Fibroblast-derived interleukin-11 as a potential biomarker for intestinal fibrostenosis in Crohn’s disease

Background: Intestinal fibrosis-associated stricture can lead to bowel complications and subsequent surgeries in patients with Crohn’s disease (CD), but there are no widely accepted biomarkers for intestinal fibrostenosis. Objectives: This study aims to investigate the value of interleukins (IL) in detecting CD-related intestinal fibrostenosis. Design: This is an observational study. Methods: Transcriptomic profiling was performed from paired CD surgical resections containing non-involved and fibrostenotic segments. Data were integrated with a public dataset and a Luminex-based serum assay to identify fibrosis-related interleukins, which were further validated at mRNA and protein levels. Correlations with clinical indicators and surgical outcome were analyzed. Lastly, an in vitro assay was used to evaluate the pro-fibrotic effect of the candidate interleukin. Results: Bulk RNA-sequencing and public dataset revealed increased expression of IL11 in the fibrostenotic intestinal segments of CD patients, which was further validated by real-time polymerase chain reaction and immunohistochemistry. The serum Luminex assay showed that serum IL11 is significantly increased in stricturing CD patients compared to that in non-stricturing CD patients. Clinically, serum IL11 was correlated with disease behavior ( r = 0.343, p = 0.006), and increased IL11 expression was linked to a higher risk of subsequent surgery ( log-rank p = 0.0055 ). Furthermore, single-cell RNA sequencing revealed that IL11 and its receptor IL11RA were mainly expressed by fibroblasts. In vitro, IL11 functionally promoted intestinal fibrosis. Conclusion: IL11, mainly derived from fibroblasts, is enriched in fibrostenotic tissue of CD and promotes intestinal fibrosis. IL11 may serve as a potential biomarker for CD fibrostenosis.