Dietary and Microbial Determinants in Food Allergy

Abstract

The steep rise in food allergy (FA) has evoked environmental factors involved in disease pathogenesis, including the gut microbiota, diet, and their metabolites. Early introduction of solid foods synchronizes with the "weaning reaction," a time during which the microbiota imprints durable oral tolerance. Recent work has shown that children with FA manifest an early onset dysbiosis with the loss of Clostridiales species, which promotes the differentiation of ROR-γt⁺ regulatory T cells to suppress FA. This process can be reversed in pre-clinical mouse models by targeted bacteriotherapy. Here, we review the dominant tolerance mechanisms enforced by the microbiota to suppress FA and discuss therapeutic intervention strategies that act to recapitulate the early life window of opportunity in stemming the FA epidemic.

Keywords: Bacteroidales; Clostridiales; FOXP3; MyD88; RORC; RORγt; Subdoligranulum variable; fecal microbiota transplantation; oral immunotherapy; regulatory T cells; weaning reaction.

Figure 1.. Oral immune tolerance is shaped by early life dietary and microbial determinants.

In the immediate postnatal period, the infant gut microbiota is organized under the influence of Immunoglobulin A and other immunological components present in the mother’s milk. Maternal EGFR-L restrains the expansion of the infant’s gut microbiota and inhibits Goblet-Cell-Associated-Passages (GAPs). The physiological drop in EGFR-L around the time of weaning (transition to a solid food diet) activates a critically timed window during which the gut microbiota expands and changes composition with the blooming Clostridales species. The concurrent opening of GAPs in the small intestine and colon facilitates the entry of luminal antigens to induce the formation of ROR-γt⁺ Treg cells that are imprinted to both bacteria and foods. This imprinting persists into adulthood, while its disruption due to dysbiosis or other insults may result in increased susceptibility to FA. Recapitulation of the weaning reaction by means of microbial therapy can induce the ROR-γt⁺ Treg cells and curtail the development of gut pathologies.

Figure 2.. Microbial metabolites regulates gut immune tolerance and barrier integrity.

Diet and host-derived metabolites generated by bacterial processing regulate mucosal immune tolerance and promote epithelial barrier integrity. SCFAs, derived by gut microbial fermentation of complex carbohydrates, induce the differentiation of gut Treg cells and augment their production of IL10. SCFAs also enforce epithelial barrier integrity by inducing mucus secretion from goblet cells and IL-22 production by ILC3, the latter by a FFAR2-dependent mechanism. Catabolism of dietary proteins results in the release of tryptophan and its catabolism into metabolites such as indole, indole propionic acid (IPA) and indolealdehyde (IAld). These metabolites decrease intestinal permeability by augmenting the epithelial cell tight and adherens junctions by signalling through the pregnane X receptor (PXR). Additionally, indole derivates activate the aryl hydrocarbon receptor (AHR) in immune cells to induce the barrier protecting cytokine IL22. Primary bile acids produced in the liver are further modified by the gut microbiota to secondary bile acids, which act to induce the differentiation of ROR-γt Treg cell by signalling through the vitamin-D receptor to promote mucosal immune tolerance.

Figure 3.. Microbial regulation of oral immune tolerance to food and its breakdown in FA

(Left) Under homeostatic conditions antigen presenting cells (classical CD103⁺ dendritic cells) sample the gut lumen and promote the formation of nascent dietary antigen-specific iTreg cells. Commensals, including Clostridiales and Bacteroidales species, deliver further signals via MyD88 in nascent iTreg cells to drive the expression of ROR-γt. Additionally differentiation signals include secondary bile acid metabolites, which promote the differentiation of ROR-γt by activating vitamin-D receptor in iTreg cells. ROR-γt⁺ Treg cells may regulate tolerance to dietary antigens by inhibiting antigen-specific helper Th 2 (Th2) cell responses, impeding the formation of pathogenic Th2 cell-like reprogramming of Treg cells, suppression of mast cells cell and innate lymphoid cell (ILC)-2 activation. SCFAs produced by the degradation of complex carbohydrates activates ILC3-dependent secretion of IL22 to promote barrier functions. (Right) The underlying dysbiosis in FA compromises barrier integrity and impairs the differentiation of ROR-γt⁺ iTreg cells, while augmenting the expansion of Treg cells with a Th2 cell-like phenotype that express GATA3 and IL-4. These pathogenic Treg cells license the gut tissue immune response by Th2 cells, Mast cells, and ILC2 to promote disease pathogenesis.

Figure 4:. Current and projected treatment modalities for FA.

Introduction of common food allergens early in life leads to the development of tolerance possibly by coinciding with the weaning reaction and imprinting durable allergen-specific iTregs cells. In FA subjects who fail to imprint early life tolerance, treatment with either OIT or EPIT results in a state of desensitization that may evolve in some patients into sustained unresponsiveness or oral tolerance to the suspect food. Immunotherapy may act by several mechanisms including the induction of allergen-specific iTregs cells and the inhibition of mast cells and basophils by concomitantly augmenting allergen-specific blocking IgG4 antibodies while suppressing allergen-specific IgE responses. Immunotherapy may also promote the deletion of Th2 cells, and the reversal of pathogenic Th2 cell-like reprogramming of Treg cells. Because immunotherapy fails to induce sustained oral tolerance in many patients, alternate therapies targeting the gut microbiota and their metabolites are currently being explored, including FMT, rationally designed bacterial consortia and precision-based individual bacterial strains and microbiota-derived metabolites. These therapies have the potential to recapitulate early life imprinting by inducing ROR-γt⁺ Treg cells and, in the case of microbial therapies, to reset the underlying dysbiosis.