Targeted Activation of Enteric Neurons Shapes the Gut Environment of Mice

The enteric nervous system (ENS) integrates cues from the brain and from local signals in the gut to coordinate responses that shape the intestinal milieu. Tools to study, and knowledge of, the ENS lag behind brain research. Herein, we deploy novel adeno-associated viral (rAAV) vectors with tropism for the gut to specifically map and activate enteric neurons in the small intestine and colon of mice, revealing unprecedented  insights into the architecture of the ENS. Targeted activation of ChAT+ or TH+ neuronal populations in the ENS altered the intestinal transcriptome, proteome, metagenome, and fecal metabolome. We reveal previously unknown roles for enteric neurons in modulating intestinal physiology, mucosal immunity, and gut microbiome structure, and propose novel interactions for the ENS such as controlling fungal colonization and shaping of bile acid profiles. Experimental tools and rich datasets with multi-parameter characterization of the gut ecosystem may enable further study of the ENS.