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》

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 ... -  《-》

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 《-》

Advances in the Treatment of Cholinergic Anti-Inflammatory Pathways in Gastrointestinal Diseases by Electrical Stimulation of Vagus Nerve.

The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve (VN), modulates the immune system in the body. Recent studies of VN stimulation (VNS) in vivo systems have shown that it plays an anti-inflammatory role through CAIP. Inflammatory diseases in the gastrointestinal tract are frequent and difficult to treat. The mechanism of the anti-inflammatory effect of VNS through CAIP is not fully known. The current review covers anatomy, molecular mechanisms, and the application in gastrointestinal diseases of the vagal CAIP. Key Messages: CAIP bridges immune and nervous systems and plays pleiotropic roles in modulating inflammation in animal models by targeting different immune, proinflammatory, epithelial and endothelial cells, and signaling pathways. Numerous animal studies have shown beneficial effects of stimulation of this pathway in models of inflammatory diseases, either through (electrical) stimulation of the VN or pharmacological approaches. In this review, we focus on the anti-inflammatory benefits of VNS as a means of providing new insights into treating inflammation-related gastrointestinal diseases, as exemplified by those described herein.

Lei W ，Duan Z 《-》

The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis.

Huston JM 《-》