microbiome and skin allergy" "SCFAs and Allergy" from 2002 to 2022 using the PubMed database. We exclude animal studies and clinical trials. We further identified the human studies that emphasize the impact of local microbiome on allergy development in distal organs. We focused on studies related to microbiome taxa, which were reproduced by more than one study. In this humancentered review, we summarize and critically discuss the current published knowledge on the organ-organ crosstalk regarding the effect of dysbiotic microbiota on allergic diseases affecting distant organs.

| Impact of the intestinal microbiota on upper and lower airway allergy
Bacterial colonization in the gut starts a few hours after birth and shows a high degree of plasticity during the first years of life. 32,33 Exposure to various environmental factors, beginning from prenatal to adulthood affect microbiome composition and molecular functions across mucosal and dermal tissues, with short and longterm consequences for host immunity. 34 Dysbiosis, that is, quantitative and/or qualitative imbalance of bacterial and/or fungal microbiota associated with an unhealthy outcome, particularly of the gut microbiota, has been associated with the development of allergic airway diseases in many cohort studies 4,9,11 Increased risk of asthma at school age has been associated with a reduction in the bacterial diversity (α-diversity) of the gut microbiota in the first week or the first month of life. 35 Imbalance in specific taxa in early life, rather than changes in the global bacterial diversity, were associated with an increased risk of asthma later in life 9,36 For instance, the early colonization with Bacteroides fragilis strains within the first 3 weeks of life is reported as a potential predictor of possible asthma development later in life. 36 Less abundance of Bifidobacterium in the feces of wheezy children was correlated with asthma at approximately 5 years old or bronchiolitis at 1 year old when compared with healthy controls. 37 Interestingly, the amount of Bifidobacterium was positively correlated with T helper type 1 (Th1) cytokines IFNγ and negatively with total immunoglobulin E (IgE), T helper type 2 (Th2), and type 17 (Th17) cytokines measured in the sera of asthmatic children. 37 This suggests that Bifidobacterium impacts the Th1/Th2/Th17 cell balance and inhibits Th2/Th17-driven inflammation in asthmatic children. A recent Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study revealed are required to elucidate the mechanisms linking dysbiotic conditions of one organ to allergic diseases in other organs.

K E Y W O R D S
allergy, asthma, atopic dermatitis, dysbiosis, heterogeneous organ-organ interactions, human microbiota

Key Message
Human association studies of heterogeneous organ-organ interactions of dysbiotic microbiota on allergic diseases focus primarily on three organs: the gut, the upper and lower airways, and the skin. The organ-organ crosstalk appears to be mainly unidirectional, that is, dysbiotic conditions of the gut influencing allergic diseases of the airways and the skin. The shifting in the microbial diversity or the abundance of certain microbiota in the gut was associated with airways and/or skin allergic diseases. Furthermore, the microbiota-derived metabolites or loss of contact with "old friends" such as H. pylori are other key factors impacting the etiology of allergic diseases. Further studies using animal models of allergic diseases are needed to figure out the causality and to reveal the mechanisms responsible for the discovered organ-organ crosstalk. that four specific bacterial genera, Faecalibacterium, Lachnospira, Veillonella, and Rothia (FLVR), were less abundant in fecal samples of 3-month-old children, which displayed a higher risk of asthma development by 3 years of age. 9 This association was accompanied by a reduced concentration of fecal acetate and dysregulation of enterohepatic metabolites in the children at risk of asthma. 9 The follow-up of the CHILD cohort study demonstrated that a lower abundance of Lachnospira in favor of Clostridium neonatale in the first 3 months of life precedes a higher prevalence of asthma at 4 years of age. 38 Thus, the Lachnospira/Clostridium neonatale ratio in feces may be regarded as a potential early-life biomarker for asthma development. 38 In addition, Fujimura et al. 11 suggested that the relative risk of childhood atopy and asthma is correlated with the existence of distinct composition of neonatal human gut microbiota at a median age of 35 days. In this study, the lower abundance of Faecalibacterium, Bifidobacterium, Akkermansia, and higher abundance of Candida and Rhodotorula fungi were identified in stool samples of neonates aged 1-11 months, who develop multisensitized atopy at 2 years of age and asthma at 4 years of age. 11 In agreement with the CHILD cohort report, an Ecuadorian birth cohort (ECUAVIDA) investigating the gut microbiota dysbiosis of 3-month-old neonates demonstrated that a higher relative abundance of Streptococcus and Bacteroides spp. and a lower relative abundance of Bifidobacterium spp. and Ruminococcus gnavus (R. gnavus) may have clinical importance as a potential predictor of atopy and wheeze at 5 years of age. 10 However, opposite findings of a twin cohort study showed that a high fecal abundance of R. gnavus was associated with the development of respiratory allergies including asthma and allergic rhinitis. 39 Clostridium difficile (C. difficile) is a prominent example of a gut bacteria that can significantly impact the composition of gut microbiota by reducing α-diversity in infancy. 40,41 On the contrary, the disturbance in the balance of gut microbiome can potentially facilitate the proliferation of C. difficile, particularly if there is an exposure to this bacterium during a period of microbial imbalance. A study in Incheon, Korea, investigated 65 infants aged 1-12 months and found a link between C. difficile colonization and/or infection in infants and increased the risk of developing allergic disease in later childhood. 40 The Korean study provides valuable insights into the relationship between antibiotic exposure and the incidence of C. difficile infection.
