Extended Data Fig. 10

Proposed model of colonic immune pathways during an allergic response under a fiber-rich (left) versus a fiber-free (right) diet. Allergic type-2 responses at the intestinal barrier are initiated by the sensing of the allergen and the release of epithelial-derived cytokines IL-25, IL-33 and TSLP that promote the recruitment and activation of type 2 immune cells Th2, M2 macrophages and ILC2, and lead to the production of IgE. Under a fiber-rich diet, Treg cells are maintained in response to microbiota-derived SCFAs, and Akkermansia muciniphila promotes Gata3⁺ Treg cells as well as Th2 cells. In this context, a conventional allergic response is driven by IgE-primed mast cell degranulation. By contrast, fiber deprivation leads to a non-canonical allergy response driven by the altered microbiota composition and the increased intestinal permeability, which altogether predisposes to a mixed inflammatory environment comprising of innate type 2 cells, M2 and ILC2, and type 1 cells, Th1, NK and CD8⁺ T cells. In this context, an allergic response is characterized by the production of IL-5 that is reinforced by CD8⁺ T cells and mediates eosinophilia. This chain of events is paralleled by higher coating of colonic bacteria by IgE, which has an unknown role in the pathology. The fiber deprivation-induced mucus changes and increased intestinal permeability are likely to facilitate the microbiota-driven type 1 responses, but further studies are needed to determine their contribution to the innate type 2 response that is promoted by A. muciniphila. Finally, the role of intestinal IgEs and their antigenic specificity in the eosinophilic reaction remain an important question to adress in the future. Created with BioRender.com.