Alterations in GIT bacterial levels or diversity dysbiosis can disrupt mucosal immunological tolerance, leading to allergic diseases including FA 35 and even asthma 36 — Moreover, low IgA levels at the intestinal surface barrier can also contribute to FA. This stimulation may occur through the production by members of the microbiome of metabolites, such as short chain fatty acids SCFAs.
Thus, the immune tolerance network in the intestinal lumen can be considered to include the gut microbiota, their metabolic products, dietary factors, epithelial cells, DCs, IgA antibodies, and regulatory T cells Figure 1. Figure 1. Interaction between gut microbiota and immune system. Gut microbiota metabolites and dietary factors constitute the main antigen load of the gastrointestinal tract.
Follicular T cells activate B cells inducing the production of IgA antibodies. Once thought to be almost sterile, the esophagus has been shown to comprise around bacteria species. Significant differences in the microbial composition of children with active esophageal inflammation caused by eosinophilic esophagitis compared with controls have been reported Importantly, both the degree of inflammation and the treatment regimen seem to impact the esophageal microbiota As with the esophagus and fetus, the lung has long been thought of as sterile; however, recent evidence has shown it to harbor various bacteria phyla, including Actinobacteria, Bacteroidetes, Firmicutes , and Proteobacteria , even in healthy subjects Similar to the gut, the lung microbiome changes rapidly in the first years of life, before beginning to stabilize 45 , Colonization occurs gradually in healthy children, starting with Staphylococcus or Corynebacterium , followed by Moraxella or Alloiococcus A breakdown in the development of the commensal population can lead to dysregulation of the IgE—basophil axis, with elevated serum IgE concentrations and increased of circulating basophil populations as has been described in murine models of allergic airway disease Importantly, this link was found to be B-cell intrinsic and dependent on the MYD88 pathway.
Moreover, the lung microbiome may also play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns.
Enterococcus faecalis can suppress Th17 immunity and symptoms of allergic airway disease, and thus it has even been considered a potential therapeutic agent for both asthma and Th17 immunity Differences in levels and diversity of the lung microbiome have been found between healthy people and patients with asthma and allergic diseases, with an increase of Proteobacteria in the latter; moreover, their presence has been linked to increased severity of asthma probably through the upregulation of Threlated genes 49 , Early colonization with Haemophilus influenzae, Moraxella catarrhalis , and Streptococcus pneumoniae has been associated with recurrent wheezing and asthma 45 , 46 , 51 , Importantly, as well as bacteria, viruses will also influence asthma development, as has been demonstrated with human rhinovirus infections of the nasopharynx in early-life In addition, other associations such as helminths may be protective for asthma, as helminth infections have been shown to increase the microbiota diversity Associations have been found between the composition of the lung and gut microbiome and the risk of respiratory allergic disease development 54 indicating that both gut and lung mucosa may function as a single organ, sharing immunological functions Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis AD and psoriasis The composition of the skin microbiota depends on the body site samples The relevance of AD, often associated with other allergic diseases, has significantly increased in the last few decades.
Outgrowths of Staphylococcus and reductions of other communities like Streptococcus or Propionibacterium species correlate with AD flares On the other hand, skin commensal Acinetobacter species have been reported to protect against allergic sensitization and inflammation, playing an important role in tuning the balance of Th1, Th2, and anti-inflammatory responses to environmental allergens Interestingly, studies of cutaneous allergic diseases have found an association with gut microbiome dysbiosis 59 , although the underlying mechanisms are still unclear.
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An initial study of 90 patients with established AD found enrichment for Faecalibacterium prausnitzii and decreased levels of SCFAs in the gut Figure 2. Dysbiosis induce qualitative and quantitative changes in the microbiota that directly affect immunological mechanisms leading to allergic diseases. The mode of delivery in childbirth can produce profound differences in the infant gut microbiome, with lower level of Escherichia coli, Bifidobacterium , and Bacteroides species in children born through cesarean section compared with those delivered vaginally 28 , 61 , Cesarean-born infants typically have a microbiome enriched with Staphylococcus and Streptococcus , comparable with the maternal skin microbiome These differences appear to be associated with higher risk of allergic diseases and asthma 64 — Transfer of maternal vaginal microbes at birth may mitigate these effects Time of gestation may also be a factor: premature births are associated with alterations of the gut microbiome, but not atopic sensitization There is mounting evidence that early-life exposure is critical for the microbiome and that gut microbial dysbiosis heavily influences immune system development Potential factors include perinatal exposure to maternal or infant diet, antibiotic use, and contact with older siblings Data from different populations show that the highest interindividual microbial variability occurs during the first 3 years of age Noteworthy, contact with the microbiome can start before birth, since a low-abundance microbiota in the placenta 69 and meconium 70 , 71 have been found.
Microbial exposure during the first months of life induces the activation of the innate immune system in different ways, with consequences for FA. Early inoculation with spore-forming Clostridium class IV and XIV species 72 and other bacteria 53 leads to decreased levels of circulating IgE in adulthood. Conversely, 3-week-old neonates with a higher fecal burden of Clostridium difficile and a higher ratio of C.
