The BB rat spontaneously develops autoimmune diabetes. Feeding these animals a hydrolyzed casein diet significantly reduces the incidence of this disease, suggesting that a dietary antigen is involved in the pathogenesis of this disease. In other syndromes associated with luminal antigens, including celiac and Crohn’s disease, increased intestinal permeability has been suggested to play an etiological role. Therefore, the objective of this study was to evaluate whether increased permeability was also present in BB rats before disease development. By measuring gastrointestinal permeability, in animals on a regular or hydrolyzed casein diet, we were able to demonstrate that increased gastric and small intestinal permeability appeared before the development of both insulitis and clinical diabetes. Although hydrolysis of dietary protein significantly reduced the incidence of diabetes, it did not alter the small intestinal permeability abnormality, suggesting that this is an early event. Increased permeability appears to have an early role in the genesis of several immunological diseases and may represent a common event in these diseases.

Colitis is associated with alterations in electrolyte and water transport. These changes give rise to some of the symptoms experienced by patients with colitis. Alterations in fluid flux may also contribute to increased susceptibility to mucosal injury. Recently, endogenous water channel proteins (aquaporins; AQPs), have been identified in colonic tissue. The expression of AQP4, AQP7 and AQP8 was examined, via reverse transcription/polymerase chain reaction, Western blotting and immunohistochemistry, in a murine model of colitis and in patients with inflammatory bowel disease or infectious colitis. Colitis was induced in C57BL/6 mice by the addition of 2.5% dextran sodium sulphate (DSS) to their drinking water. AQP expression in these mice was assessed following 12 h to 7 days of DSS exposure and during the recovery phase from 1 to 15 days following cessation of DSS exposure. Colonic water transport was measured after 1 and 3 days of DSS and following 7 days of recovery. The expression of AQP4 and AQP8 mRNA was significantly decreased after 12-24 h of DSS exposure and remained depressed throughout the treatment period. Expression of AQP7 was more variable. Protein expression followed a similar pattern to that observed for AQP mRNA. Significant alteration in colonic fluid secretion was correlated with reduced expression of AQP isoforms. Significantly, patients with active ulcerative colonic, Crohn's colitis or infectious colitis had similar dramatic reductions in AQP expression that appeared to be correlated with disease activity. Thus, colonic injury in both mouse and man is associated with a downregulation in AQP expression.

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The role of epidermal growth factor (EGF) in the acute regulation of intestinal transport of electrolytes and glucose was examined. In vivo transport studies were performed in New Zealand White rabbits (500-900 g) using a single-pass perfusion technique. In vitro net fluxes were determined under short-circuited conditions in Ussing chambers. Kinetic parameters of glucose transport in the presence and absence of EGF were measured in brush-border membrane vesicles. In vivo studies showed that the addition of 60 ng/ml EGF to the perfusate resulted in increased absorption of H2O, Na+, Cl-, and glucose from the jejunum. In Ussing chambers, the presence of EGF caused an increase in jejunal net fluxes of glucose-stimulated Na+ and 3-O-methylglucose due to an increase in mucosal-to-serosal movements. Verapamil abolished the EGF effect. In the absence of glucose, net fluxes of Na+ and Cl- were enhanced in the presence of EGF due to a decrease in the serosal-to-mucosal movement of both ions. Verapamil had no effect on this decrease. The incubation of EGF with brush-border membrane vesicles had no effect on either the maximal flux or the Michaelis constant of glucose transport. These results indicate that EGF is capable of regulating absorption of electrolytes and nutrients from the small intestine and suggest a role for this peptide in the control of intestinal transport.

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