Translational neurogastroenterology

Neurogastroenterological research has revealed that inflammatory and functional bowel diseases involve a defective or overactive innervation of the gut. A characteristic symptom of functional bowel disorders such as functional dyspepsia and irritable bowel syndrome is abdominal pain which occurs in the absence of an organic cause. Abdominal pain is thought to arise from hypersensitivity of the gut-brain axis and/or from stress-induced perturbations of the gut-brain and brain-gut interaction. The high prevalence of functional bowel disorders calls for the development of effective therapies which at present are limited. In a translational approach to this problem the current project aims at developing and validating novel experimental models that reflect key aspects of functional bowel disorders and allow for the identification of new drug targets and the quantitative testing of drug candidates. The major aims are as follows. (1) Most studies of gastrointestinal nociception are limited to the pain induced by gut distension. In contrast, the current project heads for experimental models of chemonociception in the stomach and colon and aims at identifying some of the relevant chemonociceptors. (2) Valid experimental models of functional bowel disorders require induction of gastrointestinal hypersensitivity without overt inflammation. Therefore, novel models of gastric and colonic hypersensitivity evoked by low-grade inflammation will be instituted and the molecular mechanisms of sensitization explored. (3) The hypothalamic-pituitary-adrenal axis is a major stress system and part of the brain-gut axis. Elucidation of a possible alteration of this system in gastrointestinal hypersensitivity may identify new opportunities for pharmacological intervention. (4) An important aim of the project is to reproduce the comorbidity of functional bowel disorders, anxiety and depression in experimental models of gastric and colonic hypersensitivity. The pharmacological modulation of the link between the gut-brain axis and the central regulation of mood may reveal novel therapeutic opportunities. (5) Another key aspect of the project is to model the interaction of stress with gastric and colonic hypersensitivity. In this context both the influence which gastrointestinal hypersensitivity has on the responsiveness of the brain to stress and the impact which a post-traumatic stress disorder has on the gut-brain axis will be addressed. (6) Since some drugs used in the treatment of irritable bowel syndrome (alosetron) may induce ischaemic colitis, drug candidates will be tested for their effects on the gastrointestinal circulation under normal and inflamed conditions.