IL11⁺ fibroblasts are implicated in non-response to anti-TNFα via fibrosis in inflammatory bowel disease.

Abstract

Inflammatory bowel disease (IBD) is frequently accompanied by intestinal fibrosis, with non-response (NR) to long-term anti-tumor necrosis factor α (anti-TNFα) therapy occurring in approximately 23-46% of patients. Integrated analysis of single-cell and bulk RNA sequencing datasets revealed an expansion of IL11⁺ fibroblasts in inflamed intestine and their significant enrichment in non-responders. We further identified IL11⁺ fibroblasts as a central communication hub that engaged in extensive crosstalk with monocytes and may contribute to inflammatory amplification and fibrotic remodeling. Additionally, we employed machine learning approaches including least absolute shrinkage and selection operator (LASSO), support vector machines (SVM), and random forest (RF) to derive an IL11⁺ fibroblast-related gene signature effectively predicting NR to anti-TNFα in validation and test cohorts. IHC further confirmed the overexpression of IL-11 in non-responders. The signature genes we found are not only associated with immune and inflammatory responses but also with fibrosis, indicating a robust association between fibrosis and anti-TNFα treatment failure. In summary, this study highlights the important role of IL11⁺ fibroblasts in orchestrating both inflammation and fibrosis and provides an applicable model for predicting NR to anti-TNFα in IBD, thereby laying the foundation for precision medicine and targeted therapeutic strategies.