In vitro evaluation of the aryl hydrocarbon receptor transactivity induced by human intestinal metabolites

The gastrointestinal tract is directly exposed to the environment and constitutes one of the first lines of defense against harmful antigens in the diet or the microbiota. Highly expressed in intestinal cells, the aryl hydrocarbon receptor (AhR) plays a crucial role in gut mucosal integrity and in intestinal immune function. Substances derived from food and the microbiota in the intestinal lumen can induce AhR transcriptional activity and thus maintain intestinal barrier homeostasis. We suggested the combination of a simulator of the human gut microbial ecosystem (SHIME) with cell based AhR transactivity bioassays. Thereby, the effects of human gut microbiota metabolism on the AhR signaling pathways could be evaluated. Three AhR reporter gene cell lines (T47D, HepG2, HT29) from human mammary, hepatic, and intestinal tissues, respectively, were used to test mixtures of microbiota-derived metabolites that were generated in a 3-days experiment on a SHIME system. The SHIME samples induced an AhR agonist activation in the different cell lines, with slightly tissue-dependent effects. Microbiota produced metabolites, such as short-chain fatty acids (SCFA) and tryptophan catabolites were quantified chromatographically in the SHIME samples, and they might be causing the AhR agonist activity of the mixture. However, more detailed investigations are needed to identify the contribution of individual metabolites to AhR activation. This is an innovative suggestion to study in vitro the AhR modulation caused by the human intestinal metabolism.