The findings indicate that the C. difficile-negative group had a higher likelihood of being exposed to antibiotics, which further supports the observation that infants who have not been exposed to antibiotics have a significantly higher rate of community-acquired C. difficile infection compared with adults. 40 However, caution is required when using antibiotics, as they can lead to gut microbiota dysbiosis, that is, imbalance in composition and function. 42 Early gut colonization with C. difficile in infancy, specifically within the first month of life, is linked to an increased risk of atopic manifestations such as eczema, atopic dermatitis, recurrent wheeze, and atopic sensitization in the first 2 years of life. 41 Within the National Asthma Campaign Manchester Asthma and Allergy Study ( NAC MAAS), infants with atopy (positive skin-prick test) and a history of recurrent wheeze had significantly higher C. difficile-specific IgG absorbance levels in sera when compared to the control group (skin-prick test-negative and no wheeze), this could reflect the dysbiosis in the gut microbiota between allergic and nonallergic children at 1 year of age. 43 Another cross-sectional study, which was carried out in São Paulo, Brazil, included 81 children between the ages of 5 and 11 years. Of these, 23 children had atopic dermatitis, while 58 were nonatopic dermatitis controls. The study found that children with atopic dermatitis had a different microbiota pattern than the controls, with a higher incidence of C. difficile, lower levels of Lactobacillus spp., and higher levels of Bifidobacterium spp. 44 These results may suggest a potential relationship between early-life dysbiosis of the gut microbiota and allergy and shed light on the potential role of C. difficile in leading to atopic sensitization.
New studies indicated that a reduction in α-diversity of the gut microbiota and a lower abundance of organisms of the phylum Firmicutes may contribute to the development of allergic rhinitis in early childhood. 45,46 A cross-sectional controlled study analyzing the gut microbiota profiles in asthmatic and rhinitic children aged 4-7 years 45 found a potential link between gut microbiota dysbiosis such as a lower abundance of phylum Firmicutes and higher abundance of phylum Proteobacteria, and IgE concentration in the feces of rhinitic children. 45 It has been proposed to regard the first 100 days of life as a "window of opportunity" that is crucial for the influence of microbiota on the development and education of the host immune system. 47,48 Since lack of breastfeeding, lifestyle or other factors are likely to influence the balance of gut microbiota and lead to dysbiosis, these factors may in turn cause inappropriate immune responses. 4,49,50 The association between gut microbiota and the development of airway allergy is not restricted to children. It has been found that the α-diversity of adults' gut microbiota is lower in asthmatic individuals. 31,51 In addition, the presence of specific gut taxa such as Prevotella, Escherichia, Streptococcus, Rumminococcaceae, Lachnospiraceae, and Clostridiales was found to be associated with sensitization to inhaled allergens and reduced lung function in adult asthmatic patients compared as with nonasthmatic individuals. 31,52 The human gut microbiota composition has been reported to impact the degree of airway obstruction in adult asthmatic patients with a common exposure framework and living in the tropics. 51 Here, the relative abundance of Streptococcus, Escherichia, and Shigella was higher in asthmatic individuals with a phenotype of fixed airway obstruction as compared with asthmatic individuals with a phenotype of no airway obstruction or reversible airway obstruction. 51 Strikingly, asthmatic adults with the phenotype of no airway obstruction showed a higher abundance of Rumminococcaceae and Lachnospiraceae families in their fecal samples as compared with asthmatic adults with fixed airway obstruction or reversible airway obstruction, suggesting a protective role for these bacteria against airway obstruction. 51 Further studies on the fecal microbiota profile of adult atopic asthmatic patients revealed a positive association between Lactobacilli and Escherichia coli (E. coli) and atopic asthma as compared with healthy individuals. 