Regional encoding of enteric nervous system responses to microbiota and type 2 inflammation

Enteric neurons are essential regulators of intestinal physiology, yet their responses to varying microbial and immune environments along the intestinal tract and or during challenges remain poorly understood. In this study, we regionally profiled enteric neurons across gnotobiotic, allergic, and parasite-infected mice. Timing and complexity of microbial perturbations and type 2 inflammation result in motor neuron state shifts and alter multiple functionally distinct sensory neurons, including interleukin-13- and leukotriene-responsive Nmu-hi cells and Grp-hi neurons, which expand in germ-free colonic tissue and interact with Grpr⁺ interstitial cells of Cajal. Leveraging adeno-associated virus-based Perturb-seq, we identified Edf1 and Mitf as controllers of motor neuron state transition and gastrointestinal transit time, directly linking enteric neuron states to physiology.