Nociceptor neuron-goblet cell crosstalk via CGRP-RAMP1 axis protects the gut barrier

Neuronal crosstalk with gut epithelial cells is fundamental for sensory function. However, the mechanisms by which neurons communicate with gut epithelial cells are not well understood. Here, we show that pain-mediating nociceptors signal to intestinal goblet cells to drive mucus secretion and gut barrier protection. Nociceptive nerves juxtapose goblet cells, and their loss leads to reduced mucus levels, altered goblet cell transcription, and microbial dysbiosis. Chemogenetic activation of nociceptors induces rapid goblet cell emptying and mucus secretion. Mouse and human goblet cells express Ramp1, a receptor for the neuropeptide calcitonin gene-related peptide (CGRP). Nociceptors respond to commensal microbes and capsaicin to release CGRP. CGRP and epithelial RAMP1 signaling are necessary for colonic mucus maintenance. Mice lacking nociceptors or epithelial Ramp1 signaling demonstrate increased susceptibility to colitis. By contrast, nociceptor activation or CGRP administration protected against colitis. Our findings demonstrate a nociceptor neuron-goblet cell axis orchestrating gut mucosal barrier protection.