53 In addition, another study revealed a negative association of Bifidobacterium adolescentis with long-term asthma and a positive association of the Bifidobacterium adolescentis with total IgE levels in adult asthmatic patients. 54 In this respect, gut microbiome analysis in adults with allergic rhinitis compared with healthy controls demonstrated a reduction in αdiversity measured by the Shannon index with more abundance of Bacteroidota such as Parabacteroides and less abundance of phylum Firmicutes such as Coprococcus. 55 Similar findings were reported in a Chinese study, comparing gut microbiota composition of adult allergic rhinitis with healthy controls, showing a higher abundance of the phylum Bacteroidota and a lower abundance of Actinobacteria and Proteobacteria in adult allergic rhinitis patients compared with healthy controls. 56 Within the same study, the detection of the genera Escherichia-Shigella, Lachnoclostridium, Parabacteroides, and Dialister was suggested as a potential biomarker for patients with allergic rhinitis. 56 To this end, the presented studies on the impact of gut microbiota dysbiosis on asthma and allergic rhinitis development in adults were characterized by two major limitations: On the one hand, most of these studies are focusing on the association of gut microbial dysbiosis with upper or lower airway allergy, and on the other side, no causal relationship is observed. However, these data support the role of early-life infant gut microbial dysbiosis in the development of airway allergic diseases. This knowledge may ultimately lead to novel strategies for preventing asthma and allergic rhinitis by correcting microbial dysbiosis in early childhood.
While bacterial microbiota have been extensively researched, fungi have received comparatively less attention in terms of studies. Fungi are regulators of the inflammation and homeostasis of the immune responses. 57 Shortly after birth, the genera Cladosporium, Saccharomyces, Candida, and Malassezia start to colonize the gastrointestinal tract. 58 In the context of allergy, dysbiosis in infants' gut mycobiome-as reflected by the overrepresentation of fungi in the gut-is associated positively with the development of atopic wheeze. 10,11 The ECUAVIDA birth cohort study revealed a fungal overrepresentation and higher abundance of Pichia kudriavzevii in fecal samples of 3 months old, suggesting for the first time a positive association between fungal overgrowth in the gut of infants and the development of atopic wheeze. 10 In this respect, another birth cohort study revealed that a higher abundance of Rhodotorula and Candida and a lower abundance of Malassezia were associated with an increased relative risk of atopy at two and of asthma at 4 years of age. 11 These findings suggest that dysbiosis of the gut mycobiome is just as important for the later development of airway allergy as dysbiosis of the bacterial microbiome.
Taking together, the described findings support the concept of organ-to-organ crosstalk through the gastrointestinal tract microbiome on the lung known as gut-lung axis. [59][60][61] While evidence for the existence of healthy human blood microbiome is accumulating, 62 there is no evidence of the direct transfer of gut microbiota to the upper or lower airway in asthma or allergic rhinitis, but translocation of some gut microorganisms such as Bacteroides and Enterococcus spp. were observed in the lungs during sepsis. 63 Another proposed mechanism by which the immune cells that have been primed by the microbiota or their metabolites in the gut can migrate to other tissues and organs, where they may imprint their impact on local immune cells. This process is called immune cell imprinting and can lead to the long-term modulation of the immune response in different parts of the body. Deciphering the mechanisms of this "gut-lung" axis would help to understand the role of gut microbiota in the development of airway allergy and may lead to novel therapeutic strategies, which can be used to protect the respiratory system against allergic inflammation. Microbiota that has been described to exhibit either protective or harmful effects on the "gut-lung" axis are summarized in Figure 1.

