Background
Commensal microbiota play a critical role in maintaining oral tolerance. The effect of food allergy on the gut microbial ecology remains unknown.
Objective
We sought to establish the composition of the gut microbiota in experimental food allergy and its role in disease pathogenesis.
Methods
Food allergy–prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) and wild-type (WT) control animals were subjected to oral sensitization with chicken egg ovalbumin (OVA). Enforced tolerance was achieved by using allergen-specific regulatory T (Treg) cells. Community structure analysis of gut microbiota was performed by using a high-density 16S rDNA oligonucleotide microarrays (PhyloChip) and massively parallel pyrosequencing of 16S rDNA amplicons.
Results
OVA-sensitized Il4raF709 mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial families, including the Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Porphyromonadaceae. This signature was not shared by similarly sensitized WT mice, which did not exhibit an OVA-induced allergic response. Treatment of OVA-sensitized Il4raF709 mice with OVA-specific Treg cells led to a distinct tolerance-associated signature coincident with the suppression of the allergic response. The microbiota of allergen-sensitized Il4raF709 mice differentially promoted OVA-specific IgE responses and anaphylaxis when reconstituted in WT germ-free mice.
Conclusion
Mice with food allergy exhibit a specific gut microbiota signature capable of transmitting disease susceptibility and subject to reprogramming by enforced tolerance. Disease-associated microbiota may thus play a pathogenic role in food allergy.
Background
In atopic individuals, food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays critical roles in this response and genetic polymorphisms in its components have been linked to allergy.
Objective
To test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen.
Methods
F709 mice, in which the IL-4Rα immuno-tyrosine inhibitory motif (ITIM) motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses including antibody production and Th2 responses were assessed.
Results
F709 mice, but not wild-type (WT) controls, sensitized by gavage with OVA and either cholera toxin (CT) or Staphylococcal enterotoxin B (SEB), displayed mast cell activation and systemic anaphylaxis upon enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic Th2 responses and intestinal mast cell hyperplasia as compared with WT mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high affinity receptor for IgE (FcεRI).
Conclusion
Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE-dependent.
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