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A Serological Biomarker of Laminin Gamma 1 Chain Degradation Reflects Altered Basement Membrane Remodeling in Crohn’s Disease and DSS Colitis

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Abstract

Background

The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane.

Aims

We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn’s disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis.

Methods

Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5–6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation.

Results

Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p < 0.0001). LG1M distinguished CD patients from healthy subjects, with an area under the curve (AUC) of 0.81 (p < 0.0001). Serum LG1M was decreased in DSS rats compared to controls 2 days after DSS withdrawal, and increased upon reversal of the disease.

Conclusions

Increased serum LG1M in active and inactive CD patients supports the evidence of altered LM expression in both inflamed and non-inflamed tissue. Moreover, lower LG1M levels in the early healing phase of DSS-induced colitis may reflect ongoing mucosal repair.

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Funding

This work was supported by the Danish Research Foundation and the Innovation Fund Denmark.

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Authors and Affiliations

  1. Biomarkers and Research, Nordic Bioscience, Herlev hovedgade 205-207, 2730, Herlev, Denmark

    Majken Lindholm, Tina Manon-Jensen, Morten A. Karsdal & Joachim H. Mortensen

  2. Department of Medical Gastroenterology, University of Southern Denmark and Odense University Hospital, Odense, Denmark

    Majken Lindholm, Aleksander Krag & Jens Kjeldsen

  3. First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy

    Antonio Di Sabatino & Paolo Giuffrida

  4. Institute for Liver and Digestive Health, University College of London, London, UK

    Giuseppe Mazza & Massimo Pinzani

  5. Department of Surgical Pathology, Odense University Hospital, Odense, Denmark

    Gunvor I. Madsen

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  1. Majken Lindholm
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  2. Antonio Di Sabatino
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Contributions

ML designed the animal study, collected data, performed data analysis, interpreted data, drafted the manuscript, and revised critically for important intellectual content. ADS, GM, PG, and MP designed the clinical study, collected data, and revised critically for important intellectual content. GIM scored the histological specimens and revised critically for important intellectual content. TMJ, AK, MAK, JK, and JHM designed the study, interpreted data, and revised critically for important intellectual content.

Corresponding author

Correspondence to Majken Lindholm.

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Conflict of interest

ML, TMJ, MAK, and JHM are full-time employees at Nordic Bioscience. TMJ and MAK hold stock in Nordic Bioscience. Nordic Bioscience is a privately owned small-medium-sized enterprise, partly focused in the development of biomarkers for connective tissue disorders and rheumatic diseases. None of the authors received any kind of financial benefits or other bonuses for the work described in this manuscript. ADS, GM, GIM, PG, MP, AK, and JK have no financial disclosures or conflicts of interest.

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Summary: This manuscript reports an altered remodeling of the basement membrane protein laminin γ1 chain in CD patients and in DSS rats. This is done with the use of a serological biomarker, LG1M, a MMP-9 generated neo-epitope degradation fragment of the LMγ1 chain.

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Lindholm, M., Di Sabatino, A., Manon-Jensen, T. et al. A Serological Biomarker of Laminin Gamma 1 Chain Degradation Reflects Altered Basement Membrane Remodeling in Crohn’s Disease and DSS Colitis. Dig Dis Sci 67, 3662–3671 (2022). https://doi.org/10.1007/s10620-021-07252-3

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