| Impact of the intestinal microbiota on cutaneous allergy
There is increasing evidence that intestinal microbiota also impacts immunopathological processes in the skin, including atopic dermatitis. [64][65][66][67][68] Gut microbiota composition differs between atopic dermatitis patients and healthy controls. 69 Higher frequency of occurrence of Staphylococcus and lower counts of Bifidobacterium were reported in the fecal samples of severe atopic dermatitis patients as compared with control subjects. 69 The KOALA study from the Netherlands investigated different components potentially involved in the etiology of atopic diseases such as diet, antibiotics, gut microbiota composition, and gene-environment interactions. 70 This large-scale prospective birth cohort study suggested that changes in gut microbiota composition in early infancy precede the later onset of atopic diseases such as eczema, recurrent wheeze, and allergic sensitization. 41 In addition, the KOALA birth cohort study noted a proportional and positive association between the numbers of E. coli, measured as log 10 colony-forming units (CFU) in stool samples of 1-month-old infants, and the risk of eczema development. 41 A similar positive correlation was found between the presence of C. difficile and the risk of eczema, recurrent wheeze, and allergic sensitization, regardless of the number of those bacteria. 41 The "Protection against Allergy Study in Rural Environments" (PASTURE) demonstrated that higher levels of fecal calprotectin in 2-month-old infants might predict the subsequent development of asthma and atopic dermatitis at the age of 6 years. 68 The PASTURE study also reported an inverse correlation between early colonization with E. coli at the age of 2-month and the fecal calprotectin, which is the main protein content in the cytosol of neutrophils secreted during inflammation. 68,71 In vitro stimulation of the human peripheral blood mononuclear cells isolated from healthy donors with lipopolysaccharides (LPS) from E. coli 0128:B12 induced IL-10 production from monocytes. 68 Thus, a mechanistic concept was derived that in early infancy the lack of stimulation with LPS derived from E. coli in the intestine-due to dysbiosis-disrupts the production of IL-10 from immune cells such as monocytes, and increases the intestinal inflammation and the fecal calprotectin levels, resulting in a higher risk of atopic dermatitis at the childhood. 68,72 In addition, a randomized placebo-controlled interventional trial conducted on infants treated with bacterial lysate of heat-killed E. coli and Enterococcus faecalis at an age between 5 weeks and 7 months old demonstrated that this treatment protects against the development of atopic dermatitis at the age of 3 years. This effect was particularly pronounced in children with paternal atopy. 73 Within the same interventional study, after both treatment arms were pooled together for statistical analyses, 74 the microbial α-diversity measured by the Shannon index was found to gradually increase within the first 31 weeks of life. 74 The higher gut microbial diversity of those infants was associated with a reduced risk of development of atopic dermatitis and allergic sensitization. 74 Furthermore, a significant reduction was observed in the relative abundance of Lachnobacterium and Faecalibacterium throughout infancy among children who developed atopic dermatitis. 74 In summary, these studies suggest an association between specific taxa and the development of atopic dermatitis. However, the opposite finding showed that the enrichment of Faecalibacteriuim prausnitzii (F. prausnitzii) subspecies (F06) is associated with atopic dermatitis, but no direct link could be identified for this association. 75 Taken together, these findings may suggest an important role of the early intestinal colonization with E. coli in protection against atopic dermatitis by reducing the inflammatory biomarker calprotectin and possible induction of IL-10 from monocytes, resulting in less disruption and inflammation in the intestinal lumen and less development of atopic dermatitis. 68,72 Furthermore, the data suggest that a lower diversity of gut microbiota leads to a higher risk of developing atopic dermatitis. 74 One of the triggering factors in atopic dermatitis development is skin colonization with S. aureus. 76,77 S. aureus can produce both, protein A, which is mitogenic to B cells, and enterotoxins, so-called "superantigen," which induce T-cell activation. 78 Strikingly, a negative association between gut S. aureus colonization and the later development of eczema was reported. 65 This study found that those S. aureus strains that colonized the gut of up to 2-month-old infants, who developed atopic eczema by 18 months of age, were less likely to carry certain superantigens encoded by the enterotoxin gene (egc) cluster and the elastin-binding protein encoded by (ebp) gene, as compared with the S. aureus strains isolated from infants who did not develop atopic eczema at the same time frame. 65,78 It was proposed that the intestinal S. aureus colonization might stimulate and promote the maturation of the infant's immune system and strengthen the skin and mucosal barriers. 65 It thus appears that early exposure to S. aureus superantigens in infancy exhibits a protective effect against the later development of atopic phenotypes. 65 These findings indicated that a gut-skin axis exists. Some studies have reported that dysbiosis in the gut microbiome in early life is critical and associated with the onset and severity of atopic dermatitis. 35,65,68,70,74,78,79 The lower diversity of gut microbiota in infancy due to dysbiosis may increase the risk of atopic dermatitis development. 74 Specific gut taxa such as Lachnobacterium, Faecalibacterium, Bifidobacterium, and E. coli may play a potential role in controlling atopic dermatitis development. 68,69,74 The gut microbiota that have F I G U R E 1 Association of gut microbiota with upper/lower airway and skin allergies development. The highly abundant gastrointestinal tract microbiota are involved in upper/lower airway allergies (on the left) or skin allergies such as atopic dermatitis (on the right). The microbiota were classified into allergy-associated microbiota (on the upper panel with red boxes) or anti-allergy-associated microbiota (on the lower panel with green color). Only microbiota that were reproducible and consistent in studies where considered. (AR) indicates allergic rhinitis-related microbiota, (BA) indicates Bronchial Asthma-related microbiota, (AR + BA) indicates both allergic rhinitis and asthma-related microbiota. Figure was generated by Biore nder.com repeatedly been described to be involved in the "gut-skin" interactions are summarized in Figure 1.

