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Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis

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Abstract

Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3+ T cells and CD68+ macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1β and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing.

Key messages

  • Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption.

  • In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1β and TNFα.

  • In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes.

  • In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.

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Abbreviations

DSS:

Dextran sulfate sodium

IBD:

Inflammatory bowel disease

iNOS:

Inducible nitric oxide synthase

IL-1ß:

Interleukin-1 beta

NHE3:

Na+/H+ exchanger isoform 3

PDZK1:

PDZ domain-containing 1

TNFα:

Tumor necrosis factor alpha

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Acknowledgments

The authors thank Brigitte Riederer for fruitful discussions and valuable advice. The excellent technical assistance of D. Lischke and R. Strauss is gratefully acknowledged.

Source of funding

This work has been supported in part by funding from the “Ellen-Schmidt-Habilitation” program of the Equal Opportunities Office of the Hannover Medical School (to H.L.), grants from the German Research Council (SE460/19-1 and 21-1 to U.S.) and (JO395/2-2 to A.J.) and a grant from the Lower Saxony Ministry of Science and Culture (VW-Vorab to U.S.).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    Henrike Lenzen, Jiajie Qian, Michael P Manns & Ursula Seidler

  2. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

    Anne Jörns

  3. Centre of Anatomy, Hannover Medical School, Hannover, Germany

    Anne Jörns

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  1. Henrike Lenzen
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  2. Jiajie Qian
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  3. Michael P Manns
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  4. Ursula Seidler
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  5. Anne Jörns
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Contributions

HL, US, and AJ were involved in the design of the study, acquisition, and interpretation of data and drafting the article. JQ was involved in acquisition and analysis of data and revising the article critically for important intellectual content. MPM provided key support in interpretation of data and revising the article for important intellectual content.

Corresponding author

Correspondence to Henrike Lenzen.

Ethics declarations

All animal experiments were performed according to the national and institutional guidelines and were approved by the Local Institutional Animal Care and Research Advisory Committee at the Hannover Medical School and authorized by the local government for the regulation of animal welfare (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit, LAVES, No 33.12-42502-04-14/1641).

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Figure 1

Time course of the experiments, showing the three DSS cycles and anti-TNFα treatment. Control and DSS-treated mice received a corresponding number of IgG i.p. injections of an identical volume (100 μL) instead of anti-TNFα injections. (PNG 85 kb)

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Lenzen, H., Qian, J., Manns, M.P. et al. Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis. J Mol Med 96, 831–843 (2018). https://doi.org/10.1007/s00109-018-1658-1

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  • DOI: https://doi.org/10.1007/s00109-018-1658-1

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