Background <p>Recent studies reveal that the interaction of Aryl Hydrocarbon Receptor (AhR) signaling activation with metabolic homeostasis may significantly affect the course of IBD, and the inhibition of AhR signaling may exacerbate IBD symptoms and disrupt epithelial barrier function. However, there is no recognition of how the AhR signaling pathway affects intestinal barrier function by influencing intestinal epithelial cell metabolism.</p> Methods <p>In this study, we constructed intestinal epithelial-specific AhR knockout mice, and performed comprehensive metabolomic and transcriptomic analyses on four groups of mice (WT mice, DSS mice, AhR^ΔIEC mice, and AhR^ΔIEC+DSS mice) in order to assess the metabolic and genomic effects of AhR signaling deletion in intestinal epithelial cells.</p> Results <p>Compared with wild-type mice, the knockout of the AhR gene caused characteristic changes mainly in lipid metabolism and amino acid metabolism disorders, including 69 metabolites and 64 genes. Under inflammatory conditions, changes including 94 metabolites and 3062 genes were observed in the DSS group compared to wild-type mice.In addition, down-regulation of 14 metabolites and up-regulation of 11 metabolites were observed in AhR^ΔIEC+DSS mice compared to DSS, with anti-inflammatory metabolites such as 13-hydroxy-4Z,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid、prostaglandin i2, pg 42: 11, 1,2-distearoyl-sn-glycero-3-phospho-l-serine decreased dramatically, whereas the pro-inflammatory metabolites prosapogenin a, 12,13-dihydroxy-9z-octadecenoic acid, pro-leu, n-acetyl-l-aspartic acid increased significantly. Analysis of RNA-Seq data showed that the genetic changes caused by AhR knockdown were mainly focused on lipid metabolism, amino acid metabolism and other pathways. In addition, comprehensive metabolomic and transcriptomic analyses showed that in the correlation analysis of 25 metabolites and 30 differentially expressed genes, pro-inflammatory factor Saa1 was positively correlated with multiple pro-inflammatory metabolites such as pro-leu and pheniramine, while the anti-inflammatory factor Saa3 was positively associated with several anti-inflammatory metabolites such as prostaglandin i2, 1,2-distearoyl-sn-glycero-3-phospho-l-serine.</p> Conclusion <p>These genes and metabolites involved in metabolic dysregulation pathways may provide a more specific and reliable research direction to study the protective mechanisms of AhR on the intestinal epithelial barrier and provide new insights into the effects of AhR on regulating the metabolism of intestinal epithelial cells in the development of IBD.</p>