Microbiota‐Derived Tryptophan Metabolites Activate Aryl Hydrocarbon Receptor and Induce IL‐10 Receptor Expression in Intestinal Epithelia

Abstract

Endogenous tryptophan metabolites play an important role in gut immune homeostasis, yet the role of tryptophan metabolites from host microbiota have not been extensively explored. Indole‐3‐aldehyde (IAld), a tryptophan metabolite produced by anaerobic intestinal bacteria, is known for its intercellular signal activity and serves as an aryl hydrocarbon receptor (AHR) ligand. The physiological function of AHR includes roles in immune regulation and mucosal barrier function. Further, IL‐10 is an anti‐inflammatory cytokine that inhibits production of numerous pro‐inflammatory mediators in various cell types, including intestinal epithelial cells (IECs). This cytokine functions through binding to the IL‐10 receptor alpha subunit (IL‐10R1). An unbiased metabolomic profile of whole colon tissue from healthy and colitic mice identified significant decreases in several microbial‐derived indole derivatives (e.g. indoleacetate, indolepropionate, 5‐OH‐indoleacetate). Guided by these results, we hypothesized that indole‐containing tryptophan metabolites regulate epithelial IL‐10R1 expression. Human intestinal epithelial cells were exposed to IAld and examined for expression of IL‐10R1. These results revealed a prominent induction of IL‐10R1 mRNA and protein expression following IAld treatment. Such results were explained, at least in part, by the activation of AHR by indole derivatives. Indeed, IL‐10R1 expression was diminished when IAld was administered to AHR nuclear translocator (ARNT) knockdown cells. Likewise, the AHR inhibitor, CH‐223191, significantly reduced IL‐10R1 expression in cells exposed to IAld. Together, these results provide strong evidence for the role of tryptophan‐indole derivatives in anti‐inflammatory pathways mediated by IL‐10 signaling in IECs. The discovery of tryptophan metabolites as AHR ligands provides new insight to our understanding of the host‐microbial axis during inflammatory processes. These studies also identify possible avenues for incorporating the indole‐AHR pathway as novel therapies for mucosal disease.