Regulation of oral immune tolerance by the microbiome in food allergy

Abstract

The steep rise in the incidence and prevalence of food allergy (FA) in the last few decades have focused attention of environmental mechanisms which act to promote disease, chief among which is the microbiome. Recent studies have now established the presence of pathogenic dysbiosis in FA that could be precipitated by a variety of environmental insults, including among others antibiotic usage and mode of delivery, that act to subvert the immune regulatory response that enforce tolerance to dietary antigens. A key attribute of this dysbiosis is the loss of Clostridial bacterial species that act to promote the formation of food allergen-specific nascent regulatory T cells in the gut. Significantly, different immunoprotective commensal bacteria, including members of the Clostridiales and Bacteroidales orders act to induce the transcription factor RORγt in nascent Treg cells via an upstream MyD88-dependent mechanism to promote tolerance to dietary antigens. Activation of this axis is disrupted by the dysbiosis, and can be restored by treatment with therapeutic microbiota. These findings highlight the potential for novel microbiota-based approaches to the prevention and treatment of the FA epidemic.

Figure 1.

(Left) Under homeostatic conditions, antigen presenting cells (classical CD103⁺ dendritic cells) promote the formation of nascent dietary antigen-specific iTreg cells. Further signals delivered by the commensal microbiota via MyD88 in nascent iTreg cells drives the expression of ROR-γt, which may regulate tolerance to dietary antigens by a range of mechanisms, including inhibition of antigen-specific helper T 2 (Th2) cell responses, suppression of pathogenic Th2 cell-like reprogramming of Treg cells and of mast cell activation, and the production of barrier-protective cytokines such as IL-22. (Right) Under conditions of FA, dysbiosis compromises the differentiation of naïve T cells into ROR-γt⁺ iTreg cells. Instead, there is expansion of iTreg cells with a Th2 cell-like phenotype characterized by increased GATA3 expression and IL-4 secretion. These pathogenic Treg cells are unable to suppress mast cell activation or Th2 cell expansion, leading to a dysregulated FA response with dietary allergen-specific IgE responses and a compromised barrier integrity.