Targeting the vagal pathway
The anti-inflammatory effect of the vagus nerve is part of a reflex whereby the brain detects inflammatory information at the periphery via the vagal afferents and then creates an integrated anti-inflammatory response via the vagal efferent fibres (figure 3). Studies of murine POI models have shown that vagus nerve stimulation decreases macrophage activation, reduces inflammation of the intestinal smooth muscle and is effective on POI (Tsuchida et al., 2011). Numerous studies have highlighted the timing and factors of cholinergic anti-inflammatory pathways (CAIP) (de Jonge et al., 2005; The et al., 2011; Matteoli et al., 2014). Vagus nerve involvement was first demonstrated by manipulating vagus nerve stimulation in mice. This stimulation resulted in a decrease in intestinal muscle inflammation, cytokine production and recruitment of inflammatory immune cells, leading to faster transit recovery (de Jonge et al., 2005). Matteoli et al. then showed that the protective effect of the vagal nerve on the POI was spleen-independent via local secretion of acetylcholine that inhibits resident macrophages by binding to 7αAChR (Matteoli et al., 2014). The vagus nerve only comes into indirect contact with immune cells in the intestinal wall. Indeed, vagal efferents only synapse with enteric neurons. However, anatomical studies have highlighted the proximity between cholinergic neuronal fibres and macrophages residing in the gut, both in the myenteric plexus and the lamina propria (Nemethova et al., 2013; Cailotto et al., 2014; Matteoli et al., 2014). Prokinetics such as prucalopride have shown promising results in animal models and in a patient cohort for controlling inflammation on the one hand and treating POI on the other hand (Gong et al., 2016). Other opportunities has been explored to stimulate CAIP. The efficacy of electrical abdominal vagal nerve stimulation on inflammation and transit time was recently demonstrated in preliminary studies in murine and porcine models. This electrical stimulation approach has been studied in a cohort of postoperative colorectal surgery patients. Eighteen patients were enrolled in the study and divided into three groups: one group without stimulation, one group stimulated with 5Hz and one with 20Hz. There was a significant decrease in IL6 and IL8 production in the stimulated groups compared to the sham group (Stakenborg et al., 2017).