Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 8;25(1):568.
doi: 10.1186/s12876-025-04146-w.

Serological assessment of PRO-C16 (type XVI collagen formation) reflects intestinal fibrostenotic strictures in patients with crohn's disease

Joachim H Mortensen  1 , M Lindholm  2 , L Langholm  3   4 , P Giuffrida  3   4 , D Ruane  5 , T Manon-Jensen  2 , G Mazza  6 , F Caprioli  7   8 , L Pastorelli  9 , A-C Bay-Jensen  2 , M Pinzani  6   10 , M A Karsdal  2 , A Di Sabatino  3   6
Affiliations

Serological assessment of PRO-C16 (type XVI collagen formation) reflects intestinal fibrostenotic strictures in patients with crohn's disease

Joachim H Mortensen et al. BMC Gastroenterol. .

Abstract

Background: Fibrostenotic stricturing disease affects 30-50% of patients with Crohn's disease (CD), leading to intestinal resection. Currently, there exists a great medical need to identify biomarkers related to fibrostenotic strictures for optimized patient management. Thus, we investigated PRO-C16 as a biomarker for intestinal fibrosis in patients with CD.

Methods: Human serum from two independent cohorts of CD patients (cohort 1: n = 44, cohort 2: n = 52), healthy subjects (n = 37), and serum from a chronic rat dextran sodium sulfate (DSS) colitis model were included. The Montreal classification for CD disease behavior was applied for patient phenotyping.

Results: PRO-C16 was elevated in patients with CD compared to healthy donors (P < 0.001), and in CD patients with fibrostenotic strictures in both cohorts. Furthermore, PRO-C16 was able to separate CD patients with strictures(B2) from CD patients without strictures (B1 and B3) (Cohort 1 [P < 0.01, AUC:0.75], and Cohort 2 [P < 0.05, AUC:0.71). In the chronic DSS rat colitis model, PRO-C16 was elevated after the second and fourth cycles of DSS, reflecting collagen deposition in that model.

Conclusion: The biomarker PRO-C16 was associated with a stricturing disease phenotype, indicating that PRO-C16 may be a potential marker of intestinal fibrosis in CD, with the potential to aid in the clinical development of novel stromal-immune therapeutic agents.

Keywords: Biomarkers; COL16; Collagen; Crohn's disease; Intestinal fibrosis; Stenosis; Type XVI collagen.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: All patients filed informed consent, and the study was approved by the local ethical committee (Ethics committee of the Fondazione IRCCS, protocol number 20100039131, approval no. E_20100039131). The DSS in vivo study’s ethical guidelines were followed in accordance with the legislation and under the ethical approval of the “Dyreforsøgstilsynet” (agreement number: 2017-15-0201-01171), and male Sprague Dawley rats were purchased from Envigo+++. This study adheres to the Declaration of Helsinki for ethics approval and patient consent to participate. Consent for publication: Not applicable. Competing interests: J.H. Mortensen, L. Langholm, T. Manon-Jensen, A-C. Bay-Jensen, and M.A. Karsdal are employed at Nordic Bioscience A/S which is a company involved in the discovery and development of biochemical biomarkers. T. Manon-Jensen, A-C. Bay-Jensen, and M.A. Karsdal own stocks in Nordic Bioscience. D. Ruane is employed at Janssen Immunology which is a company involved in drug development.

Figures

Fig. 1
Fig. 1
Graphical representation of FACIT type XVI collagen’s association with collagen fibrils, and how the PRO-C16 analyte is generated
Fig. 2
Fig. 2
Serum levels of PRO-C16 (type XVI collagen), in healthy donors and Crohn’s disease (CD) patients (A: cohort 1 [n=44], B: cohort 2 [n=57]), C-D: cohort 1 and 2, CDAI inactive and active disease, E-F. correlation to CRP and fecal calprotectin for cohort 1. Asterisk (*) indicates significant differences: *P<0.05, **P<0.01, ***P<0.001. Data are depicted as interquartile range [IQR] with 10–90 percentiles. Mann-Whitney UI test, Kruskal-Wallis test with Dunn’s test for multiplicity, and Spearman's Rho correlation were applied
Fig. 3
Fig. 3
Differences in PRO-C16 serum levels in Crohn’s disease (CD [n=96) phenotypes and healthy donors (HD). Montreal classification of disease behavior was applied to stratify the patients to luminal (B1), fibrostenotic strictures (B2), and fistulizing disease (B3). A) cohort 1 and B) cohort 2, Asterisk (*) indicate significant differences:*P<0.05, **P<0.01, ***P<0.001. Data are depicted as interquartile range [IQR] with 10–90 percentiles. Kruskal-Wallis test with Dunn’s test for multiplicity was applied
Fig. 4
Fig. 4
Serum levels of PRO-C16 (type XVI collagen), in healthy donors (HD, n=37) and Crohn’s disease (CD, n=96) stratified according to the Montreal classification of disease behavior were applied: luminal (B1), fibrostenotic strictures (B2), and fistulizing disease (B3) for cohort 1 and cohort 2. Receiver operator characteristics-curve (ROC-curve) analysis demonstrates that the biomarker PRO-C16 significantly separates stricturing CD (B2) vs. luminal/penetrating CD (B1/B3). Asterisk (*) indicates significant differences: *P<0.05,**P<0.01, ***P<0.001. Error bars depict the standard error of the mean (SEM)
Fig. 5
Fig. 5
Collagen deposition in healthy control rats (A-B) and DSS rats (C-J). The tissue was stained with Masson Trichrome, where blue stains collagens, red/pink stains muscle fibers, and the cytoplasm of e.g., the epithelium. A control rat at day 7, B control rat at day 56, C Cycle 1 DSS rat at day 7, D Cycle 1 DSS rat at day 14, E Cycle 2 DSS rat at day 21, F Cycle 2 DSS rat at day 28, G Cycle 3 DSS rat at day 35, H Cycle 3 DSS rat at day 42, I Cycle 4 DSS rat at day 49, J Cycle 4 DSS rat at day 56. Asterisks depict the intestinal lumen
Fig. 6
Fig. 6
Results from the Chronic DSS colitis study with four cycles of DSS. A Differences in body weight between DSS rats and control rats, B Disease activity index (DAI) between DSS rats and control rats, C Water consumption, D food consumption, E PRO-C16 levels depicted as the change from baseline between DSS rats and control rats. Asterisk (*) indicates significant difference: *P<0.05, **P<0.01, ***P<0.001. Error bars depict the standard error of the mean (SEM). Kruskal-Wallis test with Dunn’s test for multiplicity was applied
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Bos S, Laukens D. Metabolic modulation during intestinal fibrosis. J Dig Dis. 2020;21:319–25. - PubMed
    1. Giuffrida P, Pinzani M, Corazza GR, Sabatino A, Di. Biomarkers of intestinal fibrosis– one step towards clinical trials for stricturing inflammatory bowel disease. United Eur Gastroenterol J. 2016;4:523–30. - PMC - PubMed
    1. Yoo JH, Holubar S, Rieder F. Fibrostenotic strictures in Crohn’s disease. Intest Res. 2020;18:379–401. - PMC - PubMed
    1. Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in crohn’s disease - algorithm for practical management. Aliment Pharmacol Ther. 2016;43:30–51. - PubMed
    1. Ratzinger S, Eble JA, Pasoldt A, Opolka A, Rogler G, Grifka J, et al. Collagen XVI induces formation of focal contacts on intestinal myofibroblasts isolated from the normal and inflamed intestinal tract. Matrix Biol. 2010;29:177–93. - PubMed

MeSH terms

LinkOut - more resources