Abstract
Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis1,2. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule beta (RELM beta)3,4 is a critical regulator of oral tolerance. RELM beta is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELM beta protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELM beta disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes. Tolerance is maintained by the local production of indole derivatives driving FA protective ROR gamma t+ regulatory T (Treg) cells5 through activation of the aryl hydrocarbon receptor. RELM beta antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELM beta mediates a gut immune-epithelial circuit regulating tolerance to food antigens-a novel mode of innate control of adaptive immunity through microbiome editing-and identify targetable candidates in this circuit for prevention and treatment of FA.