Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway.

The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an anti-inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the anti-inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an anti-inflammatory therapy.

Bonaz B ，Picq C ，Sinniger V ，Mayol JF ，Clarençon D ... -  《-》

The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract.

Bonaz B ，Sinniger V ，Pellissier S 《Frontiers in Immunology》

Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions.

The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic-pituitary-adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti-tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastrointestinal diseases in which brain-gut communication is dysfunctional, such as inflammatory bowel disorders and others. This review presents the rationale of vagal gastrointestinal physiology and diseases and the most recent advances in vagus nerve stimulation. It also highlights the main issues to be addressed in the future to improve this bioelectronic therapy for gastrointestinal disorders.

Bonaz B ，Sinniger V ，Pellissier S 《Cold Spring Harbor Perspectives in Medicine》

Anti-inflammatory effects of vagal nerve stimulation with a special attention to intestinal barrier dysfunction.

The vagus nerve (VN), the longest nerve of the organism innervating the gastrointestinal tract, is a mixed nerve with anti-inflammatory properties through its afferents, activating the hypothalamic-pituitary adrenal axis, and its efferents through the cholinergic anti-inflammatory pathway inhibiting the release of pro-inflammatory cytokines (e.g., TNFα) by splenic and gut macrophages. In addition, the VN is also able to modulate the permeability of the intestinal barrier although the VN does not innervate directly the intestinal epithelium. Targeting the VN through VN stimulation (VNS) has been developed in experimental model of intestinal inflammation and in inflammatory bowel disease (IBD) and might be of interest to decrease intestinal permeability in gastrointestinal disorders with intestinal barrier defect such as IBD, irritable bowel syndrome (IBS), and celiac disease. In this issue of neurogastroenterology and motility, Mogilevski et al. report that a brief non-invasive transcutaneous auricular VNS in healthy volunteers consistently reduces the permeability of the small intestine induced by intravenous administration of the stress peptide corticotropin releasing hormone, known to increase intestinal permeability and to inhibit the VN. In this review, we outline the mechanistic underpinning the effect of stress, of the VN and VNS on intestinal permeability. In particular, the VN can act on intestinal permeability through enteric nerves, and/or cells such as enteric glial cells. We also review the existing evidence of the effects VNS on intestinal permeability in models such as burn intestinal injury and traumatic brain injury, which pave the way for future clinical trials in IBD, IBS, and celiac disease.

Bonaz B 《-》

Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation.

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.

Bonaz B ，Sinniger V ，Pellissier S 《-》