Villus Growth, Increased Intestinal Epithelial Sodium Selectivity, and Hyperaldosteronism Are Mechanisms of Adaptation in a Murine Model of Short Bowel Syndrome

Abstract

Background Short bowel syndrome results from extensive small bowel resection and induces adaptation of the remaining intestine. Ileocecal resection (ICR) is the most frequent situation in humans. Villus hypertrophy is one hallmark of mucosal adaptation, but the functional mechanisms of mucosal adaptation are incompletely understood. Aims The aim of the study was to characterize a clinically relevant model of short bowel syndrome but not intestinal failure in mice and to identify outcome predictors and mechanisms of adaptation. Methods Male C57BL6/J mice underwent 40% ICR and were followed for 7 or 14 days. Small bowel transection served as control. All mice underwent autopsy. Survival, body weight, wellness score, stool water content, plasma aldosterone concentrations, and paracellular permeability were recorded. Results Unlike controls, resected mice developed significant diarrhea with increased stool water. This was accompanied by sustained weight loss throughout follow-up. Villus length increased but did not correlate positively with adaptation. Plasma aldosterone concentrations correlated inversely with body weight at day 14. After ICR, intestinal epithelial (i.e., tight junctional) sodium permeability was increased. Conclusions 40% ICR results in moderate to severe short bowel syndrome. Successful adaptation to the short bowel situation involves villus elongation but does not correlate with the degree of villus elongation alone. In addition, increased intestinal epithelial sodium permeability facilitates sodium-coupled solute transport. Hyperaldosteronism correlates with the severity of weight loss, indicates volume depletion, and counterregulates water loss. Electronic supplementary material The online version of this article (10.1007/s10620-018-5420-x) contains supplementary material, which is available to authorized users.

Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency

“…Briefly, mice were anesthetized by i. p. injection of ketamine (100 mg/kg bw) and xylazine (15 mg/kg bw) and orally intubated and ventilated as described previously [15]. After midline incision, the distal small bowel and the cecum were exposed and then transected 12 cm proximal to the ileocecal junction and immediately distal to the cecum.…”

“…Body weight, wellness score [21], stool water, and aldosterone plasma concentrations were analyzed as described previously [15]. In brief, mice were weighed and scored daily using a previously, for this model, verified wellness score with 8 items.…”

“…The tube with fresh stool was immediately weighed, dried overnight at 80 °C, and then weighed with exsiccated stool. Water content was then calculated as before [15]. These exsiccated stools were then used for determination of sodium concentrations.…”

“…In total, 1-cm intestinal segments were immediately placed in MorFFFix (Morphisto ® , Frankfurt am Main, Germany) for 24 h and then paraffin-embedded as described [15]. In total, 5-µm sections were HE-stained and then used for morphometric analysis.…”

“…Although villus hypertrophy implies some gain of absorptive cell mass, the increment in villus length does not translate numerically equal into functional measures such as wet weight absorption [13]. Also, spontaneous villus elongation does not correlate with functionally effective adaptation [15].…”