The role of the gut microbiota in Asthma and Atopy
The atopic diseases (atopic dermatitis, allergic rhinitis, allergic conjunctivitis, anaphylaxis, and asthma) are characterized by IgE-mediated hypersensitivity to an external antigen (210).
Strachan’s hygiene hypothesis, proposed in 1989, suggested that exposure of children to infectious agents during infancy will decrease their susceptibility to hyper-inflammatory diseases later in life (211). A recent example of testing this theory was conducted by Ege et al. in Central Europe; they found that children growing up on farms experienced a wide range of microbial exposures and tended to be protected from childhood asthma and other atopic diseases (212).
Significant changes in gut microbiota along with noteworthy changes in immune development and diseases paralleled the industrial revolution, suggesting that environmentally induced changes in the gut microbiota are associated with the development of hypersensitivity diseases. The prevalence of asthma and allergies has continued to rise in industrialized countries and in developing countries where living conditions and hygiene standards are becoming more like those of the Western world (213). Consequently, higher sanitation standards and more readily available Antibiotics
are likely decreasing our exposure to early childhood microbial antigens at the expense of our immune development (7, 213).
The microflora hypothesis is an extension of Strachan’s hygiene hypothesis in that it argues that there are critical interactions that must occur between our gut microbiota and our immune system in early life in order to circumvent the development of hypersensitivities (214). Studies in germ-free mice show the polarization of the post-birth immune system toward a T-helper 2 cell (TH2) driven immune response (215). With the restoration of the gut microbiota, there is a shift toward a TH1 and TH17 dominated immune phenotype, suggesting that the gut microbiota is important in establishing the balance between the TH1/TH2 subtypes in early life (a balance often disrupted in subjects with atopy) (215–217).
A number of mouse model studies aim to identify that bacterial taxa play a significant role in preventing or promoting the development of atopy. Perinatal Antibiotic
treatment of OVA-challenged mice (asthma-induced) has been shown to exacerbate the disease potentially by increasing serum and surface bound IgE as well as decreasing T-regulatory cell accumulation in the colon (218). Arnold et al. show that infection of asthma-induced neonate mice versus adult mice with Helicobacter pylori protects these mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia (common asthma characteristics) (135). Furthermore, Cahenzli et al. provide evidence in mice that a less diverse gut microbiota in early life is associated with elevated mast cell surface bound IgE and exaggerated systemic anaphylaxis (219). Though these studies provide insight for the relationship between gut microbiota and the immune system, researchers are questioning whether specific microbes are actually required to prevent atopy development or whether the metagenomic and metabolomic profiles of the gut microbiota as a whole should be the main focus.
For example, the gut microbiota promotes immune tolerance through the regular stimulation of pattern-recognition receptors (PRRs) and through the production of metabolites (e.g., SCFA) (94, 220). Establishing this immune tolerance to external antigens and host microbes is necessary to prevent the development of hypersensitivity reactions, as T-regulatory cells (+FoxP3) are critical in maintaining the TH1/TH2 balance (94). SCFAs have been shown to play a role in regulating the proliferation of colonic
T-regulatory cells (94). These microbial-derived metabolites may be the key to the microbial-host crosstalk that influences systemic inflammation. Low levels of i-butyric, i-valeric, and valeric acids in stool samples from children 1 year of age were associated with the development of food allergy
at 4 years of age; however, analysis of the gut microbiota composition was not conducted (221). A recent study showed that the gut microbiota metabolized a high-fiber diet fed to adult mice and this in turn increased the amount of circulating SCFA and consequently decreased allergic inflammation in the lungs of these mice (95). Additional research that focuses on the early-life microbiota is necessary to determine whether these metabolites may be influencing the development of our immune system and thus potentially biasing us toward or away from certain inflammatory diseases.
The majority of human studies regarding the early-life gut microbiota and the development of atopic disease focuses on the role of variables such as mode of delivery (vaginal vs. cesarean birth), feeding methods (breast-milk vs. formula/solid food diet), and early-life Antibiotic
exposure. Though the infant gut microbiota is influenced significantly by the child’s mode of birth (56), there are conflicting results regarding the association of birth mode with the development of atopic diseases. For example, according to Kolokotroni et al. children born by cesarean section are at an increased risk of developing asthma later in life, yet van Nimwegen et al. argue that mode of birth is less significant than the place of birth (hospital or home) in the development of the intestinal microbiota and asthma (222, 223).
Breastfeeding is a significant contributor to the development of the infant gut microbiota (224). As discussed earlier in this review, breast-fed babies typically have higher numbers of Bifidobacteria and lower numbers of Bacteroides and Atopobium when compared to infants that are exclusively formula-fed (83, 84), whether or not data such as this can be associated with the protection or promotion of atopic disease is still under debate (225–227). However, higher proportions of certain non-digestible HMOs have been associated with a decreased risk of respiratory disease in infants (228).
Antibiotic treatment during the first few years of life has an equally significant impact on the bacterial ecology of the infant gut (107, 109, 111). Epidemiological studies in humans indicate that broad-spectrum antibiotic exposure may play a role in the development of asthma and atopy.
Muc et al. conducted a questionnaire-based study and found that antibiotic exposure in the first year of life plays a significant role in the development of asthma and allergic rhinitis in children (229).
Additionally, Hoskin-Parr et al. assessed data from 4952 children enrolled in the Avon Longitudinal Study of Parents and Children and found a dose-dependent association between antibiotic usage during the first 2-years of life and the development of asthma at 7.5 years of age (230).
The development of atopic disease in children is characterized by an extremely complex network of environmental and genetic factors, but as the current research shows, the role of the gut microbiota cannot be ignored.