Intestinal permeability : a parameter of mucosal dysfunction

Sammanfattning: The gastrointestinal tract has two opposing functions; to absorb nutrients and electrolytes, and to act as a barrier towards hazardous and non-nutritional substances. In the present thesis the barrier function of the gastrointestinal tract was studied in animal models in vivo, in situ and in vitro. Experimentally induced disorders of the intestinal barriers were evaluated in terms of altered intestinal permeability using different marker molecules, with different permeation patterns and kinetics, depending on size, lipophilicity and stability. The markers used were the proteins bovine serum albumin, ovalbumin and rat serum albumin, oxytocin peptide analogs, and the low molecular weight markers 51Cr-EDTA, 14C-mannitol, and Na-fluorescein. Diversion of pancreatic juice from the intestine increased peptide absorption. Probably due to the absence of pancreatic enzymes, but also due to an altered luminal milieu such as pH. Peptide formulations with vehicles of medium chain glycerides also enhanced peptide absorption. This was due to different mechanisms, such as a protective effect of the vehicle to luminal degradation and adhesion of the vehicle to mucosa. A reduction of the intestinal mucus layer by a mucolytic agent, increased the passage of markers, which normalized when the mucus was restituted. Acid-induced acute mucosal injury enhanced the bidirectional permeability. In this model, the blood-to-lumen barrier, especially for macromolecules, was suggested to be less restrictive than in the reverse direction. During spontaneous intestinal inflammation, as shown in transgenic rats, no altered intestinal permeability was observed. This suggested that inflammation progressed with intact intestinal integrity. Intestinal permeability, as a parameter to estimate mucosal integrity, was found to be useful to confirm mucosal dysfunctions. However, evaluation of the abnormal intestinal conditions induced, revealed the importance of chosing relevant models and suitable marker molecules.