Nerves of Steel: How the Gut Nervous System Promotes a Strong Barrier

Abstract

In this issue of Cell, Jarret et al., Lai et al., and Matheis et al. demonstrate the extensive interplay between the nervous system and immune and epithelial cells of the gut to orchestrate host defense in homeostasis and following Salmonella infection.

Figure 1.. A Competent Barrier in the Gut Is Maintained by Strong Neuro-Immune Interactions

(A) In the ileum of the small intestine, Lai et al. found that CGRPα is constitutively produced by TRPV1+ nociceptors to control microfold (M) cell numbers by limiting their proliferation (Lai et al., 2019). This promotes colonization of segmented filamentous bacteria in Peyer’s patches and villi and limits points of entry for Salmonella. Infection by Salmonella heightens CGRPα secretion by nociceptors, reducing M cell numbers to prevent systemic infection. (B) Matheis et al. discovered that intrinsic enteric-associated neurons undergo Nlrp6/Casp11-mediated cell death upon Salmonella infection (Matheis et al., 2019). Upon infection, local stress-induced catecholamines promote a neuroprotective program in muscularis macrophages, causing polyamine release to restrain further neural loss to subsequent infection. (C) At homeostasis, Jarret et al. identified that enteric nerves of the colon constitutively produce IL-18 to stimulate antimicrobial peptide secretion by goblet cells (Jarret et al., 2019). Sufficient antimicrobial peptide levels promote a sterile mucus layer, preventing colonization by Salmonella.