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P018. The role of human colonic ion transporters in diarrhea-associated diseases

É. Pallagi-Kunstár1, K. Farkas1, Z. Rakonczay Jr.1, F. Nagy1, Z. Szepes1, V. Venglovecz2, Z. Rázga3, J. Maléth1, T. Wittmann1, T. Molnár1, P. Hegyi1, 1University of Szeged, First Department of Medicine, Szeged, Hungary, 2University of Szeged, Department of Pharmacology and Pharmacotherapy, Szeged, Hungary, 3University of Szeged, Department of Pathology, Szeged, Hungary

Background

Human colonic electroneutral NaCl absorption is mainly mediated via the parallel activities of Na+/H+ exchangers (NHEs) and Cl/HCO3 exchanger (AEs). The investigation of these transporters in diarrhea-associated diseases (inflammatory bowel diseases or bile acid malabsorption) would help in the differential diagnosis of diarrhea. Our aims were to examine the activities of NHEs and AEs in ulcerative colitis (UC) and to characterise the effects of bile acids on these ion transporter activities of human colonic crypts.

Methods

Active UC, control, ileum-resected or cholecystectomised patients with negative colonoscopic findings were enrolled in the study, who developed diarrhea after the surgery. Colonic crypts were isolated from biopsy samples by collagenase digestion, and intracellular pH (pHi), Ca2+ concentration ([Ca2+]i) and ATP levels (ATPi) were measured by microspectrofluorometry. The activities of different NHE isoforms were determined with the selective inhibitor HOE642. Intracellular mophological changes were analysed with transmission electronmicroscopy. Alteration of mitochondrial transmembrane potential (MTP) was assessed by confocal microscopy.

Results

Impaired NHE and AE activities were observed in colonic crypts of UC patients. Ion transporter activities were reduced in colonic crypts isolated from patients who developed diarrhea after ileum-resection or cholecystectomy compared to control patients. Treating healthy crypts with 0.3 mM of the non-conjugated bile acid chenodeoxycholate resulted in decrease of NHE and AE activities. No such inhibitory effect was observed in case of the conjugated glyco­cheno­deoxycholate (GCDC). Transmission electronmicroscopy revealed mitochondrial damage after 1 mM CDC-treatment, but no remarkable alteration was detected in case of lower concentrations of CDC or 1 mM GCDC. 0.3 mM CDC induced an increase in [Ca2+]i and a reversible decrease in MTP and ATPi. Chelation of intracellular Ca2+ did not prevent, while depletion of ATPi mimicked the inhibitory effect of CDC on ion transporter activities.

Conclusion

Both Na+ and Cl transport processes are damaged in UC. Non-conjugated bile acids inhibit ion transport mechanisms most likely via an ATP-dependent pathway. The reduced transporter activities may inhibit colonic fluid and electrolyte absorption, thus may promote the development of diarrhea.

This work was supported by OTKA, MTA and NFÜ (TÁMOP).