IL11+ fibroblasts are implicated in nonresponse to anti-TNF-α via fibrosis in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is frequently accompanied by intestinal fibrosis, with nonresponse to long-term anti-TNF-α therapy occurring in approximately 23%-46% of patients. Integrated analysis of single-cell and bulk RNA-seq datasets revealed an expansion of IL11+ fibroblasts in inflamed intestine and their significant enrichment in nonresponders. 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, support vector machines, and random forest, to derive an IL11+ fibroblast-related gene signature effectively predicting nonresponse to anti-TNF-α in validation and test cohorts. IHC further confirmed the overexpression of IL-11 in nonresponders. 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-TNF-α 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 nonresponse to anti-TNF-α in IBD, thereby laying the foundation for precision medicine and targeted therapeutic strategies.