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Project
The role of impaired mucosal integrity in the pathogenesis of postinflammatory gastrointestinal motor dysfunction.
Functional gastrointestinal disorders (FGID) such as irritable bowel syndrome (IBS) and functional dyspepsia (FD) are characterized by bothersome gastrointestinal complaints in the absence of an organic, systemic ormetabolic cause that is likely to explain the symptoms. Despite the high prevalence, the pathophysiology of this heterogeneous group of disorders is still elusive and reflected by the limited effectiveness of the few available treatment options.
In the present PhD project we focused on the role of intestinal barrier function in the pathophysiology ofFGID. Several groups have reported increased intestinal permeability not only in FGID, but also in organic gastrointestinal disorders such as inflammatory bowel disease. A plausible and popular working hypothesis for both functional and organic intestinal disorders is that increased penetration of food- and bacteria-derived antigens from the intestinal lumen incites a low-grade immune activation in the gastrointestinal tract, which in the case of FGID is characterized by an increased presence and/or activity of mast cells and eosinophils. Nonetheless, the evidence is merely associative and a cause-effect relation has never been demonstrated. A well-characterized animal model would fill in an unmet need in the functional gastrointestinal research field to better appreciate the roleof the intestinal barrier function. Moreover, knowledge about the etiology of the intestinal barrier defect in FGID is limited.
In the first part of the project, we have characterized the BioBreeding rat as asuitable model for FGID since it shares key pathophysiological featureswith human disease, i.e. increased intestinal permeability, low-grade intestinal inflammation and disturbed intestinal motility. We have described in detail the natural history of these events and demonstrated that the earliest demonstrable defect is an intestinal permeability defect that preceded a progressive immune activation, which ultimately resulted in invasion of the enteric nervous system with a motility disorder of theintestine due to loss of nitrergic neurons. We also showed that the inflammatory reaction was predominated by an infiltration of mast cells andeosinophils. Unfortunately, we were not successful in normalizing the early permeability defect with larazotide, a recently developed regulatorof intestinal permeability. Altogether, our data identify the BioBreeding rat as a promising model to study the pathophysiology of FGID and to help advancing preclinical drug development for FGID.
Subsequently we have investigated possible mechanisms for the observed intestinal barrier defect in FGID. The first possible candidate was psychological stress. In animal models, stress has been shown to cause low-grade intestinal inflammation through the induction of intestinal hyperpermeability, but data in humans were lacking. We performed a study in healthy volunteers and provided the first evidence of increased intestinal permeabilityduring public speech as a model for psychological stress in humans. This effect could be reproduced by administration of corticotropin-releasing hormone and was blocked by mast cell stabilization. This study provides a possible mechanism why psychological stress affects symptom severityand disease course, both in FGID and inflammatory bowel disease. Subsequently, in an animal model of chronic social stress, we showed a synergistic effect of acute and chronic stress on the colonic barrier function and investigated changes of the expression of proteins involved in mucosal integrity. Finally, we reported an increased susceptibility of the distal compared to the proximal small intestine to stress-induced hyperpermeability, possibly related to the higher bacterial load in this part ofthe intestine.
A second candidate as a contributor to impaired barrier function in FGID, was acid. Increased presence of acid in the duodenum has been suggested to be involved in symptom generation in a subgroup of FD patients through the induction of a reflex with gastric relaxation and hypersensitivity to distention of the stomach. In healthy volunteers, we showed that perfusion of the duodenum with acid gives rise to increased intestinal permeability and activation of mast cells. In two more mechanistic studies we have explored the contribution of two pathways, one mediated through the 5-HT3 receptor and one through nerve endingsimmediately below the epithelium of the duodenum. We showed that blocking the 5-HT3 receptor decreased the sensitivity of the stomach after duodenal acid perfusion and that blocking the superficial nerve endings attenuated the acid-induced gastric relaxation.
