IL11+ fibroblasts are implicated in nonresponse to anti–TNF-α via fibrosis in inflammatory bowel disease
Wangyue Li, Wei Huang, Jiaxin Wang, Yiwen Tu, Qidi Yang, Yao Zhou, Zile Zhang, Haiming Zhuang, Yubei Gu, Duowu Zou, Yao Zhang
Wangyue Li, Wei Huang, Jiaxin Wang, Yiwen Tu, Qidi Yang, Yao Zhou, Zile Zhang, Haiming Zhuang, Yubei Gu, Duowu Zou, Yao Zhang
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Research Article Gastroenterology Inflammation

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

Abstract

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.

Authors

Wangyue Li, Wei Huang, Jiaxin Wang, Yiwen Tu, Qidi Yang, Yao Zhou, Zile Zhang, Haiming Zhuang, Yubei Gu, Duowu Zou, Yao Zhang

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Figure 1

Cellular composition of the inflamed gut in IBD at single-cell resolution.

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Cellular composition of the inflamed gut in IBD at single-cell resolutio...
(A) Schematic of the integrated scRNA-seq dataset (including GSE134809, SCP259, and SCP1884) comprising 57 patients with CD, 18 with UC, and 25 healthy controls as well as 75 healthy, 175 noninflamed, and 82 inflamed intestinal tissue samples from these patients, where 505,578 cells were identified for analysis. Created with BioRender.com. (B) UMAP plot showing 6 intestinal cell subclusters from the integrated scRNA-seq dataset, including 96,139 cells from healthy control group, 286,897 from noninflamed group, and 122,542 from inflamed group, totaling 505,578 cells. (C) Bar graph showing the proportions of 6 intestinal cell subclusters across the inflamed, noninflamed, and healthy control groups. (D) Changes in the inflammation score (Δ Inflammation score = inflammation score of a subcluster in the inflamed group minus inflammation score of a subcluster in the healthy control group) for each intestinal cell subcluster. (E) UMAP plot showing 10 stromal cell subclusters from the integrated scRNA-seq dataset, including 12,555 cells from healthy control group, 30,695 from noninflamed group, and 7,802 from inflamed group, totaling 51,052 cells. (F) Dot plot showing the characteristic marker genes for each stromal cell subcluster. Dot color and size represent average expression level and expression percentage, respectively. (G) Bar graph showing the proportions of stromal cell subclusters across the inflamed, noninflamed, and healthy control groups. (H) Box plots showing the inflammation scores for each stromal cell subcluster. Median, quartiles, and range are shown. (I) Proportion of IL11+ fibroblasts in the healthy control, noninflamed, and inflamed groups. Statistical significance was determined by Wilcoxon’s rank-sum test (NS P > 0.05; ****P ≤ 0.0001).