Effects of arylhydrocarbon receptor ligands 2,3,7,8-TCDD and dietary indole-3-carbinol on the gut microbiome, immune-mediated barrier function and metabolism

• Applicant: Professorin Dr. Charlotte Esser
• Subject Area: Toxicology, Laboratory Medicine ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 376818135

• Final Report Year: 2022

Final Report Abstract

This project was a basic research project, rooted in a toxicological question, namely the environmental concern over persistent xenobiotic AHR ligands such as TCDD. We wanted to study TCDD-induced changes in the gut microbiome (environmental TCDD exposure is mainly oral), but unexpectedly found that at our highest envisioned dose, no such changes were detectable within a week. We therefore did not do further the planned lower-dose short-term feedings. However, when feeding low doses of TCDD for several months, microbiome changes became detectable. A surprising and note-worthy finding concerned the strong sex-specific differences, both in microbial community structure, in weight-gain of AHR-deficient mice by a high-fat diet, and also in the reaction to feeding a high-fat diet supplemented with fibers. AHR activation in in vitro cultures of gut-epithelial cells, even if supplemented with mucus producing cells, did not strengthen the barrier when looking at barrier gene expression or the functional parameter of tight barrier formation of the cells. However, deletion of AHR in these epithelial cells by CRISPR/Cas changed their morphology, and slowed down their formation of tight layers or of closing a scratch in their monolayers. This reflects the known impaired barrier in AHR-deficient mice. An important result of the project was the development of an easy and robust workflow to analyze microbial community shifts by FACS, whether of gut bacteria, or even skin bacteria. This will be useful in screening studies for large cohorts. FlowSoFine provides the tools to boost application in this regard and to further unleash the potential of flow cytometry.

Publications

• 4th AHR Meeting, 29-31 August 2018 in Paris, France and German PharmTox Summit, 26.2.- 1.3.2018 Göttingen Measuring microbial pattern changes in the murine gut by high-resolution flow cytometry
  Alona Weker, Katrin Hochrath, Frederick Heinrich, Hyun-Dong Chang, Charlotte Esser
  
• Old Receptor, New Tricks—The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29–31 August 2018 in Paris, France. International Journal of Molecular Sciences, 19(11), 3603.
  Esser, Charlotte; Lawrence, B. Paige; Sherr, David H.; Perdew, Gary H.; Puga, Alvaro; Barouki, Robert & Coumoul, Xavier
  
• 15th International Congress of Toxicology, 15.-18. Juli 2019, Hawaii, USA AHR-related microbial pattern changes in the murine gut after TCDD treatment measured by high-resolution flow cytometry (Katrin Hochrath won a travel fellowship by the DGPT with this abstract)
  Katrin Hochrath, Nicole Dauzenroth, Jonathan Rathjens, Katja Ickstadt, Charlotte Esser
  
• Beyond sequencing: fast and easy microbiome profiling by flow cytometry. Archives of Toxicology, 93(9), 2703-2704.
  Esser, Charlotte; Hochrath, Katrin; Teichweyde, Nadine; Krutmann, Jean & Chang, Hyun-Dong
  
• A novel tool for analysing microbial pattern changes detected by flow cytometry. Zeitschrift für Gastroenterologie (2020, 8). American Geophysical Union (AGU).
  Kupschus, J.; Dauzenroth, N.; Rathjens, J.; Ickstadt, K.; Janssen, S.; Esser, C. & Hochrath, K.
  
• German PharmTox Summit, Leipzig 3.-5.3.2020 Microbial pattern changes in the murine gut after TCDD treatment measured by high-resolution flow cytometry
  Katrin Hochrath, Jonas Kupschus, Rene Maier, Hyuan-Dong Chang, Stefan Janssen, Charlotte Esser
  
• FlowSoFine - an analyzing tool for microbial pattern changes detected by flow cytometry. Zeitschrift für Gastroenterologie (2021, 9). American Geophysical Union (AGU).
  Kupschus, J.; Rathjens, J.; Ickstadt, K.; Janssen, S.; Esser, C. & Hochrath, K.
  
• The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications. Experimental Dermatology, 30(10), 1477-1483.
  van den Bogaard, Ellen H.; Esser, Charlotte & Perdew, Gary H.
  
• Rapid detection and online analysis of microbial changes through flow cytometry. Cytometry Part A, 103(5), 419-428.
  Kupschus, Jonas; Janssen, Stefan; Hoek, Andreas; Kuska, Jan; Rathjens, Jonathan; Sonntag, Carsten; Ickstadt, Katja; Budzinski, Lisa; Chang, Hyun‐Dong; Rossi, Andrea; Esser, Charlotte & Hochrath, Katrin