Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection

• Published in: Cell Vol. 185; no. 22; pp. 4190 - 4205.e25
• Main Authors: Yang, Daping, Jacobson, Amanda, Meerschaert, Kimberly A., Sifakis, Joseph Joy, Wu, Meng, Chen, Xi, Yang, Tiandi, Zhou, Youlian, Anekal, Praju Vikas, Rucker, Rachel A., Sharma, Deepika, Sontheimer-Phelps, Alexandra, Wu, Glendon S., Deng, Liwen, Anderson, Michael D., Choi, Samantha, Neel, Dylan, Lee, Nicole, Kasper, Dennis L., Jabri, Bana, Huh, Jun R., Johansson, Malin, Thiagarajah, Jay R., Riesenfeld, Samantha J., Chiu, Isaac M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-10-2022
• Subjects: Animals; bacteria; Biochemistry & Molecular Biology; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; calcitonin; Calcitonin Gene-Related Peptide - metabolism; Cell Biology; CGRP; cgrp receptor; colitis; Colitis - metabolism; enteric nervous-system; gene-related peptide; goblet cell; Goblet Cells - metabolism; gut barrier; gut-brain axis; Humans; immune; induced colitis; interactions; Mice; mucus; Mucus - metabolism; neuroepithelial crosstalk; nociceptor; Nociceptors - metabolism; pain; Ramp1; Receptor Activity-Modifying Protein 1 - metabolism; secretion; sensory neuron; sensory neurons; nociceptor; sensory neuron; colitis; goblet cell; gut barrier; CGRP; neuroepithelial crosstalk; Ramp1; mucus; gut-brain axis
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2022.09.024

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
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•Nav1.8+CGRP+ nociceptors neighbor goblet cells and induce rapid mucus secretion•Commensals trigger CGRP release, which signals to Ramp1 expressed by goblet cells•Nociceptor or Ramp1 ablation leads to decreased mucus levels and microbial dysbiosis•Neuron-goblet cell signaling via a CGRP-Ramp1 axis protects against colitis
Pain sensory neurons induce mucus release from nearby intestinal goblet cells via a CGRP-Ramp1 axis in response to commensal and dietary cues to orchestrate gut mucosal protection.