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

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 demon-strate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
gene-related peptide
enteric nervous-system
sensory neurons
immune
interactions
induced colitis
cgrp receptor
calcitonin
secretion
bacteria
pain
Biochemistry & Molecular Biology
Cell Biology

Jacobson, A. (author)
Meerschaert, K. A. (author)
Sifakis, J. J. (author)
Wu, M. (author)
Chen, X. (author)
Yang, T. D. (author)
Zhou, Y. L. (author)
Anekal, P. V. (author)
Rucker, R. A. (author)
Sharma, D. (author)
Sontheimer-Phelps, A. (author)
Wu, G. S. (author)
Deng, L. W. (author)
Anderson, M. D. (author)
Choi, S. (author)
Neel, D. (author)
Lee, N. C. L. (author)
Kasper, D. L. (author)
Jabri, B. (author)
Huh, J. R. (author)
Johansson, Malin E V,1971Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology(Swepub:gu)xjomal (author)
Thiagarajah, J. R. (author)
Riesenfeld, S. J. (author)
Chiu, I. M. (author)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi (creator_code:org_t)

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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