Role of the Aryl Hydrocarbon Receptor Activity in Intestinal Epithelial Cells in the Formation of Colonic Tertiary Lymphoid Tissue and Colorectal Cancer Development

Abstract

Functioning as both a boundary and gatekeepers between the external environment and internal tissues, intestinal epithelial cells (IECs) play a significant role in overall gut homeostasis. Dysfunction of the colonic mucosal epithelial barrier allows intestinal bacteria to gain access to gut immune cells, thereby contributing to intestinal inflammation and colorectal cancer (CRC). It has been demonstrated that Aryl hydrocarbon receptor (AhR) activation with xenobiotics, dietary, and microbial-derived ligands can decrease inflammation in the gut via immune-mediated pathways and maintain gut-barrier function. As an environmental sensor, the AhR is a ligand-activated transcription factor implicated in maintaining gut homeostasis. However, the interaction between dietary fat and diet-derived ligands with the activity of the AhR in terms of CRC and the development of tertiary lymphoid tissues (TLTs) remains unclear. In the present work, we first examined the effects of a high-fat diet on IEC-specific AhR knockout mice during sporadic CRC. Loss of AhR activity in IECs and a high-fat diet significantly increased the development of premalignant lesions through increased cell proliferation and altered expression of pro-inflammatory and pro-carcinogenic genes while modifying the microbial communities and their production of AhR metabolites. Moreover, the loss of AhR in IECs resulted in fewer TLTs. As organized structures that develop at sites of inflammation or infection in the colon, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis. Using a model of acute colitis in conditionally IEC-specific AhR knockout mice, we determined that the formation and composition of TLTs were dependent on both AhR activity on IECs and sex. Furthermore, AhR activation in IECs by 3,3ʹ-diindolylmethane (DIM) promoted intestinal barrier integrity through the upregulation of various tight junction (TJ) genes and genes and downstream signaling required for the formation of TLTs after an inflammatory event in a sex-dependent manner. Taken together, the present study demonstrates the modifying effects of the diet and AhR deletion on IECs in gut-associated lymphoid tissue development, tumor initiation, and progression and adds to the growing body of literature indicating that AhR activation in IECs modulates gut homeostasis.