Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

Narges Tajik, Michael Frech, Oscar Schulz, Fabian Schälter, Sébastien Lucas, Vugar Azizov, Kerstin Dürholz, Franziska Steffen, Yasunori Omata, Andreas Rings, Marko Bertog, Aroldo Rizzo, Aida Iljazovic, Marijana Basic, Arnd Kleyer, Stephan Culemann, Gerhard Krönke, Yubin Luo, Klaus Überla, Udo S. Gaipl, Benjamin Frey, Till Strowig, Kerstin Sarter, Stephan C. Bischoff, Stefan Wirtz, Juan D. Cañete, Francesco Ciccia, Georg Schett and Mario M. Zaiss ()
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Narges Tajik: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Michael Frech: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Oscar Schulz: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Fabian Schälter: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Sébastien Lucas: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Vugar Azizov: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Kerstin Dürholz: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Franziska Steffen: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Yasunori Omata: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Andreas Rings: University of Hohenheim
Marko Bertog: Friedrich-Alexander University Erlangen-Nürnberg
Aroldo Rizzo: University of Palermo
Aida Iljazovic: Helmholtz Centre for Infection Research
Marijana Basic: Hannover Medical School
Arnd Kleyer: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Stephan Culemann: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Gerhard Krönke: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Yubin Luo: West China Hospital
Klaus Überla: Deutsches Zentrum für Immuntherapie (DZI)
Udo S. Gaipl: Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen
Benjamin Frey: Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen
Till Strowig: Helmholtz Centre for Infection Research
Kerstin Sarter: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Stephan C. Bischoff: University of Hohenheim
Stefan Wirtz: Deutsches Zentrum für Immuntherapie (DZI)
Juan D. Cañete: Hospital Clínic de Barcelona e IDIBAPS
Francesco Ciccia: University of Palermo
Georg Schett: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Mario M. Zaiss: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

Date: 2020
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DOI: 10.1038/s41467-020-15831-7

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