Role of nerves in enteric infection. (Leading Article).

Peripheral and central effects of enteric infection are considered. Nerves play a vital part in the immediate response to enteric infection, promoting pathogen expulsion by orchestrating intestinal secretion and propulsive motor patterns. Laboratory studies indicate that therapeutic agents aimed at modulating the neural response can profoundly alter the outcome of infection. As our understanding of the role of nerves increases, exciting new targets for therapeutic intervention will emerge in both acute and chronic disorders induced by enteric infection.

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Anyone who has experienced the severe abdominal cramps, vomiting, and violent diarrhoea associated with infective gastroenteritis will be in no doubt that the nerves in the gut are profoundly affected by enteric infection. They probably also remember the lethargy, nausea, and profound food aversion mediated by effects on the central nervous system (CNS). Both these peripheral and central effects will be considered in this article.

Organisms causing enteric infection have evolved exquisite adaptations to their host, interacting with, and subverting, normal host signalling pathways. The key elements of the host response are vomiting, profuse intestinal secretion, propulsive motor patterns, and behavioural adaptations to avoid future infection. An immediate response is vital in view of the rapid multiplication of enteric organisms; on first encounter acquired immunity has little role. Innate defensive mechanisms including lysozyme, gastric acid, intestinal defensins, and mucus secretion are all important but the simple non-specific clearance of gut contents by vomiting and profuse fluid secretion is a highly efficient way of eliminating organisms, regardless of their specific characteristics. The nervous system is ideally suited to provide such a rapid response and to coordinate the host response, being characterised by speed, plasticity, and learning.

GUT INNERVATION

The gut is richly innervated containing approximately [10.sup.8] neurones, as many as the entire spinal cord. Nerves interacting with enteric infections can be conveniently divided into four groups: (1) intrinsic enteric, (2) extrinsic afferent, (3) extrinsic efferent, and (4) CNS. Intrinsic nerves comprise the bulk of gut nerves. Their cell bodies lie in the submucous and myenteric plexuses, which can be simplistically thought of as controlling mucosal secretory and longitudinal/circular muscle functions, respectively. Predominant excitatory neuromediators are acetylcholine, substance P, 5-hydroxytryptamine (5-HT), and vasoactive intestinal peptide (VIP), with nitric oxide (NO) being the main inhibitory mediator. The extrinsic sensory nerves have cell bodies in the dorsal root ganglia of the spinal cord and the nodose ganglia. Major neuromediators are calcitonin gene related peptide (CGRP), substance P, and glutamine. Their main function is higher order integration of digestion via their input to the brain c entres which control such functions as gastric emptying, eating behaviour, pancreaticobiliary secretion, and colonic transit via extrinsic motor nerves to the gut. Postganglionic sympathetic (adrenergic) neurones exert a largely inhibitory influence on secretion and inhibition of this sympathetic "brake" increases the secretory response. Finally, the relevant CNS nerves responding to infection are mainly in the brainstem from where they can influence extrinsic motor nerve output. We can consider the role of these nerves in infection under five major functional headings (see table 1).

AMPLIFICATION OF LOCAL SECRETORY RESPONSE

The gut mucosa contains numerous free nerve endings whose cell bodies lie in the submucous and myenteric plexuses. Intrinsic primary afferent nerves (IPANs) have free nerve endings in the mucosa and express a number…