Mechanisms of diarrhea in collagenous colitis

Background & Aims: Collagenous colitis is an inflammatory disease of unknown etiology with diarrhea as the leading symptom.. The aim of this study was to examine the pathogenic mechanisms of this disease. Methods: Biopsy specimens of the sigmoid colon were obtained endoscopically. Short-circuit current and Na-22 and Cl-36 fluxes were measured in miniaturized Ussing chambers. Alternating current impedance analysis discriminated epithelial from subepithelial resistance. Tight junction proteins occluding and claudin 1-5 were characterized in membrane fractions by Western blotting. Apoptotic ratio was determined by PAPI and TUNEL staining. Results: In collagenous colitis, net Na+ flux decreased from 8.8 +/- 1.8 to 0.2 +/- 1.5 and net Cl- flux from 11.2 +/- 3.0 to -3.0 +/- 2.7 mumol (.) h(-1 .) cm(-2), indicating a pronounced decrease in NaCl absorption. The fact that short-circuit current increased from 1.5 +/- 0.4 to 3.9 +/- 0.8 mumol (.) h(-1 .) cm(-2), together with the negative net Cl- flux, points to activation of active electrogenic chloride secretion. Subepithelial resistance increased from 7 +/- 1 to 18 +/- 2 Omega (.) cm(2) due to subepithelial collagenous bands of 48 +/- 8-mum thickness. Epithelial resistance was diminished from 44 +/- 3 to 29 +/- 2 Omega (.) cm(2), and this was accompanied by a decrease in occludin and claudin-4 expression. Neither mucosal surface area nor apoptotic ratio was altered in collagenous colitis. Conclusions: Reduced net Na+ and Cl- absorption is the predominant diarrheal mechanism in collagenous colitis, accompanied by a secretory component of active electrogenic chloride secretion. The subepithelial collagenous. band as a significant diffusion barrier is a cofactor. Downregulation of tight junction molecules but not epithelial apoptoses is a structural correlate of barrier dysfunction contributing to diarrhea by a leak flux mechanism.