Scope Many dietary phytochemicals have been reported to promote gut health. Specific dietary phytochemicals, such as luteolin, as well as specific microbial metabolites of tryptophan are ligands of the aryl hydrocarbon receptor (AhR), which plays a role in immunity and homeostasis of the gut barrier. Here, the fate of luteolin during colonic fermentation and the contribution of tryptophan metabolites to AhR activity in different parts of the colon are investigated. Methods and results Several polyphenols are screened for AhR activation and oregano, containing the ligand luteolin, is added to batch cultures of human microbiota from the distal colon. Luteolin is rapidly metabolized, with no measurable increase in AhR activity. In the second experiment, using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME), not all luteolin is metabolized in the ascending colon, but disappear rapidly in the transverse colon. The greatest AhR activity is due to microbiota‐derived metabolites of tryptophan, particularly in the descending colon. Conclusions Luteolin in food is rapidly metabolized in the transverse colon. Tryptophan metabolism by the microbiota in the colon contributes substantially to the pool of lumen metabolites that can activate the AhR.

The aryl hydrocarbon receptor (AhR) plays an important role in intestinal homeostasis, and some microbial metabolites of tryptophan are known AhR agonists. In this study, we assessed the impact of tryptophan supplementation on the formation of tryptophan metabolites, AhR activation, and microbiota composition in the simulator of the human intestinal microbial ecosystem (SHIME). AhR activation, microbial composition, and tryptophan metabolites were compared during high tryptophan supplementation (4 g/L tryptophan), control, and wash-out periods. During tryptophan supplementation, the concentration of several tryptophan metabolites was increased compared to the control and wash-out period, but AhR activation by fermenter supernatant was significantly decreased. This was due to the higher levels of tryptophan, which was found to be an antagonist of AhR signaling. Tryptophan supplementation induced most microbial changes in the transverse colon including increased relative abundance of lactobacillus. We conclude that tryptophan supplementation leads to increased formation of AhR agonists in the colon.

Glucosinolates in broccoli can be converted upon chewing and processing into Aryl hydrocarbon Receptor (Ahr) ligands.

Another important connection between host, diet and microbiota is the AhR-immune axis.AhR is a cytosolic receptor expressed by many cells in the human body and previously known to bind, amongst others, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), contributing to its detoxification 32 . However, recent studies have demonstrated that AhR also participates in the establishment and maintenance of intestinal homeostasis, including maintaining epithelial barrier integrity, protection from pathogens and regulation of commensal gut microbiota 12,16,33 .The diet can influence AhR-dependent mechanisms by providing a source of potential AhR ligands. In addition, the microbiota can produce AhR ligands through metabolism of tryptophan.AhR can be considered as an important anti-inflammatory receptor which combines dietary, microbial, metabolic and endogenous signals to activate immune response and alter the gut microbiota composition 1 . AhR is expressed by a number of immune cells, and thus, AhR signalling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response 34 . AhR pathwayAhR consists of a basic helix-loop-helix (bHLH) protein belonging to the Per-Arnt-Sim (Pas) family 35 . The receptor resides in the cytosol and it is ligand-activated. Several domains and regions are functionally important within the AhR protein complex. At the amino terminal part, the bHLH-Pas region is a key player in the interaction with hsp90, binding of DNA and dimerisation with AhR nuclear translocator (Arnt). Arnt is also involved in translocation of the receptor to the nucleus, involving a nuclear localisation signal (NLS) and a nuclear export signal (NES). Additionally, AhR has a Pas domain, which contains two structural repeats: Pas A and Pas B. While Pas A is involved in the dimerisation of AhR with Arnt, Pas B binds the ligands and interacts with hsp90. The Pas domain is not only important at the amino terminal, but also at the carboxy terminal part where it is involved in the interaction of AhR with XAP2, an AhR associated protein. The carboxy terminal consists of a transactivation domain with three subdomains. The total AhR has a size of 95 to 125 kDa, varying amongst different species 36-38 .When AhR ligands enter the cell, they pass the plasma membrane and bind the receptor 39 (Figure 2). At that moment, AhR is present as an inactive complex consisting of multiple proteins and resides in the cytosolic compartment. It contains 2 hsp90 molecules: XAP2 and P23 [40][41][42] .Hsp90 in the cytoplasm has the function to localize AhR in the absence of a ligand, where it protects its degradation and transformation. XAP2 minimises the degradation of AhR and plays a role in the regulation of the translocation of AhR to the nucleus. Moreover, it boosts AhR signalling when it is joined with hsp90 43,44 . P23 is involved in the stabilisation of the AhR complex 45 . PolyphenolsPolyphenols are secondary metabolites from plants and have been widely studied for their antioxidant properties to inh...

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