O2161: Activation of the Aryl Hydrocarbon Receptor (AHR) Pathway Improves Intestinal Adaptation in Mice with Short Bowel Syndrome

Background: Short Bowel Syndrome (SBS) occurs when there is inadequate intestinal length to meet
nutritional needs and can be lethal in up to 10% of children. Our lab has previously reported increased intestinal adaptation associated with increased IL-22 expression following SBS in mice lacking lipocalin-2. Given that AHR agonists have been shown to increase IL-22 production by intestinal lymphocytes, we hypothesized that AHR activation would lead to improved adaptation in SBS.

Methods: C57Bl6 mice were randomized to receive the AHR agonist, indole-3-carbinol (I3C), mixed into the liquid diet or control diet. Mice underwent massive a small bowel resection (SBR) consisting of a 75% enterectomy with a jejuno-ileal anastomosis. I3C supplementation was maintained perioperatively. Weights were monitored daily, and intestinal architecture, markers of adaptation and IL-22 production were assessed.

Results: Dietary I3C supplementation resulted in weight gain during recovery from SBR, compared to control DMSO-treated mice (*p= 0.04 at day 7). AHR receptor expression was found to be increased in SBS intestinal tissue. Proliferation was increased in I3C-treated SBS tissue compared to control SBS. Increased functional adaptation was noted by increased enterocyte production of sucrose isomaltase and lysozyme, as well as increased expression of barrier proteins E-cadherin and mucin in I3C-treated SBS mice. Moreover, Il-22 levels were indeed found to be significantly increased in the intestines of I3C-treated SBS mice compared to control.

Conclusion: We present a role for AHR agonists as a potential therapeutic in SBS and novel insights into molecular mechanisms involving AHR activation, the intestinal barrier and adaptation.