| Impact of short-chain fatty acids (SCFAs) on airway and skin allergy
Gut microbiota-produced SCFAs such as acetate, propionate, and butyrate interaction with the immune system has been studied to some extent. 80 89 A study on the fecal metabolome profile and its association with asthma and allergic rhinitis in children aged between 4 and 7 years revealed that butyrate and amino acid histidine are significantly reduced in children with rhinitis and asthma, respectively, while the rare amino acid β-alanine is significantly higher in asthmatic children as compared with healthy controls. 46 Analyzing the gut microbiota composition in those asthmatic children revealed a reduction in the abundance of butyrateproducing bacteria in the gut, such as Faecalibacterium and Roseburia spp., and increases in Clostridium spp., indicating an important role of Clostridium spp. in suppressing the butyrate-producing bacteria and elevating the risk of asthma in children. 46 To this end, the gut SCFAs seem to be an important modulator of immune responses in airway allergy such as asthma and rhinitis in the gut-lung axis. 9 A lower abundance of SCFAs-producing bacteria due to gut dysbiosis may lead to a higher risk of asthma or allergic rhinitis in childhood. 46 In skin allergy, Faecalibacterium prausnitzii (F. prausnitzii) is considered a beneficial gut-bacterial microbiota with anti-inflammatory properties and the ability to produce SCFAs such as butyrate. 75,92 Impairment of the gut epithelial barrier induced by inflammation (leaky gut syndrome) may lead to dysbiosis caused by a shift in the proportion of different F. prausnitzii strains, that is, domination of low butyrate-producer strains, such as L2-6, over high butyrateproducer strains, such as A2-165. Consequently, above mentioned intraspecies compositional dysbiosis leads to a substantial reduction in SCFAs production such as butyrate and propionate, which possess anti-inflammatory properties, and may thus exaggerate the gut epithelial inflammation and cause the epithelium to become more permeable, allowing undigested foods, toxins, and pathogenic microbes to pass through and enter the systemic circulation. This can ultimately lead to harmful substances reaching the skin. Additionally, it may induce an abnormal Th2-type immune response in the skin and thereby accelerate the progression of atopic dermatitis. 75 In a birth cohort study conducted in Singapore, the levels of SCFAs (acetate, propionate, and butyrate) were decreased in allergensensitized atopic dermatitis individuals compared with healthy or non-allergen-sensitized atopic dermatitis individuals, indicating the importance of SCFAs levels in the development of atopic dermatitis with allergen sensitization. 93 A few studies have elucidated the mechanisms by which SCFAs exert their anti-inflammatory effects in allergy-induced inflammation. SCFAs become active upon binding to specific ligands, including G protein-coupled receptors 4 (GPR41, GPR43, and GPR109A) and aryl-hydrocarbon receptor (AHR). [94][95][96] This binding leads to an anti-inflammatory response by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway in the host. 97,98 Additionally, SCFAs have the ability to hinder histone deacetylases (HDAC) activity, resulting in increased expression of forkhead box P3 (FOXP3) in CD4 + T cells and suppressing the release of C-X-C motif chemokine ligand 10 (CXCL10). 99,100 Furthermore, SCFAs have been shown to effectively decrease the production of tumor necrosis factor-alpha (TNFα) and interleukin 6 IL6 by downregulating HDACs mRNA, which helps to reduce systemic inflammation. 101 Conclusively, more specific studies are needed to reveal the exact role of SCFAs in humans and to resolve the underlying mechanism responsible for shaping the immune responses in other organs and tissues.

