Nociceptors protect the body by detecting noxious stimuli and initiating protective reflexes and behaviours. Gut nociceptors detect gastrointestinal disturbances and drive responses including vomiting, diarrhoea and visceral pain. Chiu and colleagues now show that, in mice, these nociceptors can also regulate mucosal host defence mechanisms.

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Salmonella enterica serovar Typhimurium (STm), a major cause of gastroenteritis in humans, invades the body via lymphoid nodules in the ileum known as Peyer’s patches (PPs), which also receive sensory innervation. To investigate whether gut nociceptors assist in the defence against STm, the authors used genetic and pharmacological tools to ablate these neurons in mice. Following oral infection with STm, nociceptor-ablated mice exhibited greater PP invasion and systemic STm dissemination than control mice, suggesting an important role for these neurons in host defence against STm.

Commensal bacteria are a vital contributor to host defence. Nociceptor ablation altered ileum commensal bacterial diversity and, in particular, reduced the levels of the segmented filamentous bacteria (SFB) that attach to the epithelium of PP. In mice lacking SFB, nociceptor ablation did not alter STm infection, whereas SFB introduction (via gavage) to SFB-lacking or nociceptor-ablated mice provided protection against STm.

Nociceptor ablation also increased the abundance of PP microfold (M) cells, the main cellular entry point for STm. M cell depletion in these mice restored protection against STm to levels present in wild-type mice and M cell depletion also reduced PP SFB levels. Thus, by regulating M cells, nociceptors may both limit STm entry and boost host resistance to the bacteria. The authors’ findings further indicate that both of these effects might be mediated by the neuropeptide CGRP (calcitonin gene-related peptide): STm induced release of CGRP from nociceptors in culture and in vivo, and mice lacking CGRP exhibit increased M cell density and reduced levels of SFB.

by regulating M cells, nociceptors may both limit STm entry and boost host resistance to the bacteria

These findings indicate an important role for gut-innervating nociceptors in host defence against an invading enteric pathogen. By dissecting some of the cellular mechanisms involved, this study may also contribute to the identification of new targets for therapeutic intervention.