Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine.

The small intestine (SI) absorbs nutrients and acts as a barrier against pathogens. Diet enables the absorptive function of the SI while maintaining immune homeostasis. But how the SI transmits nutritional signals to the immune response and adapts to dietary intake remains unclear. Here, we demonstrated that epithelial gasdermin D (GSDMD) in the SI facilitated the absorptive function of enterocytes, subsequently empowering an epithelial-immune cooperation to modulate host defense. Unlike its pyroptotic function, GSDMD determines the absorptive versus the defensive zonation of enterocytes and promotes brush border assembly. This diet-induced, GSDMD-mediated adaptation promoted lipid absorption and subsequently rewired enterocyte metabolism to support intraepithelial γδ T lymphocytes (γδ T-IELs), thereby enhancing barrier function. Impairment of this GSDMD-mediated circuit exacerbated barrier-dysfunction-associated enteritis. Our results reveal how epithelial cells and lymphocytes co-adapt to nutrient signals in the SI, thereby adjusting the equilibrium between nutrient uptake and host defense in response to environmental change.