The vagal innervation of the gut and immune homeostasis

One of the main tasks of the immune system is to discriminate and appropriately react to “danger” or “non-danger” signals. This is crucial in the gastrointestinal tract, where the immune system is presented with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and symbionts are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homoeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can results in chronic activation of the intestinal immune response resulting in intestinal disorders such as inflammatory bowel disease (IBD). Recent evidence from our research group supports the idea that an additional actor, the vagus nerve via the enteric nervous system may play a critical role in modulating the intestinal microenvironment preserving immune homeostasis and tolerance. For the first time we were able to show that activation of enteric neurons (ENs) via electrical stimulation of vagus nerve or via specific chemical compounds, lowered intestinal inflammation, reduced cytokines expression and decreased recruitment of inflammatory immune cells in a murine model of postoperative ileus (Matteoli G, et al.; Gut. 2014 Jun;63(6):938–48). This effect was dependent on resident macrophages expressing α7nAChR. Indeed, α7nAChR activation reduces ATP-induced Ca²⁺ increase “in situ” in small intestine resident macrophages. Our present study suggests that intestinal muscularis resident macrophages, modulated by neurotransmitters release by enteric neurons, representing the ultimate target of the gastrointestinal cholinergic anti-inflammatory pathway.