| Impact of Helicobacter pylori on airway and skin allergy: loss of a friend or a foe?
At the genus level, the dominant members of the healthy human stomach microbiota include Prevotella, Streptococcus, Veillonella, Rothia, and Haemophilus. However, the composition of this microbiota is not static and can be influenced by various factors, such as diet, drugs, and diseases. Although these microbiota have been extensively studied in the context of the intestinal microbiota, their role in allergy within the stomach is still uncertain. 102 By contrast, H. pylori is one of the well-studied members of the stomach microbiota, owing to its potential for pathogenicity and contribution to human immune homeostasis. Changing trends in the prevalence of Helicobacter pylori (H. pylori) infection were reported over the last decades in many epidemiological studies. [103][104][105][106][107] Notably, fewer cases of H. pylori infection were recorded, particularly in western countries among children and adults, which might be due to the modern hygiene practices and the improvements in sanitary and living standards. [103][104][105][106][107][108] One of the hypotheses known as the hygiene hypothesis suggests that the incidence of H. pylori infection in early life is much higher in an unhygienic family environment or lifestyle, resulting in a lower risk of atopy or asthma. 109,110 A loss of contact with "old friends" such as H. pylori seems to play an important role in airway allergic diseases such as asthma. 111 Blaser et al. 112 reported for the first time an inverse association of H. pylori with asthma and allergic rhinitis in children. Furthermore, H. pylori infection demonstrated a significant negative association with atopy and asthma in different cross-sectional studies. [113][114][115][116] The proposed inverse association between H. pylori and asthma was also supported by a metaanalysis of eighteen observational studies, indicating that H. pylori infection, particularly those with virulence factor CagA(+), is inversely associated with the risk of childhood asthma. 117 However, there is little known about the underlying protective mechanisms of H. pylori in atopy or asthma, but many hypotheses are accumulating. 109 In addition, another hypothesis suggests an important role of H. pylori neutrophil-activating protein (HP-NAP) in stimulating Th1 cells, leading to reduced Th2 response and lowering the risk of allergen-induced asthma. 109,110 In contrast to asthma, it has been shown that the clinical outcomes of skin diseases such as atopic dermatitis may worsen upon failure of the eradication treatment in H. pylori infection and even move the disease into an uncontrolled or chronic form. 118 However, many studies demonstrated a significant inverse association of H. pylori infection with atopic dermatitis and atopy. 115,116,119 The contradiction in H. pylori clinical studies, including cross-sectional and case-control studies, 110

| IMPAC T OF THE AIRWAY MI CROB I OTA ON FOOD AND CUTANEOUS ALLERGY
While there is substantive evidence on the impact of gut microbiota on allergic airway diseases, the reverse connection has been less investigated in humans. 120 In addition, the underlying mechanism of lung microbiota effects on food allergy development is not clear yet. [121][122][123] Recently, some evidence indicated that the gut-lung axis is a bidirectional connection 8 . In this respect, a reverse influence of the lung on the gut has been described in some animal models. [124][125][126] The impact of oropharyngeal microbiota and industrial/western lifestyles on the development of food allergy has been reported. 127 As compared to Chinese children living in China, Australian immigrant Chinese children presented with a lower α-diversity of their oropharyngeal microbiota and a higher abundance of Actinobacteria, Fusobacteria, and Bacteroidetes. These differences as well as the higher prevalence of food allergy and wheezing were attributed to the western environment/lifestyle in Australia. 127 Furthermore, there is a lack of studies on the role of airway microbiota on the development of skin allergy, although in most cases atopic dermatitis is frequently associated with airway allergies such as asthma. [128][129][130] Therefore, it would be highly interesting to investigate whether the airway microbiota could impact the development of food or cutaneous allergy.

