Food allergy and the microbiome: Current understandings and future directions

Abstract

Growing evidence points to an important role for the commensal microbiota in susceptibility to food allergy. Epidemiologic studies demonstrate associations between exposures known to modify the microbiome and risk of food allergy. Direct profiling of the gut microbiome in human cohort studies has demonstrated that individuals with food allergy have distinct gut microbiomes compared to healthy control subjects, and dysbiosis precedes the development of food allergy. Mechanistic studies in mouse models of food allergy have confirmed that the composition of the intestinal microbiota can imprint susceptibility or resistance to food allergy on the host and have identified a unique population of microbially responsive RORγt-positive FOXp3-positive regulatory T cells as critical for the maintenance of tolerance to foods. Armed with this new understanding of the role of the microbiota in food allergy and tolerance, therapeutics aimed at modifying the gastrointestinal microbiota are in development. In this article we review key milestones in the development of our current understanding of how the gastrointestinal microbiota contributes to food allergy and discuss our vision for the future of the field.

Keywords: Food allergy; dysbiosis; microbiome; microbiota; prebiotic; probiotic; regulatory T cells; short-chain fatty acids; symbiotic.

Figure 1:. Pathways to development of microbial therapeutics for food allergy.

Evidence for an important contribution of the gut microbiota to the pathogenesis of food allergy is derived from observational studies of distinct microbial composition in allergic and healthy human cohorts, and in mice with susceptibility versus resistance to food allergy. Evidence that changes in microbial composition lead to meaningful changes in host immunity come from studies utilizing fecal microbiota transplants (FMT) into germfree mice with susceptibility to food allergy. Additional functional evidence can be derived from in vitro culture systems examining the impact of stool extracts on immune phenotype. Based on the weight of this pre-clinical evidence, clinical trials utilizing defined microbial transfer, probiotics, prebiotics, synbiotics, and FMT are in process to determine efficacy of microbial therapeutics for the treatment of food allergy.

Figure 2:. Contribution of the microbiota to immune mechanisms of tolerance and allergy to foods.

Healthy microbiota, or consortia composed of Clostridiales strains, Bacteroidales strains, or individual microorganisms including S. variabile or A. caccae, protect susceptible germ-free mice from food allergy. Mechanisms of protection include the generation of RORγt+ Foxp3+ Tregs by MyD88 signaling in Tregs, which enhances anti-microbial and anti-food allergen specific IgA production while suppressing IgE production, and suppresses generation of GATA3+ “Th2 reprogrammed” Tregs. Short chain fatty acids (SCFA) derived from the healthy microbiota drive a change in the mucosal DC phenotype to a more tolerogenic phenotype. RORgt+ Tregs suppress DCs via elevated CTLA4 expression to suppress costimulatory-driven priming. In food allergy, production of IL-4 from innate lymphoid cells type 2 (ILC2) and IgE-activated mast cells cooperates with DCs to promote the generation of Th2 reprogrammed Tregs that express GATA-3, produce IL-4, and contribute to rather than protect from food allergy. Epithelial-derived cytokines contribute to the immune milieu that drives this deviation of the normal regulatory response.