2017 - CIRTA


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4a- Animal Models of Intestinal Failure/Regeneration

30.4 - NOD2 deficiency impairs the intestinal tight junction barrier in a murine short bowel model

Presenter: Johannes, Reiner, Rostock, Germany
Authors: Johannes Reiner, Maria Witte, Peggy Berlin, Julia Steinig, Madeleine Bartsch, Sabeth Lindemann, Robert Jaster, Georg Lamprecht

NOD2 deficiency impairs the intestinal tight junction barrier in a murine short bowel model

Johannes Reiner1, Maria Witte2, Peggy Berlin1, Julia Steinig1, Madeleine Bartsch1, Sabeth Lindemann1, Robert Jaster1, Georg Lamprecht1.

1Division of Gastroenterology and Endocrinology, University Medical Center, Rostock, Germany; 2Department of General, Vascular, Thoracic and Transplantation Surgery, University Medical Center, Rostock, Germany

Introduction: Short bowel syndrome with chronic intestinal failure occurs after extensive small bowel resection. Despite intestinal adaptation, protein, energy, fluid and micronutrient balance cannot be maintained by a conventional diet. NOD2 mutations are a risk factor for chronic intestinal failure independent of the underlying disease. The mechanisms are not well understood. In a murine short bowel model the epithelial barrier function in the adapted jejunum was studied in the presence and absence of NOD2.

Methods: Male C57BL6/J NOD2 knockout (-/-) and wild type (+/+) mice underwent 40% ileocecal resection (ICR). Sham control mice received transsection of the ileum. Mice were followed up for 14 days. At baseline (d0) 1cm of the most proximal resected ileum was studied in a vertical Ussing chamber and histologically. After 14d 1cm of the most distal remaining small intestine was studied and compared to baseline. In order to study the paracellular leak pathway, flux of 4kDa FITC-dextran was measured. The pore pathway was characterized by transepithelial resistance (TER) and NaCl diultion potentials.

Results: Both +/+ and -/- animals showed similar morphologic adaptation 7 days after ICR such as significantly increased villus height (+/+ 229% P=0.028 vs. d0 and -/- 191% P=0.028 vs. d0, n=6-7 each) and crypt depth (+/+ 153% P=0.028 vs. d0 and -/- 129% P=0.028 vs. d0, n=6-7 each). The barrier to uncharged macromolecules (4 kDa FITC-dextran flux) was largely unaffected by NOD2 status. TER was not different in jejunal segments of +/+ and -/- mice at baseline levels (d0) and increased in the adapted jejunum. TER increase at d14 was significantly higher in -/- mice (74.5±6.0 Ω*cm2 +/+ ICR vs. 105.0±10.6 Ω*cm2 -/- ICR, n=5). In line with this, relative permeability to sodium was more severely impaired in the adapted tissue of -/- mice (+/+ ICR d0 7.7±0.4 vs. 14d 6.9±0.3 P=0.35, -/- ICR d0 6.3±0.1 vs. 14d 5.7±0.1 P=0.0157, n=5 each).

Conclusion: Profound morphologic adaptation occurs after extensive ileocecal resection. The paracellular leak flux across the adapted epithelium is unaffected by NOD2 status. In contrast, TER is increased after adaptation and more so in absence of NOD2. This may in part be explained by an altered internal electric field in the structurally altered mucosa. However, adaptation of the tight junction barrier occurs as well. Our studies indicate that NOD2 function specifically contributes to the regulation of tight junction mediated charge selective ion flux in the adapted jejunum.


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