Activation of the Ah Receptor Modulates Gastrointestinal Homeostasis and the Intestinal Microbiome

Abstract

The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a variety of structurally diverse exogenous and endogenous small molecules. The AHR has been implicated in both host and microbiota homeostasis. Understanding the role of the AHR in gastrointestinal health and the appropriate level of AHR activation has implications in determining whether the AHR is an appropriate target for dietary or drug intervention. The discovery of previously unrecognized AHR ligands of dietary, environmental, and pharmaceutical origin continues to expand, including many tryptophan derivatives (e.g., 2-oxindole, kynurenic acid). AHR activation can lead to organ and cell type-specific effects through altered gene expression. Most recent studies have focused on the role of the AHR in immune cell function especially within the gastrointestinal tract. The AHR plays an important role in xenobiotic metabolism within the intestine. In addition, the AHR regulates proliferation and differentiation status of intestinal epithelial cells. The lack of AHR expression and activation of the AHR are both capable of altering the composition of the gut microbiota in mice. Dietary AHR ligand exposure has been shown to attenuate toxicity due to gastrointestinal challenge. However, activation by persistent AHR ligands can lead to intestinal dysfunction. Many questions remain to be answered as to the suitability of utilizing the AHR as a target to maintain gastrointestinal health and treat various disease states. Nevertheless, the potential of AHR ligands to improve intestinal health appears to be quite significant.