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The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons

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Abstract

Background

Transient receptor potential vanilloid type-1 (TRPV1)-expressing sensory neurons release neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), which play a crucial role in the pathomechanism of experimental colitis. We investigated whether innervation density and neuropeptide release were responsible for the proximodistal aggravation of murine dextran-sulfate-sodium-salt (DSS) colitis.

Methods

Whole mount TRPV1/CGRP immunostained mouse colon preparations were semiquantitatively analyzed. TRPV1 activation by capsaicin and acidic solution (pH 5.1) induced colonic CGRP/SP release, measured by EIA. Single cell quantitative PCR was employed to measure TRPV1 expression levels in DiI-labeled colonic dorsal root ganglion (DRG) neurons. The proximodistal gradient of DSS colitis severity was investigated in WT, CGRP−/−, SP−/−, and resiniferatoxin (RTX)-desensitized mice, employing mouse endoscopy, histology, and body weight measurement.

Results

TRPV1/CGRP-positive nerve fiber density was increased in the distal colon wall. CGRP/SP release induced by TRPV1 activation from the distal colon was greater than that from the proximal colon. This gradient further increased in colitis. TRPV1 gene expression increased in colonic DRGs projecting to the distal, compared to that in colonic DRGs projecting to the proximal colon, and was further enhanced during colitis. In contrast to WT and CGRP−/− mice, SP−/− and RTX-desensitized mice showed amelioration of DSS colitis accompanied by a loss of the proximodistal gradient of inflammation.

Conclusions

The spatial correlation among increased colonic innervation density, TRPV1 receptor expression, stimulated SP release, and colitis severity suggested that TRPV1/SP-expressing sensory neurons should be considered as a therapeutic target in human ulcerative colitis.

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Acknowledgments

We thank I. Izydorczyk, A. Kuhn and S. Haux-Oertel for technical assistance, J. Schramm and R. Fischer for excellent maintenance of animal breeding and D. Metzner for graphical assistance (Institute of Physiology and Pathophysiology). Thank you to S. Groß for help with single cell PCR measurements. Thanks also to A. Hecht, K. Loeschner and H. Symowski for preparing the histological slides (Institute of Anatomy I). P.W.R. and M.A.E. were supported by the Federal Ministry of Education and Research (BMBF0315449C); M.A.E. received additional support from the Johannes und Frieda Marohn-Stiftung of the Friedrich-Alexander-Universität Erlangen-Nürnberg. The mouse endoscope was funded by Universitätsbund Erlangen-Nürnberg e.V.

Conflict of interest

None.

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Authors and Affiliations

  1. Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054, Erlangen, Germany

    Matthias A. Engel, Mohammad Khalil, Sonja M. Mueller-Tribbensee & Peter W. Reeh

  2. First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany

    Matthias A. Engel, Mohammad Khalil, Christoph Becker & Markus F. Neurath

  3. Institute of Anatomy I, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstr. 9, 91054, Erlangen, Germany

    Winfried L. Neuhuber

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Correspondence to Matthias A. Engel.

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Engel, M.A., Khalil, M., Mueller-Tribbensee, S.M. et al. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J Gastroenterol 47, 256–265 (2012). https://doi.org/10.1007/s00535-011-0495-6

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