GFRAL neurons remodel intestinal structure and type 2 immunity

The brain has emerged as a key regulator of immune functions, but the underlying neural mechanisms remain poorly understood. Here we show that brainstem GFRAL-expressing neurons prime type 2 immunity and shape intestinal epithelial structure in mice. Type 2 inflammation results in activation of GFRAL neurons and potentiation of their excitatory synaptic inputs. Enhancing GFRAL neuron excitability is sufficient to remodel intestinal type 2 immunity through a polysynaptic vagal brain-gut circuit, expanding tuft and goblet cell populations and increasing intestinal type 2 cytokine expression; while inhibiting GFRAL neurons leads to largely opposite changes. Accordingly, manipulating GFRAL neuron function reshapes intestinal structure and pathophysiology in food allergy, helminth infection and colitis models. Thus, GFRAL neurons orchestrate type 2 immune responses to facilitate recovery from intestinal diseases.