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Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms

Author

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  • Sina Riemschneider

    (Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
    These authors contributed equally to this work.)

  • Maximilian Hoffmann

    (Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
    These authors contributed equally to this work.)

  • Ulla Slanina

    (Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany)

  • Klaus Weber

    (AnaPath GmbH, CH-4410 Liestal, Switzerland)

  • Sunna Hauschildt

    (Faculty of Life Sciences, University of Leipzig, 04103 Leipzig, Germany)

  • Jörg Lehmann

    (Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
    Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, 04103 Leipzig, Germany)

Abstract

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are multifactorial inflammatory disorders of the gastrointestinal tract, characterised by abdominal cramps, bloody diarrhoea, and anaemia. Standard therapies, including corticosteroids or biologicals, often induce severe side effects, or patients may develop resistance to those therapies. Thus, new therapeutic options for IBD are urgently needed. This study investigates the therapeutic efficacy and safety of two plant-derived ligands of the aryl hydrocarbon receptor (AhR), quercetin (Q), and indol-3-carbinol (I3C), using a translationally relevant mouse model of IBD. Q and I3C are administered by gavage to C57BL/6 wild-type or C57BL/6 Ahr -/- mice suffering from chronic colitis, induced by dextran sulphate sodium (DSS). The course of the disease, intestinal histopathological changes, and in-situ immunological phenotype are scored over 25 days. Our results show that both Q and I3C improved significantly clinical symptoms in moderate DSS colitis, which coincides with a significantly reduced histopathological score. Even in severe DSS colitis I3C, neither Q nor the therapy control 6-thioguanine (6-TG) can prevent a fatal outcome. Moreover, treatment with Q or I3C restored in part DSS-induced loss of epithelial integrity by induction of tight-junction proteins and reduced significantly gut inflammation, as demonstrated by colonoscopy, as well as by immunohistochemistry revealing lower numbers of neutrophils and macrophages. Moreover, the number of Th17 cells is significantly reduced, while the number of Treg cells is significantly increased by treatment with Q or I3C, as well as 6-TG. Q- or I3C-induced amelioration of colitis is not observed in Ahr -/- mice suggesting the requirement of AhR ligation and signalling. Based on the results of this study, plant-derived non-toxic AhR agonists can be considered promising therapeutics in IBD therapy in humans. However, they may differ in terms of efficacy; therefore, it is indispensable to study the dose-response relationship of each individual AhR agonist also with regard to potential adverse effects, since they may also exert AhR-independent effects.

Suggested Citation

  • Sina Riemschneider & Maximilian Hoffmann & Ulla Slanina & Klaus Weber & Sunna Hauschildt & Jörg Lehmann, 2021. "Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms," IJERPH, MDPI, vol. 18(5), pages 1-17, February.
    • Handle: RePEc:gam:jijerp:v:18:y:2021:i:5:p:2262-:d:505477
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    References listed on IDEAS

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    1. Estelle Bettelli & Yijun Carrier & Wenda Gao & Thomas Korn & Terry B. Strom & Mohamed Oukka & Howard L. Weiner & Vijay K. Kuchroo, 2006. "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, Nature, vol. 441(7090), pages 235-238, May.
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