RELMβ sets the threshold for microbiome-dependent oral tolerance

Emmanuel Stephen-Victor, Gavin A. Kuziel, Monica Martinez-Blanco, Bat-Erdene Jugder, Mehdi Benamar, Ziwei Wang, Qian Chen, Gabriel L. Lozano, Azza Abdel-Gadir, Ye Cui, Jason Fong, Elisa Saint-Denis, Iris Chang, Kari C. Nadeau, Wanda Phipatanakul, Angela Zhang, Farida Abi Farraj, Faye Holder-Niles, Daniel Zeve, David T. Breault, Klaus Schmitz-Abe, Rima Rachid, Elena Crestani, Seth Rakoff-Nahoum () and Talal A. Chatila ()
Additional contact information
Emmanuel Stephen-Victor: Boston Children’s Hospital
Gavin A. Kuziel: Boston Children’s Hospital
Monica Martinez-Blanco: Boston Children’s Hospital
Bat-Erdene Jugder: Boston Children’s Hospital
Mehdi Benamar: Boston Children’s Hospital
Ziwei Wang: Boston Children’s Hospital
Qian Chen: Boston Children’s Hospital
Gabriel L. Lozano: Boston Children’s Hospital
Azza Abdel-Gadir: Boston Children’s Hospital
Ye Cui: Boston Children’s Hospital
Jason Fong: Boston Children’s Hospital
Elisa Saint-Denis: Boston Children’s Hospital
Iris Chang: School of Medicine
Kari C. Nadeau: Harvard T.H. Chan School of Public Health
Wanda Phipatanakul: Boston Children’s Hospital
Angela Zhang: Boston Children’s Hospital
Farida Abi Farraj: Boston Children’s Hospital
Faye Holder-Niles: Boston Children’s Hospital
Daniel Zeve: Boston Children’s Hospital
David T. Breault: Boston Children’s Hospital
Klaus Schmitz-Abe: Boston Children’s Hospital
Rima Rachid: Boston Children’s Hospital
Elena Crestani: Boston Children’s Hospital
Seth Rakoff-Nahoum: Boston Children’s Hospital
Talal A. Chatila: Boston Children’s Hospital

Nature, 2025, vol. 638, issue 8051, 760-768

Abstract: 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 β (RELMβ)3,4 is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELMβ 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 RORγt+ regulatory T (Treg) cells5 through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ 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.

Date: 2025
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DOI: 10.1038/s41586-024-08440-7

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