Neuroimmune interaction in the gut: from bench to bedside.
The enteric nervous system plays a crucial role in the control of gastrointestinal motility and coordinates relaxation and contraction of the smooth muscle cells. Relaxation of the gut is mainly mediated by inhibitory non-adrenergic non-cholinergic (NANC) neurons, a subpopulation of enteric neurons which release a neurotransmitter different from acetylcholine and noradrenaline. Via in vitro work performed in Antwerp, we demonstrated in 1990 that these neurons release nitric oxide. Thereafter, my research has focused on the role of the inhibitory NANC neurons in the pathophysiology of postoperative ileus. This iatrogenic condition is characterized by general hypomotility of the entire gastrointestinal tract. In a rat model, we have confirmed that manipulation of the bowel indeed leads to activation of inhibitory NANC neurons during and immediately after abdominal surgery. However, this neuronal component is short lasting and does not explain the observation that ileus lasts several days. Based on this consideration, our research in recent years rather focused on this late phase of postoperative ileus. In Amsterdam, we developed a mouse model studying gastric emptying 24 hours after surgery as read out of postoperative ileus. This research provided new insights regarding the interaction between the immune system and the innervation of the gut. Manipulation of the bowel induced mast cell degranulation and activation of macrophages present in the gut wall leading to influx of inflammatory cells in the vicinity of the myenteric plexus. This local infiltrate subsequently activates inhibitory spinal pathways paralyzing the entire gastrointestinal tract. Conversely, we showed that stimulation of the vagus nerve before and during abdominal surgery prevents this infiltrate. Both in vitro and in vivo studies showed that acetylcholine release prevents activation of macrophages via nicotinic receptors. This finding illustrates the bidirectional communication between the immune system and the enteric nervous system. Next we showed that pharmacological interventions with mast cell stabilizers, antibodies against adhesion molecules and nicotinic agonists can prevent the influx of inflammatory cells and thereby shorten postoperative ileus. Especially as we also demonstrated mast cell activation and intestinal inflammation following surgery in man, these findings provide opportunities to develop new therapeutic strategies for the treatment of postoperative ileus. In summary, our work illustrates that the innervation of the intestine intensely communicates with the immune system. Inflammation activates inhibitory neural pathways whereas vagus nerve stimulation can suppress the immune system, in particular macrophages. These findings have led to the identification of new "targets" for the development of new treatments, not only for postoperative ileus, but possibly also for other gastrointestinal inflammatory diseases.
Boeckxstaens
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Academic Medical Centre, Department of Gastroenterology & Hepatology, Meibergdreef 9-NL. 1105 AZ Amsterdam.
D000818:Animals; D017615:Enteric Nervous System; D005769:Gastrointestinal Motility; D041981:Gastrointestinal Tract / Q000276:immunology / Q000294:innervation / Q000502:physiology*; D006801:Humans; D045823:Ileus / Q000276:immunology* / Q000503:physiopathology; D009433:Neural Inhibition; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011183:Postoperative Complications
D019001:Nitric Oxide Synthase