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Cholinergic modulation of immune homeostasis: new opportunities for treatment

Final Report Summary - CHOLSTIM (Cholinergic modulation of immune homeostasis: new opportunities for treatment)

In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis, not only to prevent chronic inflammation and tissue damage, but also to prevent lethal infection or uncontrolled growth of tumor cells. In 2000, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. A few years later, we provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation reduced inflammation of the intestinal muscle layer and restored gastrointestinal transit in a model of postoperative ileus. In the present project, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy (reduced cholinergic tone) lost their ability to develop tolerance to oral feeding of an antigen, whereas vagus nerve stimulation (increased cholinergic tone) reduced mucosal inflammation in a model of food allergy and colitis. We went on to show that this immunomodulatory effect results from vagal input to cholinergic enteric neurons acting on resident macrophages. Activation of enteric neurons by electrical stimulation or pharmacological stimulation with the serotonin 4 receptor agonist prucalopride reduced macrophage activation in situ, an effect similar to that of vagus nerve stimulation in vivo. Moreover, we provided evidence that enteric neurons release mediators skewing macrophages towards a tolerogenic phenotype via the release of TGF-b and fractalkine. Of note, also in human, pharmacological stimulation of enteric neurons with prucalopride dampened intestinal inflammation in the muscularis externa of patients undergoing resection of the pancreas, resulting in faster postoperative recovery. Finally, using single cell RNA sequencing, we identified a unique macrophage population playing a key role in the survival of enteric neurons, further illustrating the vital bidirectional interplay between enteric neurons and resident macrophages in the gastrointestinal tract.
Taken together, in this project, we have provided extensive evidence expanding the immune-modulatory role of the vagus nerve / enteric nervous system to the adaptive immune system, knowledge that is of crucial importance to develop novel therapeutics, including vagal nerve stimulation, for the treatment of immune-mediated gastrointestinal disorders.