The vagal anti‐inflammatory pathways to the viscera: from basic understanding to therapeutic implications

The articles by Bonaz et al. (2016 a), Goverse et al. (2016) and De Lartigue (2016) address the topic of The vagal pathways to the viscera: from basic mechanisms to therapeutic applications. These three reviews were part of a symposium that took place during the meeting of the International Society for Autonomic Neuroscience (ISAN2015) held in Stresa, Italy.

Tracey and colleagues (Borovikova et al. 2000) provided the original experimental demonstration that electrical vagal stimulation induces an anti‐inflammatory action. Since then, a growing number of original studies have expanded on the key role of the parasympathetic nervous system in the modulation of inflammation as it relates to underlying neuronal circuitries, and the cellular and intracellular mechanisms (Tracey, 2007). These seminal observations provided the impetus for ground breaking clinical studies of chronic vagal stimulation to improve visceral diseases in the setting of immune dysfunction. These aspects are detailed in the articles by Bonaz et al. (2016 b) and Goverse et al. (2016), which focus on intestinal cholinergic anti‐inflammatory pathways along with the potential therapeutic application in the context of inflammatory bowel disease, pancreatitis and post‐operative ileus. Convergent reports indicate that the vagal cholinergic anti‐inflammatory pathway is mediated by the α7‐subtype of the nicotinic acetylcholine receptor (α7nAChR) localized on intestinal immune cells, namely macrophages, leading to the intracellular activation of JAK2–STAT signalling. In vivo, the use of surgical, pharmacological and genetic approaches have demonstrated that vagotomy, α7nAChR antagonist treatment or α7nAChR gene deletion resulted in increased severity of experimental colitis and pancreatitis (Goverse et al. 2016). Conversely, electrical vagal stimulation or α7nAChR agonists alleviate many of the clinical and biochemical features of colitis in rodents and intestinal inflammation of the muscularis externa in a murine model of postoperative ileus (Goverse et al. 2016; Bonaz et al. 2016 b). Neural circuitries mediating vagal stimulation‐induced anti‐inflammatory effects involved the vagal efferent innervation of enteric neurons that activate resident macrophages in the intestine as well as an indirect action through vago‐sympathetic pathways occurring most likely at the level of the coeliac ganglia (Bonaz et al. 2016 b). However, there are still some debates regarding the exact neuro‐immune interaction involved in the vagal cholinergic modulation at the level of the spleen, where several neuro‐anatomical pathways put forward have been either confirmed or refuted by different groups (Bonaz et al. 2016 b). Vagal afferents, which encompass the majority (80%) of fibres contained in the vagus nerve, are also part of the anti‐inflammatory reflex whereby inflammatory mediators activate these afferents and thereby the interrelated brain neuroendocrine network including the hypothalamic–pituitary–adrenal axis and central autonomic circuits. This leads to endocrine (glucocorticoids) and vagal efferent modulation of the inflammation (Bonaz et al. 2016 b). Based on these preclinical studies, the anti‐inflammatory effect of vagal stimulation is starting to be tested under conditions of chronic inflammation of the digestive tract (Bonaz et al. 2016 b). A recent pilot study by Bonaz et al. (2016 a) showed the therapeutic efficacy of chronic low frequency vagal stimulation assessed at the end of 6 month peirod by clinical, biological and endoscopic monitoring of remission in a small cohort of patients with Crohn's disease (Bonaz et al. 2016 a).

De Lartigue (2016) presents another facet of the bidirectional communication between the viscera and the brain through vagal pathways. His focus is on the role of vagal afferents in the regulation of meal size and satiety and the neuromodulation of the vagus nerve as a target for the treatment of obesity. Experimental evidence has established that the volume of the meal within the stomach drives negative feedback to the brain through the activation of mechanosensitive vagal afferents while neuroendocrine chemical signalling derived from nutrients initiates meal termination also through vagal afferents. Novel insight on the underlying cellular mechanisms came from the demonstration that enteroendocrine cells harbour receptors for different nutrients and display neuropodes allowing for transynaptic connection with vagal afferents (Bohorquez & Liddle, 2015). Of importance was the recognition that vagal afferent neurons undergo rapid plasticity in response to changes in the nutritional status, providing adaptive regulation of food intake (Dockray & Burdyga, 2011). However, under conditions of chronic ingestion of palatable food or calorie‐rich diets, there is a reduced sensitivity of vagal afferents to the negative feedback of gastrointestinal (or adipose tissue) hormones released by food as well as gastric mechano‐sensitivity. The disrupted vagal signalling to the brain of nutritional status contributes to hyperphagia and obesity (De Lartigue, 2016). Unravelling these mechanisms has opened new avenues to apply neuromodulation of the vagus nerve as a target for treatment of obesity. The outcomes of several clinical studies are exhaustively reviewed in De Lartigue's article.

In conclusion, these reviews address timely topics, and highlight the increasing recognition of the multifaceted role exerted by the vagus nerve and the use of ‘electroceuticals’ as potentially promising additional therapeutic options for intestinal inflammatory disorders (Bornstein & Ben‐Haim, 2015). In addition, the FDA recently approved an electroceutical device for intermittent modulation of vagal activity to treat adults with morbid obesity (Sinha, 2015). Whether the established immune cells cross talk in obesity (Seijkens et al. 2014) is part of the mechanisms underpinning weight loss in response to the modulation of vagal activity warrant further investigations.

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Competing interests

None declared.