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Increased Epithelial Permeability Is the Primary Cause for Bicarbonate Loss in Inflamed Murine Colon

Juric, Marina*; Xiao, Fang MD*; Amasheh, Salah PhD; May, Oliver*; Wahl, Kristin*; Bantel, Heike MD*; Manns, Michael P. MD*; Seidler, Ursula MD*; Bachmann, Oliver MD*

doi: 10.1097/MIB.0b013e3182813322
Original Basic Science Articles

Background: Bicarbonate loss into the lumen occurs during intestinal inflammation in different species. However, candidate pathways like CFTR or DRA are inhibited in the inflamed gut. This study addressed the question whether and how inflammation-associated increased intestinal permeability may result in epithelial HCO3 loss.

Methods: Murine proximal colon was studied because it does not express functional DRA but is inflamed in the tumor necrosis factor α overexpressing mouse model (TNFΔARE). Luminal alkalization, 3H-mannitol fluxes, impedance spectroscopy, and dilution potentials were measured in Ussing chambers, whereas expression and localization of tight junction–associated proteins were analyzed by Western blots and immunohistochemistry.

Results: Luminal alkalization rates and 3H-mannitol fluxes were increased in TNF+/ΔARE proximal colon, whereas forskolin-stimulated Isc was not altered. Epithelial resistance was reduced, but subepithelial resistance increased. The epithelial lining was intact, and enterocyte apoptosis rate was not increased despite massively increased Th1 cytokine levels and lymphoplasmacellular infiltration. Measurement of dilution potentials suggested a loss of cation selectivity with increased anion permeability. Western analysis revealed a downregulation of occludin expression and an upregulation of both claudin-2 and claudin-5, with no change in ZO-1, E-cadherin, claudin-4, and claudin-8. Immunohistochemistry suggested correct occludin localization but reduced tight junction density in TNF+/ΔARE surface epithelium.

Conclusions: Inflammation during TNF-α overexpression leads to increased epithelial permeability in murine proximal colon, decreased tight junctional cation selectivity, and increased HCO3 loss into the lumen. Inflammation-associated colonic HCO3 loss may occur through leaky tight junctions rather than through HCO3 secreting ion transporters.

Article first Published online 14 March 2013Supplemental Digital Content is Available in the Text.

*Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; and

Institute of Clinical Physiology, Charité, Campus Benjamin Franklin, Berlin, Germany. Dr. Xiao is now with the Department of Gastroenterology and Hepatology, Tongji Hospital, Wuhan, China.

Reprints: Oliver Bachmann, MD, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany (e-mail:

The first two authors share the first, and the last two share the corresponding authorship.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Supported by grants from the Deutsche Forschungsgemeinschaft to O. Bachmann (SFB621-C10) and to U. Seidler (SFB621-C9 and DFG SE460/13-4).

The authors have no conflicts of interest to disclose.

Received August 31, 2012

Accepted September 06, 2012

© Crohn's & Colitis Foundation of America, Inc.
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