Over time of intestinal barrier function, mucosal and neuromuscular inflammation and loss of nitrergic motor neuron function in the normoglycemic BB-DP rat. We hypothesize that intestinal permeability is an early feature of the normoglycemic BB-DP rat, preceding inflammation and neuromuscular alterations, suggesting its disease-initiating role. In the current study we described the complex chain of events leading from early impaired mucosal integrity to myenteric BAY 73-4506 755037-03-7 ganglionitis and dysmotility in a spontaneous rat model of leaky gut. We demonstrated the presence of intestinal hyperpermeability prior to the development of mucosal immune activation in BB-DP rats, suggesting a disease-initiating role. At later time points, half of the animals developed a transmural inflammatory reaction with myenteric ganglionitis. Finally, in the older rats with intraganglionic inflammation, a loss of nitrergic neurons and function was observed. Our findings suggest that impaired mucosal integrity can give rise to a transmurally progressing inflammation resulting in disturbed motility, providing an insightful model for human FGID. Increased intestinal permeability and low-grade inflammatory alterations in the gastrointestinal tract have been suggested to contribute to the pathogenesis of FGID. A cascade in which intestinal permeability represents the first hit, leading to immune activation and subsequent neuromuscular alterations, is often proposed in the literature. However, because of the lack of drugs which can restore the leaky barrier and the fact that patients will only present themselves at the time of symptoms, it is challenging to separate cause from effect in humans. In the current study in BB-rats, we found an impaired barrier function in young rats of 50 days, a time point at which no immune cell infiltration or increased MPO-activity was observed. Furthermore, the expression of TNFa, IFNc, IL1b and IL13 was not increased in these young rats. This is of particular importance since it is well established that these cytokines can impair intestinal barrier function. We speculate that the initial defect in the intestinal barrier leads to the subepithelial penetration of unprocessed antigens, inciting an inflammatory reaction, which in turn maintains the permeability defect at the later time points. These events may lead to a vicious cycle as suggested by the correlation between the permeability and inflammatory parameters in the older animals and by the fact that the permeability parameters in the older animals without ganglionitis were comparable to controls. In order to definitely confirm this hypothesized biphasic permeability defect, experiments using anti-inflammatory treatments are warranted. The barrier function of the intestinal mucosa is regulated primarily by the apical junction complex, of which the tight junction is the most critical component.