Similarly, high levels of fecal E. Remarkably, the same colonization pattern can have different consequences at different ages. For example, colonization of S. Furthermore, respiratory tract infections during early-life are associated with asthma development 76 , This may be because viral infections favor other opportunistic respiratory pathogens such as M. Other possible mechanisms may involve respiratory rhinovirus interacting with airway epithelial cells, increasing IL and IL production and contributing to Th2 immune responses This is in line with the higher levels of house dust mite-specific IgE found in children infected with rhinovirus Moreover, rhinovirus infection can also induce mucus hypersecretion and airway hyperresponsiveness in neonatal mice compared with adults Another key factor influencing gut microbiome diversity is infant feeding, and especially breastfeeding, which has been shown to increase colonization by Lactobacilli and Bifidobacteria Breast milk contains oligosaccharides and a wide range of fatty acids, which will affect the gut microbiome and its capacity to produce metabolites that protect against allergies and asthma 83 through the development of Treg cells This effect is also produced by the intake of unprocessed milk during the first year of life, probably related to higher levels of peptides in the serum fraction and unsaturated omega-3 fatty acids Other dietary components such as polyphenols and fish oils are also important for microbiome diversity 86 — Some noteworthy bacteria, such as Lachnospiraceae and Ruminococcaceae , can also influence the gut microbiome by producing SCFAs—including propionate, butyrate, and acetate—through fermentation of complex dietary carbohydrates.
The introduction of antibiotics in the s is associated with an increasing incidence of allergy. This is thought to be causes by antibiotics inducing dysbiosis which has been shown to directly impact the development of AD 92 and asthma Intrapartum antibiotics have been shown to lead to a modified microbiome in children at 3 and 12 months Other studies showed that antibiotics affect the microbiome in older subjects 96 , Antibiotic administration is associated with severe allergic airway inflammation in neonates, but not in adults Even low doses of antibiotics can affect microbiome composition 99 ; however, the associations between antibiotic consumption and allergic diseases increase with the number of antibiotics prescribed, and variable effects have been found for different antibiotic families.
Some studies have indicated that betalactam antibiotics are the most common triggers when FA is diagnosed before 2 years of age, while macrolides are associated with FA when it is diagnosed later For asthma, further studies are needed to clarify whether it is the infection rather than the antibiotics themselves that increase susceptibility The microbiota can be considered a therapeutical target for treating allergy; moreover, certain species can be used to enhance tolerance response induction.
Different approaches for restoring the microbiome involve probiotics, prebiotics, and synbiotics. They do so by promoting the appropriate balance of gut microbiota.
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The health benefits attributed to one probiotic strain are not necessarily applicable to another one even within one given species Furthermore, the effectiveness may depend on the time of intervention and aspects of the current microbiota composition. In fact, different studies have shown that timing is crucial In the case of FA, co-administration of bacterial adjuvants with oral immunotherapy OIT has been suggested as a potential treatment.
Some investigations have shown that the oral administration of probiotics may benefit allergic rhinitis patients — ; similarly, local nasal administration of Lactococcus lactis NZ can affect local and systemic immune responses against S.
However, Ivory et al. It has been suggested that probiotics can help preventing eczema and they also show some beneficial effects for other allergic diseases including asthma — ; furthermore, another approach based on the intranasal application of bacterial products endotoxin or flagellin has demonstrated immunomodulatory ability, mimicking the effect of probiotics, for the lung in different animal models, reducing experimental asthma by either re-establishing the expression of the ubiquitin-modifying enzyme A20 at the endothelial barrier or inducing Tregs , Therefore, it seems that the optimal time periods to apply probiotic intervention are before, during, and just after birth represents.
Nevertheless, more studies, using clinical trial methodologies when possible, should be carried out to confirm these findings and determine the optimal probiotics to use. Prebiotics are non-digestible food components that benefit the host by selectively stimulating the growth and activity of microorganisms. Studies have shown that fibers and oligosaccharides can improve immunity and metabolism 8 and that the treatment of pregnant and lactating mice increases the proportions of Lactobacillus and Clostridium leptum and promotes a long-term protective effect against FA in the offspring A recent Cochrane review has shown that although the addition of prebiotics to infant food may reduce the risk of eczema, it is not clear whether their use may affect other allergic diseases including asthma When the use of a combination of prebiotics and probiotics produce synergistic health benefits it is described as a symbiotic.
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In FA mice models, both the microbiome and diet can affect the development of food tolerance by the induction of Treg cells A recent meta-analysis has shown their beneficial effects for eczema treatment However, further well-conducted, randomized, placebo-controlled longitudinal studies are still needed in this area The microbiota is a highly dynamic environment influenced by multiple environmental and dietary factors, with a complex role in allergic diseases. Further studies with larger number of well-characterized patients and controls are needed to dissect the role of microbiome in allergic diseases are the performance.
However, the field is still relatively new and we expect many key findings to be made in the next few years. Detailed prospective, randomized, placebo-controlled studies will be essential for this purpose. CM, MP and MP-G conceived and designed this manuscript and were involved in manuscript production contributing equally to this work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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