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).