Microbial regulation of allergic responses to food

Abstract

The incidence of food allergy in developed countries is rising at a rate that cannot be attributed to genetic variation alone. In this review, we discuss the environmental factors that may contribute to the increasing prevalence of potentially fatal anaphylactic responses to food. Decreased exposure to enteric infections due to advances in vaccination and sanitation, along with the adoption of high-fat (Western) diets, antibiotic use, Cesarean birth, and formula feeding of infants, have all been implicated in altering the enteric microbiome away from its ancestral state. This collection of resident commensal microbes performs many important physiological functions and plays a central role in the development of the immune system. We hypothesize that alterations in the microbiome interfere with immune system maturation, resulting in impairment of IgA production, reduced abundance of regulatory T cells, and Th2-skewing of baseline immune responses which drive aberrant responses to innocuous (food) antigens.

Figure 1. Why is the prevalence of food allergy increasing?

Gene-by-environment interactions are likely to be at the heart of the increasing prevalence of allergic disease in Western countries. Environmental factors that may influence allergic susceptibility include antibiotic use, high-fat diet, elimination of enteric pathogens, reduced exposure to infection, and Caesarean birth and formula feeding. All of these stimuli can alter the commensal microbiome of the host and lead to dysbiosis, which, in a genetically susceptible individual may drive the development of atopic disease.

Figure 2. Both allergen-specific and bacterially induced Tregs are required to prevent allergic responses to food

In a healthy individual, dietary antigen is carried to the MLN by migratory CD103⁺ DC and presented to naïve T cells to induce antigen specific Foxp3⁺Tregs. Secretion of retinoic acid (RA) and TGF-β by these CD103⁺DC upregulates the expression of the homing molecules α4β7 and CCR9 which allows these antigen specific Foxp3⁺ Tregs to migrate back to the small intestinal LP and expand for the induction of oral tolerance. New work from our laboratory shows that tolerance to dietary antigen also relies on bacteria-induced Tregs and IgA. Microbiota-induced Tregs and IgA are reduced in the intestines of Tlr4^−/− and antibiotic treated mice (and absent in germ free mice). Impairment of this mucosal Treg/IgA compartment correlates with the enhanced production of food allergen specific IgE and IgG1 in response to sensitization. Reintroduction of a conventional microbiota to antibiotic-treated mice restores the Treg and IgA compartments and blocks the allergic response. Colonization of germ free mice with a microbiota containing Clostridium species induces both Foxp3⁺ Tregs and intestinal IgA and attenuates allergic sensitization.