Gut-innervating nociceptor neurons protect against enteric infection by modulating the microbiota and Peyer’s patch microfold cells

SUMMARY Gut-innervating nociceptor sensory neurons respond to noxious/tissue-damaging stimuli by initiating protective responses and releasing mediators that regulate tissue inflammation, gastrointestinal secretion, and motility. The role of nociceptors in host defense against enteric pathogens is unclear. Here, we found that gut-extrinsic nociceptor neurons are critical in protecting the host against Salmonella typhimurium (STm) infection. Nociceptors responded to STm by releasing the neuropeptide calcitonin gene-related peptide (CGRP). Targeted depletion of Nav1.8 and TRPV1 neurons from gut-extrinsic dorsal root ganglia and vagal ganglia increased STm colonization, invasion, and dissemination. Nociceptors regulated the gut microbiota at homeostasis, specifically segmented filamentous bacteria (SFB) levels in the ileum, which protected against STm by colonization resistance. Nociceptors also regulated the density of microfold epithelial cells in the Peyer’s patch via CGRP to limit points of entry for STm invasion into host tissues. Understanding how host sensory neurons crosstalk with pathogenic bacteria may impact treatments for enteric infections. HIGHLIGHTS Nav1.8 and TRPV1 nociceptors defend against Salmonella typhimurium (STm) infection Nociceptors shape the gut microbiota and SFB levels which resist pathogen colonization Nociceptors suppress Peyer’s patch microfold cell density to limit pathogen invasion Neurons sense STm and release CGRP to modulate microfold cells and host defense