In the final part ofthe PhD project, we investigated how the stem and progenitor cells of the gut contribute to the barrier function. We studied a parasite infection model in mice and found that miR-365, a regulator of gene expression,is involved in the regulation of the stem cell compartment to maintain the barrier upon infection.
In the present PhD project we focused on the role of intestinal barrier function in the pathophysiology ofFGID. Several groups have reported increased intestinal permeability not only in FGID, but also in organic gastrointestinal disorders such as inflammatory bowel disease. A plausible and popular working hypothesis for both functional and organic intestinal disorders is that increased penetration of food- and bacteria-derived antigens from the intestinal lumen incites a low-grade immune activation in the gastrointestinal tract, which in the case of FGID is characterized by an increased presence and/or activity of mast cells and eosinophils. Nonetheless, the evidence is merely associative and a cause-effect relation has never been demonstrated. A well-characterized animal model would fill in an unmet need in the functional gastrointestinal research field to better appreciate the roleof the intestinal barrier function. Moreover, knowledge about the etiology of the intestinal barrier defect in FGID is limited.
In the first part of the project, we have characterized the BioBreeding rat as asuitable model for FGID since it shares key pathophysiological featureswith human disease, i.e. increased intestinal permeability, low-grade intestinal inflammation and disturbed intestinal motility. We have described in detail the natural history of these events and demonstrated that the earliest demonstrable defect is an intestinal permeability defect that preceded a progressive immune activation, which ultimately resulted in invasion of the enteric nervous system with a motility disorder of theintestine due to loss of nitrergic neurons. We also showed that the inflammatory reaction was predominated by an infiltration of mast cells andeosinophils. Unfortunately, we were not successful in normalizing the early permeability defect with larazotide, a recently developed regulatorof intestinal permeability. Altogether, our data identify the BioBreeding rat as a promising model to study the pathophysiology of FGID and to help advancing preclinical drug development for FGID.
Subsequently we have investigated possible mechanisms for the observed intestinal barrier defect in FGID. The first possible candidate was psychological stress. In animal models, stress has been shown to cause low-grade intestinal inflammation through the induction of intestinal hyperpermeability, but data in humans were lacking. We performed a study in healthy volunteers and provided the first evidence of increased intestinal permeabilityduring public speech as a model for psychological stress in humans. This effect could be reproduced by administration of corticotropin-releasing hormone and was blocked by mast cell stabilization. This study provides a possible mechanism why psychological stress affects symptom severityand disease course, both in FGID and inflammatory bowel disease. Subsequently, in an animal model of chronic social stress, we showed a synergistic effect of acute and chronic stress on the colonic barrier function and investigated changes of the expression of proteins involved in mucosal integrity. Finally, we reported an increased susceptibility of the distal compared to the proximal small intestine to stress-induced hyperpermeability, possibly related to the higher bacterial load in this part ofthe intestine.
A second candidate as a contributor to impaired barrier function in FGID, was acid. Increased presence of acid in the duodenum has been suggested to be involved in symptom generation in a subgroup of FD patients through the induction of a reflex with gastric relaxation and hypersensitivity to distention of the stomach. In healthy volunteers, we showed that perfusion of the duodenum with acid gives rise to increased intestinal permeability and activation of mast cells. In two more mechanistic studies we have explored the contribution of two pathways, one mediated through the 5-HT3 receptor and one through nerve endingsimmediately below the epithelium of the duodenum. We showed that blocking the 5-HT3 receptor decreased the sensitivity of the stomach after duodenal acid perfusion and that blocking the superficial nerve endings attenuated the acid-induced gastric relaxation.
In the final part ofthe PhD project, we investigated how the stem and progenitor cells of the gut contribute to the barrier function. We studied a parasite infection model in mice and found that miR-365, a regulator of gene expression,is involved in the regulation of the stem cell compartment to maintain the barrier upon infection.
Date:25 Aug 2009 → 2 Dec 2014
Keywords:Motor dysfunction
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences
Project type:PhD project