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, Mario M Zaiss, 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, Mario M Zaiss
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.
Conflict of interest statement
The authors declare no competing interests.
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References
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