Nociceptor neuron regulation of gastrointestinal barrier protection and host defense

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PROJECT SUMMARY Nociceptor neurons are peripheral sensory neurons that densely innervate the gastrointestinal tract, detecting noxious/harmful stimuli to mediate protective neural reflexes including pain. However, the role of nociceptor neurons or their molecular mediators in regulating gut physiology, barrier protection, and host defense is not well understood. Here we hypothesize that specific gut-innervating nociceptors signal to epithelial cells to modulate gut barrier defenses at homeostasis and during bacterial invasion. Our preliminary data show that nociceptor neurons and the nociceptor neuropeptide calcitonin gene-related peptide (CGRP) signal to intestinal goblet cells and microfold (M) cells, two types of gut epithelial cells that mediate barrier protection and host defenses. Recent molecular phenotyping of DRG neurons show that multiple types of nociceptors innervate the gut. In this project, we will utilize targeted genetic and molecular approaches to: 1) Determine whether Nav1.8+ nociceptor neurons or their specific subsets (CGRP+, MRGPRD+) are necessary for maintenance of gut epithelial cell function during homeostasis, and barrier protection against the enteric pathogens Salmonella Typhimurium or Citrobacter rodentium; 2) Determine whether chemogenetic (DREADD) or dietary ligand activation of nociceptor neurons is sufficient to induce changes in gut epithelial cells and barrier function; 3) Define the role of the nociceptor neuropeptide CGRP-RAMP1 axis in regulating barrier epithelial (goblet cells, M cells) and immune cells in modulating barrier host defenses. We aim to use innovative and interdisciplinary approaches from neurobiology, gastroenterology, and immunology to interrogate the role of nociceptor neurons in gut barrier function and enteric host defense. The team includes experts in nociceptor neurons and neuroimmunology (Chiu lab), and gut microbial and immune responses (Huh lab). A role for the nervous system in regulating gastrointestinal barrier defenses could lead to novel approaches to treat autoimmune and inflammatory diseases. A greater understanding of how neurons signal to epithelial cells and immune cells the gastrointestinal tract could lead to novel insights in tissue barrier homeostasis. Our findings could also have relevance to disease conditions where gut barrier dysfunction occur such as autoimmune or inflammatory diseases. Targeting neurons or CGRP signaling could therefore lead to novel approaches to enhance barrier integrity to treat gastrointestinal diseases.