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. 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.

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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
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