Reflection of Atopic Genotype

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Incomplete knowledge of the genetic characteristics of allergic diseases restricts the full understanding of their possible influence on the development of gut microbiota (58). Theoretically, microbial colonization could be directly affected for example if the atopic genotype was associated with receptor expression on epithelial cells or production of intestinal mucus. There is some indication that the atopic genotype is associated with

Table 1 Possible Causes for Microbial Compositional Differences in Atopic versus Healthy Children

Atopic genotype related defects in the host's ability to interact with bacteria The role of microbial stimulus in the normal maturation of the immune system away from allergic type responsiveness

The influence of allergic symptoms and consequent inflammation on microbial colonization The effects microbes have on allergen processing and uptake, for example, by inducing gut inflammation

Environmental factors that affect the expression of atopy in parallel with the microbiota or via the microbiota

Figure 2 Mechanisms by which specific components of intestinal microbiota may protect from allergic sensitization and/or alleviate symptoms. "Adequate" microbial composition may reduce allergen uptake by providing maturational stimulus for gut barrier function, enhancing allergen degradation by production of digestive enzymes (this may also reduce allergen allergenicity), improving mucosal integrity by direct exclusion of pathogens that may cause epithelial damage or by enhancing secretory IgA (sIgA) production (possibly via inducing TGF-b secretion) and by inducing secretion of anti-inflammatory cytokines, which may break a vicious circle where inflammation increases gut permeability allowing invasion of pathogens and allergens, which then results in further inflammation. Danger signals caused by epithelial damage and inflammation promote the maturation of dendritic cells, which influence the differentiation of naive Th cells. Presentation of allergen in absence of danger signals may promote formation of regulatory T cells (Treg) and thus formation of tolerance to the allergen. The fate of Th cells in the presence of danger signals depends on additional stimulus: presence of TGF-b (produced, e.g., by epithelial cells) may promote development of Treg population and again tolerance to the allergen, presence of IL-12 andIFN-g (produced, e.g., by macrophages or dendritic cells) promotes development of Th1 population and non-allergic type immune responses, whereas presence of IL-10 may promote formation of allergen specific Th2 cells. In the symptomatic phase induction of antiinflammatory cytokines may also directly alleviate the allergic inflammation by active suppression. Abbreviations: sIgA, secretory IgA; M, M-cell; iDC, immature dendritic cell; mDC, mature dendritic cell; IL, interleukin; TGF, transforming growth factor; Th, T-helper; Treg, regulatory T-cell; MF, macrophage.

immunological deviancies that could result in impaired recognition of specific bacterial groups and thus allow them to flourish. These defects include compromised expression of Toll-like receptor (TLR) 4 and its soluble co-receptor CD14 (sCD14), albeit the results regarding sCD14 are conflicting (59-64). However, also low breast-milk levels of sCD14 have been associated with subsequent development of eczema in children irrespective of atopy (65). TLR4 and sCD14 are pattern recognition receptors of innate immune systems that are important in detection of components in both Gram-positive and Gram-negative bacteria but especially the cell-wall lipopolysaccharides (LPS) in the latter (66,67). Notably, CD14-independent recognition of LPS would seem to be defective during the neonatal period (68). Compromised recognition may facilitate colonization by bacteria which would otherwise be cleared or reduced in numbers due to immune responses mounted against them. This could partly explain why relatively a high prevalence and numbers of potentially pathogenic Gram-negative bacteria but low numbers of Gram-positive bacteria appear to accompany atopic eczema and high levels of IgE (18,39,42-45,50).

From another perspective, microbial compositional differences may reflect their influence on allergic sensitization and disease development. If the recognition of gut colonizers is compromised, then so may be the interactions that drive the normal immunological maturation (10,32,60,69,70). Recognition of peptidoglycan, a major component of Gram-positive cell-wall, is less dependent on CD14 and TLR4 but rather on co-operation between TLRs 2 and 6 (71-73). Thereby, an atopic host, with deficient TLR4 and CD14 recognition, may have better chances to interact with Gram-positive than Gramnegative bacteria. This interaction may, on one hand, limit the ability of Gram-positive bacteria to colonize the gut, but on the other, provide maturational stimulus for the developing immune system (44,69).

Whereas the recognition of one specific bacterial component occurs primarily via one or two different pattern recognition receptors, the recognition of whole bacterium is likely to involve a set of different receptors such as TLR9 recognizing unmethylated bacterial CpG DNA and TLR5 recognizing flagella (74). Accordingly, a quantitatively strong enough exposure may compensate the poor recognition of Gram-negative bacteria, especially due to ligation of TLR9. This would be in agreement with the observation that postnatal administration of exogenous Gram-negative bacteria, namely non-enteropathogenic E. coli strain, was associated with reduced risk of developing allergic diseases later in life (14,15).

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