Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor

Abstract

Accumulating evidence indicates that nutrition can modulate the immune system through metabolites, either produced by host digestion or by microbiota metabolism. In this review, we focus on dietary metabolites that are agonists of the Aryl hydrocarbon Receptor (AhR). AhR is a ligand-activated transcription factor, initially characterized for its interaction with xenobiotic pollutants. Numerous studies have shown that AhR also recognizes indoles and tryptophan catabolites originating from dietary compounds and commensal bacteria. Here, we review recent work employing diet manipulation to address the impact of nutritional AhR agonists on immune responses, both locally in the intestine and at distant sites. In particular, we examine the physiological role of these metabolites in immune cell development and functions (including T lymphocytes, innate-like lymphoid cells, and mononuclear phagocytes) and their effect in inflammatory disorders.

Keywords: AhR; aryl hydrocarbon receptor; immunity; intestine; microbiota; tryptophan.

Figure 1

Sources of nutritional AhR ligands. Nutritional AhR ligands are derived either from the breakdown of food components or from tryptophan catabolism by intestinal microbiota. Several types of indoles are present in cruciferous vegetables. In particular, indole-3-carbinol (I3C) is converted in the stomach into high affinity AhR ligands Diindolylmethane (DIM) and indole[3,2-b]carbazole (ICZ). Tryptophan is metabolized by Lactobacillus bacteria into indole-3-acetic acid (IAA), tryptamine (TA) and 3-methyl indole. In addition, tryptophanase-expressing bacteria degrade tryptophan into indole, which is metabolized by host liver cells into indoxyl-3-sulfate (I3S) and indole-3-proprionic acid (IPA).

Figure 2

Nutritional AhR ligands in intestinal immunity. Nutritional AhR ligands are involved in the maintenance of intestinal intra-epithelial lymphocytes (IEL) and type innate-like lymphoid cells (ILC3). ILC3 are the main producers of IL22, which acts on intestinal epithelial cells to induce the secretion of antimicrobial peptides. In the absence of dietary AhR ligands, IEL and ILC3 are reduced, and microbiota diversity is altered.

Figure 3

Nutritional AhR ligands in monocyte differentiation. Nutritional AhR ligands modulate monocyte differentiation in the skin. AhR activation from dietary agonists favors monocyte differentiation towards dendritic cells via the induction of the transcription factors Irf4 and Blimp-1. In the absence of AhR signaling, monocytes differentiate preferentially into macrophages.