The vagal innervation of the gut and immune homeostasis

Abstract

The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.

Keywords: Enteric Nervous System; Gastrointestinal Immune Response; Gut Immunology; Neuroimmunology.

Figure 1

Schematic representation of the cholinergic anti-inflammatory pathway. During systemic inflammation, the central nervous system is activated via the circumventricular organs and by vagal afferents. After integration, this sensory input will trigger the efferent arm via the coeliac superior mesenteric ganglion modulating the immune response in the spleen. The activation of adrenergic neurones in the spleen leads to the release of norepinephrine that induces the release of acetylcholine by a subset of T cells. Acetylcholine interacts with α7nAChR expressed on cytokine producing macrophages reducing the release of tumour necrosis factor, IL-1, IL-18, HMGB1, and other cytokines. During intestinal inflammation the central nervous system is activated via the vagal afferents arm which will trigger activation of the vagal efferent arm directly contacting the myenteric neurones in the intestinal wall. Activation of enteric neurones induces the release of acetylcholine and possibly of other immune-modulatory neurotransmitters leading to the control of intestinal inflammation and restoring intestinal immune homeostasis.

Figure 2

Cholinergic (vagal) tone and intestinal immune homeostasis. The cholinergic tone determines immune homeostasis either shifting the balance towards tolerance (normal to enhanced tone) or inflammation (decreased tone).

Figure 3

Electrical vagal nerve stimulation (EVNS) and α7-selective agonists ameliorate intestinal inflammation in a murine model of postoperative ileus. (A) Gastric retention of a semiliquid test meal in mice that had undergone laparotomy (L, empty bar) or intestinal manipulation (IM, black bar) 24 h previously after sham treatment (sham), EVNS, nicotine or the α7-selective agonist AR-R17779 (AR-R). (B) Quantitative analysis of IM-induced inflammatory cell infiltrates 24 h after indicated treatment and surgery. Reproduced with permission from The FO et al Gastroenterology, Volume 133, Issue 4, October 2007, pp. 1219–1228.