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P027. Enhanced luminal alkalization and increased epithelial permeability in TNF‑α overexpressing murine proximal colon

M. Juric1, F. Xiao1, S. Amasheh2, K. Wahl1, H. Bantel1, G. Kollias3, M.P. Manns1, U. Seidler1, O. Bachmann1

1MHH, Dept. of Gastroenterology, Hepatology, and Endocrinology, Hannover, Germany; 2Charité, Institute of Clinical Physiology, Berlin, Germany; 3Biomedical Sciences Research Center Alexander Fleming, Institute of Immunology, Vari, Greece

Background: Damage to the epithelial barrier during chronic intestinal inflammation has been described in different experimental models, but its pathophysiological consequences for epithelial acid-base balance are largely unknown.

Methods: We therefore studied this issue in TNF‑α overexpressing mice (TNF+/ΔARE) and used the proximal colon, which is, due to its low HCO3 secretory rates, particularly suited to address this question.

Results: Histologically, this segment displays a pronounced inflammatory infiltrate extending partially into the submucosa, but an intact epithelial lining and an unaltered apoptosis rate. Serosal to mucosal net 3H-mannitol fluxes as a measure of epithelial permeability were increased in heterozygous compared to healthy animals. Accordingly, impedance spectroscopy showed a significantly reduced epithelial, and an increased subepithelial resistance in the inflamed proximal colon. Dilution potentials pointed to a shift towards enhanced anion permeability, and western blot analysis revealed a differential expression pattern for tight junction associated proteins, including a stronger signal for pore-forming claudin‑2, in heterozygous compared with healthy tissue. To test whether these findings have implications for apical HCO3 output, we studied luminal alkalization in the Ussing chamber. The basal rate was relatively low compared to other segments, but significantly higher in inflamed than in normal tissue. However, this was not paralleled by altered Slc26a3 mRNA expression levels or an increase in forskolin-stimulated Isc, arguing against upregulated active transport.

Conclusions: Taken together, inflammation during TNF‑α overexpression leads to increased epithelial permeability in murine proximal colon, which is likely causally linked to the elevated luminal alkalization rate we observe. We speculate that our findings could translate into a more general model of altered epithelial permeability leading to acid-base disturbances in the chronically inflamed intestinal epithelium.