Collagenous colitis : The influence of inflammation and bile acids on intestinal barrier function

Sammanfattning: Background and aims: Collagenous colitis (CC) is a diarrheal disorder with an incidence rate of 5-6/100000 inhabitants, affecting mainly middle-aged women. The diagnosis is made by histology of the colonic mucosa. Classical findings are a thickened subepithelial collagenous layer and chronic inflammation in the lamina propria. In inflammatory bowel disease (IBD) the mucosal barrier function is important in pathogenesis. The main purpose of the thesis was therefore to describe the barrier function in CC. The cause of CC is uncertain but the condition seems to be associated with bile acid malabsorption. Increased faecal bile acids are known to induce diarrhea. In functional studies the influence of bile acids on mucosal permeability in biopsies of healthy human individuals and in patients with CC was investigated.Methods and patients: In the first paper a single patient with intractable CC was examined before surgery, with loop-ileostomy and after bowel reconstruction. For the other studies a total of 25 patients with CC were included (20 women, 5 men, mean age 66 years). There were three groups (14 patients in clinical remission without medical treatment, 11 with active disease, and 8 of these again after 6 weeks of budesonide treatment); 17 individuals with normal histology served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (Isc), transepithelial resistance (TER), and transmucosal passage of chemically killed E. coli K12 after addition of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA). The biopsies were further investigated with confocal microscopy to assess bacterial transepithelial passage.Results: Para- and transcellular permeability was increased in active CC, but normalized with histological improvement due to faecal stream diversion. After bowel reconstruction, permeability to CrEDTA and HRP increased again.In CC, bacterial uptake in colonic biopsies was significantly higher in all groups than in controls. Despite significant alleviation of symptoms, budesonide did not normalize the increased bacterial passage. Histology was unchanged after 6 weeks of budesonide treatment. DCA augmented mucosal permeability to CrEDTA in a dose-dependent manner and even such a low dose as 100 μmol/l DCA increased bacterial uptake significantly. The combination of bile acids and E.coli K12 had additive effects on TER.100 μmol/l CDCA and DCA increased bacterial uptake in biopsies of CC patients in remission 4-fold, but had no additive effect on biopsies from patients with active disease. Furthermore, patients in clinical remission on budesonide treatment showed no bile acidinduced effects on E.coli K12 passage.Conclusion: Collagenous colitis presents with increased para/transcellular permeability and bacterial uptake, irrespective of disease activity or budesonide treatment, signifying an underlying mucosal barrier defect. Faecal stream diversion can normalize the barrier dysfunction, but budesonide does not, despite its beneficial clinical effects which alleviate diarrhea or bowel symptoms. Bile acids in physiological concentrations have the potential to augment bacterial uptake, especially in mucosa from CC patients in remission. Budesonide treatment appears to counteract the bile acid induced mucosal impairment. These detrimental effects of bile acids on mucosal barrier function might facilitate initiation and perpetuation of mucosal inflammation in CC.