Microbial Dysbiosis Tunes the Immune Response Towards Allergic Disease Outcomes

Abstract

The hygiene hypothesis has been popularized as an explanation for the rapid increase in allergic disease observed over the past 50 years. Subsequent epidemiological studies have described the protective effects that in utero and early life exposures to an environment high in microbial diversity have in conferring protective benefits against the development of allergic diseases. The rapid advancement in next generation sequencing technology has allowed for analysis of the diverse nature of microbial communities present in the barrier organs and a determination of their role in the induction of allergic disease. Here, we discuss the recent literature describing how colonization of barrier organs during early life by the microbiota influences the development of the adaptive immune system. In parallel, mechanistic studies have delivered insight into the pathogenesis of disease, by demonstrating the comparative effects of protective T regulatory (Treg) cells, with inflammatory T helper 2 (Th2) cells in the development of immune tolerance or induction of an allergic response. More recently, a significant advancement in our understanding into how interactions between the adaptive immune system and microbially derived factors play a central role in the development of allergic disease has emerged. Providing a deeper understanding of the symbiotic relationship between our microbiome and immune system, which explains key observations made by the hygiene hypothesis. By studying how perturbations that drive dysbiosis of the microbiome can cause allergic disease, we stand to benefit by delineating the protective versus pathogenic aspects of human interactions with our microbial companions, allowing us to better harness the use of microbial agents in the design of novel prophylactic and therapeutic strategies.

Keywords: Adaptive immunity; Allergy; Atopy; CD4 +; Hygiene; Microbiome.

Fig. 1

Influences of environmental and microbial interactions on adaptive immune responses and allergic disease. A wide array of factors including, genetic, environmental, and dietary inputs can all potentially modulate the gut immune-microbiome axis and influence the occurrence of allergy. The microbiome in turn modulates the cohort of regulatory cells induced during development and allows for the establishment of a tolerogenic environment, which mediates the suppression of T cells that arise from inflammatory lineages. However, a dysbiosis of the microbiome leads to impairment of this tolerogenic environment leading to development of allergic diseases along with greater expansion in cells of the Th2 inflammatory lineage

Fig. 2

Microbial Product Signaling Influences T Cell Immune Responses in Homeostasis and Dysbiosis. A A diverse microbiome promotes homeostatic maintenance and the induction of immune tolerance. Crosstalk between the microbiome and the immune system is mediated by microbial products that promote the differentiation of pTreg and the upregulation of RORγt in response to stimulation with food derived antigens. B Microbial dysbiosis results in the production of microbial products that promote inflammatory responses and modulate Th2 differentiation in response to the presentation of Ag’s and stimulate ILC2 recruitment, resulting in type 2 inflammation in affected tissue following the recruitment of innate cell mediators of disease including mast cells and eosinophils

Fig. 3

Cellular Basis for Hygiene Hypothesis and Old Friends/Biodiversity models. A The original hygiene hypothesis focused on an absence of a sufficient viral/bacterial pathogenic burden to educate the immune system in childhood, allowing for the induction of an aberrant Th2 response. Mechanistically this was seen due an imbalance in the reciprocal regulatory relationship that exists between Th1 and Th2 responses mediated by IL-4 and IFN-ɣ. B Old friends/biodiversity hypotheses’ additionally factors in the presence of regulatory mechanisms that are essential for control of both autoimmunity and allergic responses and are associated with the presence of a diverse microbiome. Here, the lack of sufficient regulatory responses accounts for the parallel rise in both autoimmune disease (Th1) and allergy (Th2) seen in recent history