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THE ROLE OF ARYL HYDROCARBON RECEPTOR PATHWAY AFTER SMALL BOWEL RESECTION
Emily J. Onufer^*1, Kristen Seiler¹, David Alvarado², Misty L. Good³, Matthew A. Ciorba², Brad W. Warner^1
1Surgery, Washington Univeristy in St. Louis, St. Louis, MO; ²Gastroenterology, Washington University in St. Louis, St. Louis, MO; ³Neonatology, Washington University in St. Louis, St. Louis, MO

Introduction: Aryl hydrocarbon receptor (AhR) has been shown to play crucial roles in gut homeostasis by modulating inflammatory responses to intraluminal and epithelial stimuli. Pathways downstream of AhR stimulation include expansion of immune populations such as innate lymphoid cells, T-helper 17 cells, and T-regulatory cells, downregulation of Th1 cytokines, and induction of IL-22 expression. Additional studies implicate AhR in tissue regeneration and, furthermore, demonstrate metabolic sequelae of AhR-mediated homeostasis. Following massive small bowel resection (SBR) in mice, there is an adaptive tissue regenerative response to compensate for lost mucosal surface area, which is marked by significant IL-22 upregulation. This is accompanied by metabolic changes (resection-associated metabolic syndrome, or RAMS) including preferential fat (rather than lean body mass) deposition, pancreatic islet cell hyperplasia, and hepatic steatosis. This led us to hypothesize that AhR may be involved in small intestinal adaptation following SBR, potentially mediating RAMS.
Methods: Wild type C57/B6 mice were subjected to 50% proximal SBR or control sham operation (transection and anastomosis). On post-operative day (POD) 3 and 7, remnant small intestine was harvested for RNA analysis of AhR and its downstream products of cytochrome p450 enzymes CYP1A1 and CYP1B1, as well as AhR repressor (Ahrr). Each time point included SBR (n=5) and sham (n=3) mice.
Results: AhR expression showed a significant two-fold increase in SBR versus sham mice on POD3 (p<0.0001), with normalization by POD7 (Figure 1). Downstream products of AhR then show significant elevation on POD7, with a two-fold increase in CYP1A1 (p=0.02), CYP1B1 (p=0.01), and Ahrr (p=0.01, Figure 2).
Conclusion: Massive SBR results in significant AhR upregulation by POD3 with a delayed temporal response showing its downstream products significantly elevated at POD7. Our results suggest that AhR, an inflammatory mediator, is involved in the initial adaptive response after SBR and that, despite its subsequent downregulation, downstream products persist until at least POD7. Additional work is needed to characterize immediate and long-term AhR activity following SBR, including its potential metabolic sequelae in RAMS.

Figure 1. Significant two-fold elevation in AhR expression after SBR on POD3 (**** indicates p<0.001).

Figure 1. Significant two-fold elevation in AhR expression after SBR on POD3 (**** indicates p<0.001).

Figure 2. Downstream products of AhR showing significant mRNA elevation on POD7 (* indicates p=0.02, ** indicates p=0.01).

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