Regulation of Intestinal Immunity by Aryl Hydrocarbon Receptor Signaling in Necrotizing Enterocolitis

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PROJECT SUMMARY/ABSTRACT Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in preterm infants in the neonatal intensive care unit (NICU). The discovery of effective therapeutic and preventative strategies against NEC remains an ongoing priority. Although the multiple components of the innate and adaptive immune system have a described role in the pathogenesis of NEC, the overall immune cell signature during NEC compared to intestinal homeostasis has not been described. Preliminary data has shown the important anti-inflammatory role of the aryl hydrocarbon receptor and its dietary ligand, indole-3-carbinol, in attenuating inflammation during NEC and preserving intestinal architecture. The preliminary data further shows that mice lacking AhR in CD11c+ cells (AhR∆CD11c) have an increased expression of pro-inflammatory IL-1β during NEC, whereas mice lacking AhR in the intestinal epithelial cells (IEC) (AhR∆IEC) experience no difference in the severity of NEC. The anti- inflammatory functions of some dietary AhR ligands have been described in adult experimental colitis, but their role in NEC is unknown. Therefore, this proposal tests the central hypothesis that the inflammation in the small intestine of infants with NEC contains a distinct immune cell infiltrate and that dietary AhR ligands activate signaling pathways during NEC to attenuate the inflammatory response. This proposal will use next generation sequencing tools to evaluate the immune cell infiltrate of the small intestine during our experimental murine model of NEC and in surgically resected human small intestine NEC tissue. Further, the effects of a dietary AhR ligand on the pro-inflammatory response and epithelial barrier dysfunction during NEC will be investigated using our experimental murine NEC in wild-type mice, mice with AhR cell-specific knockouts, and human preterm enteroids. This research has significant translational relevance and addresses a critical knowledge gap in the understanding of the immune-related mechanisms in NEC pathogenesis. The outcomes of this work will define how a dietary ligand supplement to infants with immature immunity and immure gut barrier function may serve as a novel immunotherapeutic and nutritional strategy to protect the intestine against this deadly disease.