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

How pain sensors make the gut weep

“…They further underscored the crucial importance of the gut microbiome-nociceptorgoblet cell crosstalk by showing that fecal transplantation from specific pathogen-free (SPF) mice into GF mice restored the colonic mucus thickness, a finding that was lost in nociceptor-deficient GF mice. 2 These findings indicate that the microbiome triggers mucus secretion, a process mediated by Nav1.8 + nociceptors (Fig. 1).…”

“…In a recent issue of Cell, Yang et al elegantly revealed that microbial-mediated activation of Nav1.8 + nociceptors innervating the gut promoted MUC2 mucin secretion by goblet cells via a CGRP-Ramp1 axis during homeostasis and in the context of colitis. 2 Initial evidence indicating a role for host goblet cell-microbiota communication in the maintenance of the mucus layer came from studies in germ-free (GF) mice. Whereas the colonic inner mucus layer of conventionally-raised mice was impenetrable to microorganisms, that of GF mice was more permeable and thinner.…”

“…7 Yang et al now discovered a previously unrecognized crosstalk between the gut microbiome, nociceptors and goblet cells. 2 Chemogenetic stimulation of Nav1.8 + nociceptors increased colonic mucus thickness, while genetic ablation of Nav1.8 + nociceptors reduced mucus growth. Single-cell RNA sequencing revealed that goblet cells highly expressed RAMP1, the co-receptor of CGRP.…”

“…In a next step, Yang et al further attempted to unravel the interaction between the microbiome and nociceptors. 2 The authors observed that fecal supernatant from SPF mice induced more calcium influx into the dorsal root ganglion (DRG) cultures and caused more CGRP release than that from GF mice. Moreover, chemical TRPV1 denervation decreased CGRP release and mucus thickness in conventionalized GF mice.…”

“…Although of great interest, it remains to be further elucidated how commensal-derived products promote the activation of gut Nav1.8 + and TRPV1 + nociceptors. 2 One potential mechanism could be via the production of short chain fatty acids or other mediators produced by the microbiome during the fermentation of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs). Indeed, feeding of FODMAPs provoked mucus discharge, which was associated with an increased number of mast cells.…”