| CON CLUS I ON S AND FUTURE PER S PEC TIVE S
Colonization with a diverse microbiota early in life appears to be critical for shaping and modulation of the immune system throughout life. 1,4,[131][132][133][134] Imbalance in the local microbiota is not only triggering a local effector loop as seen in the gut microbiota dysbiosis linked to food allergy, upper/lower airway microbiota dysbiosis linked to rhinitis or asthma, and skin microbiota dysbiosis linked to atopic dermatitis, but also impacting other anatomical sites in a context of organ-organ crosstalk in particular via the immune system. [8][9][10][11][29][30][31] Further research on the oral microbiota in allergy has been limited by several factors, including the relative novelty of this field and the complex, ever-changing bacterial community within the oral cavity. 135,136 Recently it has been found that alterations in the composition of the oral microbiota may be linked to sensitization and the emergence of allergic reactions, such as peanut allergies and asthma. [137][138][139] In a 7-year longitudinal study by Dzidic et al., the composition of oral bacteria was linked to the development of allergy and asthma. The study analyzed DNA from saliva samples taken from children who were developing allergic symptoms and sensitizations (n = 47) and from healthy children up to 7 years of age (n = 33). 137 Furthermore, the composition of sputum and oral microbiota may have varying effects on the immune response in individuals with atopic asthma and atopic nonasthma. 140 Some evidence suggests that dental biofilm, particularly the prevalence of Fusobacterium nucleatum, may play a role in the development of allergy and asthma in children. 135 However, research on the link between oral inflammation, dysbiosis, and allergy is still in its early stages, and further investigation is necessary to establish any causal relationships.
In this review, we discussed the impact of different gut microbiota and their metabolites on the development of upper and or lower respiratory allergy (gut-lung axis) and their impact on the development of skin allergy (gut-skin axis). The collected data demonstrate that the gut dysbiosis reflected by shifts in the diversity of microbiota as well as imbalance of specific taxa and/or their metabolites may impact the development of asthma, allergic rhinitis, and atopic dermatitis. The main limitation of most studies is their particular focus on classifying the qualitative and/or quantitative composition of the local microbiota and relating those findings to atopic and allergic effects in the studied target organ. However, only a small number of studies go beyond the descriptive level and address mechanistic questions. The latter is an important element in order to reveal causality. Thus, there is an ultimate need to design human-controlled studies to investigate the causality relationships between microbiota, their metabolites, and the immune response on allergic diseases. On the other side, most of these mechanistic studies on the role of microbiota are conducted in animal models, which is not the ideal system to study their impact on health. Furthermore, it remains in most cases unclear, whether the observed effects are a result of direct taxa input on the immune system or whether other yet unknown taxa operate as intermediates within the hosts. One important example of mechanistic studies is to elucidate the role of gut microbiota-produced SCFAs and the regulation of the immune responses in lung and skin allergic diseases, since SCFAs such as butyrate and propionate seem to have beneficial effects in asthma, allergic rhinitis, and atopic dermatitis. Furthermore, detailed mechanistic studies on the role of H. pylori in asthma and atopic dermatitis may clarify the role of microbiota in two similar immunopathological diseases in two different organs. Mechanistic studies on the interaction between H. pylori and lung or skin allergies will not only help to understand the old friend hypothesis but also will clarify whether the hypothesis is relevant for two anatomically different organs suffering almost from the same type of allergy as seen in asthma and atopic dermatitis. Furthermore, we lack knowledge, even in epidemiological studies, on the impact of airway microbiota on both cutaneous and food allergies. In addition, there is a lack of data on the relationship mechanisms between skin microbiota and their impact on the development of airway allergy or food allergy.
A key observation of our review is that there is a wealth of data on the influence of dysbiotic conditions of the gut on airway allergies (gut-lung axis) and on cutaneous allergies (gut-skin axis), with only a few of the studies going beyond pure description, but there are close to none studies analyzing the reverse effects, that is, dysbiotic conditions of the airways affecting food (lung-gut axis) or skin allergies (lung-skin axis) as well as dysbiotic skin conditions affecting either food (skin-gut axis) or airway allergies (skin-lung axis).
