Mechanisms of diarrhea in collagenous colitis.
OBJECTIVE
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 (22)Na and (36)Cl fluxes were measured in miniaturized Ussing chambers. Alternating current impedance analysis discriminated epithelial from subepithelial resistance. Tight junction proteins occludin and claudin 1-5 were characterized in membrane fractions by Western blotting. Apoptotic ratio was determined by DAPI 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 micromol x h(-1) x 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 micromol x h(-1) x 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 x cm(2) due to subepithelial collagenous bands of 48 +/- 8-microm thickness. Epithelial resistance was diminished from 44 +/- 3 to 29 +/- 2 Omega x 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. Down-regulation of tight junction molecules but not epithelial apoptoses is a structural correlate of barrier dysfunction contributing to diarrhea by a leak flux mechanism.
Bürgel
Natalie
N
Department of Gastroenterology, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany.
Bojarski
Christian
C
Mankertz
Joachim
J
Zeitz
Martin
M
Fromm
Michael
M
Schulzke
Jörg-Dieter
JD
D000328:Adult; D017209:Apoptosis; D002712:Chlorides / Q000378:metabolism; D062445:Claudin-1; D003967:Diarrhea / Q000209:etiology*; D017097:Electric Impedance; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D017136:Ion Transport; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D062793:Occludin; D012964:Sodium / Q000378:metabolism
C568108:CLDN1 protein, human; D002712:Chlorides; D062445:Claudin-1; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D012964:Sodium