The length of the remaining small bowel after 14 days was significantly increased in ICR mice that survived to the designated endpoint compared to mice that died earlier. But correlation of the length of the resected segment at the time of the operation and the length of the remaining small intestine at autopsy did not indicate longitudinal growth as a mechanism of adaptation (data not shown). This is in line with previous findings by Dekaney et al. [
13]. Furthermore, we correlated body weights of surviving mice at day 14 with their remaining bowel lengths, in order to find out if differences in body weight reflect a different severity of SBS, but again there was no correlation. Thus, in surviving mice, the variation in remaining bowel lengths was not responsible for the severity of SBS.
ICR mice displayed persistent weight loss that was significantly higher compared to sham controls. In line with the observations of Dekaney et al. [
13], neither body weights of ICR mice nor body weights of sham controls fully recovered until day 14 after surgery. Also in line with the study of Dekaney et al. [
13], villus lengths and crypt depths were 2–2.5-fold higher in ICR mice at days 7 and 14 compared to baseline. In contrast, in our adult mice histomorphological adaptation was almost complete after 7 days. However, ICR mice showed a high degree of variation both in body weight and in villus length on day 14. Unexpectedly, the increase in villus length was inversely correlated with the relative body weight in mice that survived until the end of the experiment. Thus, good clinical adaptation as assessed by recovery of body weight does not require extensive villus elongation. This finding suggests that other epithelial mechanisms, such as barrier function and transport, are also operative during adaptation. In order to find out if epithelial barrier function is involved in adaptation, we studied the two major paracellular routes, the leak, and the pore pathway [
28]. While the epithelial tight junction barrier is the main determinant of paracellular transport in vivo, the subepithelial and intravillous tissue, which cannot be removed by stripping, contributes to the transmural barrier that is being measured in the Ussing chamber in vitro [
29]. This was reflected by the transmucosal electrical resistance (TMER) which was increased in a similar magnitude as the villus length and the subepithelial intravillous tissue. Similarly, although mucosal surface area was increased as a result of villus hypertrophy, macromolecular leak appeared not to be increased. While this at first sight might indicate a tightened paracellular barrier, it may instead rather reflect the increased subepithelial diffusion barrier. Epithelial tight junctions represent the paracellular pore pathway. In the intestine, they are largely sodium selective [
30], while the electrical resistance of the subepithelial loose tissue is nonselective. In order to specifically address changes in the epithelium, this permselectivity was measured using Na/Cl dilution potentials and was found to be unchanged in the adapted jejunum with hypertrophied villi. If the increase in the transmucosal electrical resistance was entirely due to the enlarged subepithelial intravillous tissue, one would expect a decreased sodium selectivity. But the permselectivity remained unchanged, indicating that the epithelial sodium permeability was increased in the adapted jejunum. This would facilitate paracellular back-leakage of absorbed sodium to enhance sodium–nutrient-coupled transport. Future studies will test if the transcellular transport route is enhanced in the adapted epithelium as well. This experimental SBS model in mice appears suitable for these studies because genetically manipulated mice facilitate testing of specific physiological processes.
In this study, we have analyzed a mouse model of 40% ICR that mimics moderate to severe human SBS. It is a suitable tool to study mechanisms of intestinal adaptation as well as to characterize genetic risk factors for intestinal failure. Both increased stool water content and villus elongation are hallmarks of this model. Our functional studies indicate that increased intestinal epithelial sodium permeability is a mechanism of epithelial adaptation that is active in addition to villus growth. Furthermore, hyperaldosteronism counteracts stool water loss in this murine extensive ileocecal resection model. Future studies are needed to address additional epithelial mechanisms such as transport function in the complex process of adaptation to severe SBS.