Project Details
Projekt
The role of AHR for the gut-skin inflammatory axis
Applicant
Professorin Dr. Charlotte Esser
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
Microorganisms that live in and on the body of animals and humans and the nutrients or messenger substances they produce are important for health and disease. Chemicals can be sensed through cellular receptors, and trigger adaptive reactions. One such chemical sensor, the aryl hydrocarbon receptor (AHR), is a transcription factor and becomes activated upon binding to certain small molecule chemicals (“AHR ligands”). AHR ligands include metabolites of the essential amino acid tryptophan, which are generated by certain intestinal bacteria, but are also certain indoles from food plants, e.g. from the family Brassicaceae. We had previously shown that the expression of the AHR in intestinal epithelial cells affects the composition of the intestinal microbiota. In addition, we showed using gene-deficient mice that the presence of AHR and dietary AHR ligands are important for a healthy skin barrier and may thus contribute to the gut-skin axis. For instance, addition of AHR ligands to the mouse diet attenuated pea peanut allergy in a mouse model. Furthermore, we showed that the skin barrier is weakened when the AHR is genetically lost, and could even be strengthened in wild-type mice by long-term feeding of AHR ligands. In the present project, we will investigate the role of the AHR for the gut-skin axis in mice. In particular, we want to investigate in which cells the AHR must be expressed in order to bring about a change in the gut microbiome, i.e. dysbiosis. We know from preliminary work that mice with an AHR-deficiency in intestinal epithelial cells have a different gut microbiota profile than wild-type mice. Since certain gut bacteria are known to be particularly good producers of AHR ligands, dysbiosis could lead to different levels of AHR-ligands in the serum. Central experiments of our project are feeding studies, which will allow us to investigate the role of the gut microbiota for the skin barrier using an inflammatory skin disease associated with barrier damage, atopic dermatitis, in mice. Specifically, we will orally transfer intestinal bacteria (“fecal transplants”) from AHR-deficient mice with dysbiosis into wild-type mice via gavage, and subsequently induce an AD-like inflammation using a standard method, followed by a thorough characterization of its extent. Similar experiments will be performed with high-affinity, pure AHR ligands, which are also used by other members of the consortium, and which are suspected to differentially activate the AHR pathway. This set of experiments is also about the generation of e.g. ligand- and cell-specific gene expression profiles that can be used in later meta-analyses. Finally, we will identify AHR ligands in mouse sera and attempt to associate them with the altered bacterial abundance. In the long term, we want to create a rational basis for therapeutic intervention with probiotic bacteria for the gut-skin axis.
DFG Programme
Research Units
Co-Investigator
Dr. Doreen Reichert
