Maryam Keshavarz1,2, Schayan Faraj Tabrizi1,2, Anna-Lena Ruppert3, Uwe Pfeil1,2, Yannick Schreiber4, Jochen Klein5, Isabell Brandenburger6,1, Günter Lochnit7, Sudhanshu Bhushan8, Alexander Perniss1,2, Klaus Deckmann1,2, Petra Hartmann1,2, Mirjam Meiners1,2, Petra Mermer1,2, Muhammad Rafiq1,2, Sarah Winterberg3, Tamara Papadakis1,2, Dominique Thomas9,10, Carlo Angioni10, Johannes Oberwinkler11, Vladimir Chubanov12, Thomas Gudermann12, Ulrich Gärtner2, Stefan Offermanns6,1, Burkhard Schütz3, Wolfgang Kummer1,2
1Excellence Cluster Cardio-Pulmonary Institute, Justus Liebig University Giessen, Giessen, Germany.
2Institute of Anatomy and Cell Biology, German Center for Lung Research, Justus Liebig University Giessen, Giessen, Germany.
3Institute of Anatomy and Cell Biology, Philipps University, Marburg, Germany
4Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany
5Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Goethe University Frankfurt, Frankfurt, Germany.
6Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
7Institute of Biochemistry Justus Liebig University Giessen, Giessen, Germany
8Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus Liebig University Giessen, Giessen, Germany.
9Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Frankfurt, Germany
10Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany.
11Philipps-Universität Marburg, Institut für Physiologie und Pathophysiologie, Marburg, Germany.
12Walther Straub Institute of Pharmacology and Toxicology, German Center for Lung Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Tóm tắt
The gallbladder stores bile between meals and empties into the duodenum upon demand and is thereby exposed to the intestinal microbiome. This exposure raises the need for antimicrobial factors, among them, mucins produced by cholangiocytes, the dominant epithelial cell type in the gallbladder. The role of the much less frequent biliary tuft cells is still unknown. We here show that propionate, a major metabolite of intestinal bacteria, activates tuft cells via the short-chain free fatty acid receptor 2 and downstream signaling involving the cation channel transient receptor potential cation channel subfamily M member 5. This results in corelease of acetylcholine and cysteinyl leukotrienes from tuft cells and evokes synergistic paracrine effects upon the epithelium and the gallbladder smooth muscle, respectively. Acetylcholine triggers mucin release from cholangiocytes, an epithelial defense mechanism, through the muscarinic acetylcholine receptor M3. Cysteinyl leukotrienes cause gallbladder contraction through their cognate receptor CysLTR1, prompting emptying and closing. Our results establish gallbladder tuft cells as sensors of the microbial metabolite propionate, initiating dichotomous innate defense mechanisms through simultaneous release of acetylcholine and cysteinyl leukotrienes.