Although this finding is surprising at first sight, the reason becomes quite obvious upon a closer look at the three organ systems studied: Whereas surface areas of the human gastrointestinal tract and the lungs are comparable in size (about 30 and 50 m 2 , respectively), the human skin surface is with about 2 m 2 more than 10 times smaller. 141 However, the human intestine harbors the by far largest variety (over 1000 different species) 142 and the number of microbiota (over 10 13 bacteria, not even counting fungi and viruses). 143 In addition, the gut is also the by far largest lymphoid organ harboring 70% of all antibody-producing plasma cells as well as a large fraction of B-and T-lymphocytes. 144,145 The human airways, in particular the lungs, are far less populated with respect to both, diversity and a sheer number of microbiota. The same holds true for the human skin. 146 Keeping these numbers in mind, it is not surprising that the intestinal microbiota dominates the interaction with the immune system and thereby also allergic diseases affecting other organs. Since the challenges for the immune system to differentiate between potentially harmful (infectious agents) and harmless epitopes (food components, pollen, etc.) depends largely on the sheer number of different epitopes that have to be discriminated appropriately, the intestine has most likely the highest-burden in this respect and thus also the highest risk of false decisions, that is, allergic reactions against harmless molecular structures that may also be found in airways and on skin. Cross-reactivity between harmful and harmless epitopes may also play an important role in this respect. 147,148 A functional interaction between similar epitopes on viruses and allergens has been reported. 149,150 However, this does not exclude at all those reciprocal effects that may also play an important role, that is, dysbiotic situations of the lung or the skin affecting other organs, including the gastrointestinal system. These effects are just far less likely to be identified by chance. In this respect, focused studies are needed that analyze the association of highly deviant dysbiotic states of the lung or skin with allergies affecting other organs.
In summary, the available data in this review point toward an important role of organ-organ interactions mediated by microbiota in allergic diseases such as asthma, rhinitis, and atopic dermatitis.
However, there is not sufficient circumstantial evidence for organorgan interaction to reach a vigorous conclusion in this regard. The gut is the best-studied microbiome location so far. This may be attributed to the ease of access to stool samples for analysis. Other organs are well behind and require further studies. In addition, the gastrointestinal microbiota may mediate this effect via immunological TA B L E 1 Top key points on the impact of local microbiota on other organs in the context of allergic diseases.
• Dysbiosis in the gut microbiota in early life reflected by reduction in the diversity of gut microbiota or changes in the abundance of gut-specific taxa is associated with the development of allergic airway diseases such as asthma or allergic rhinitis in childhood or mucosal signals between the organs. Although translocation of gut microbiota to the upper or lower airway in asthma or allergic rhinitis has recently been ruled out and was only found during sepsis, 63 further studies on the translocation of microorganisms or microbial components are needed in the context of allergic diseases affecting other organs. Maybe the reciprocal path, lung-to-intestine translocation, plays a more important role as it is known that some airborne virus are also able to infect the intestine following disease progression, as has been shown most lately for SARS-CoV-2. 151 Additionally, probiotics have been proposed as a potential strategy for the prevention and treatment of allergic diseases. In the case of infants diagnosed with atopic dermatitis, certain probiotics like Lactobacillus rhamnosus and Lactobacillus GG have shown a slight advantage compared with a placebo. 152 However, the effectiveness of probiotics in treating or preventing asthma or allergic rhinitis remains uncertain. 153 Therefore, more clinical and translational studies are essential to elucidate the precise role of probiotics in managing allergic disorders.
Further understanding of the mechanisms by which the local microbiota regulates the immune system and influences the development of allergic diseases will be pivotal for the development of

ACK N OWLED G EM ENTS
Open Access funding enabled and organized by Projekt DEAL.

PEER R E V I E W
The peer review history for this article is available at https:// www.webof scien ce.com/api/gatew ay/wos/peer-revie w/10.1111/ pai.13976.

TA B L E 2
Top open questions on the impact of local microbiota on other organs in the context of allergic diseases.
• What are the precise cellular and molecular nature of immunological signals between the gut and the lung/skin?
• Does the impact of early changes in the gut microbiota at the first month of life have a permanent or long-lasting effect on the immune responses of the host?
• What is the durability of the association between microbiota and allergic diseases and how stable is the microbial pattern throughout life?
• Is the gut microbiota able to translocate to the skin or upper/ lower airway?
• What is the contribution of the gut or lung microbiome to the development of different endotypes of asthma?
• What is the underlying mechanism mediating the negative association between Helicobacter pylori and asthma or allergic rhinitis? And what is the impact of Helicobacter pylori on atopic dermatitis?
• How could gut or skin fungi may exert their progressive or protective effects on asthma?