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. 2025 Jan 6;31(1):11-27.
doi: 10.1093/ibd/izae156.

Estrogen Receptor β Activation Mitigates Colitis-associated Intestinal Fibrosis via Inhibition of TGF-β/Smad and TLR4/MyD88/NF-κB Signaling Pathways

Fangmei Ling  1   2 , Yidong Chen  1 , Junrong Li  1 , Mingyang Xu  1 , Gengqing Song  3 , Lei Tu  1 , Huan Wang  1 , Shuang Li  1 , Liangru Zhu  1
Affiliations

Estrogen Receptor β Activation Mitigates Colitis-associated Intestinal Fibrosis via Inhibition of TGF-β/Smad and TLR4/MyD88/NF-κB Signaling Pathways

Fangmei Ling et al. Inflamm Bowel Dis. .

Abstract

Background: Intestinal fibrosis, a complex complication of colitis, is characterized by excessive extracellular matrix (ECM) deposition. Estrogen receptor (ER) β may play a role in regulating this process.

Methods: Intestinal tissue samples from stenotic and nonstenotic regions were collected from Crohn's disease (CD) patients. RNA sequencing was conducted on a mouse model to identify differentially expressed mRNAs. Histological, immunohistochemical, and semiquantitative Western blotting analyses were employed to assess ECM deposition and fibrosis. The roles of relevant pathways in fibroblast transdifferentiation, activity, and migration were examined.

Results: Estrogen receptor β expression was found to be downregulated in the stenotic intestinal tissue of CD patients. Histological fibrosis score, collagen deposition, and profibrotic molecules in the colon of an intestinal fibrosis mouse model were significantly decreased after activation of ERβ. In vitro, ERβ activation alleviated transforming growth factor (TGF)-β-induced fibroblast activation and migration, as evidenced by the inhibition of col1α1, fibronectin, α-smooth muscle actin (α-SMA), collagen I, and N-cadherin expression. RNA sequencing showed that ERβ activation affected the expression of genes involved in ECM homeostasis and tissue remodeling. Enrichment analysis of differentially expressed genes highlighted that the downregulated genes were enriched in ECM-receptor interaction, TGF-β signaling, and Toll-like receptor (TLR) signaling. Western blotting confirmed the involvement of TGF-β/Smad and TLR4/MyD88/NF-κB signaling pathways in modulating fibrosis both in vivo and in vitro. The promoter activity of TGF-β1 and TLR4 could be suppressed by ERβ transcription factor.

Conclusion: Estrogen receptor β may regulate intestinal fibrosis through modulation of the TGF-β/Smad and TLR4/MyD88/NF-κB signaling pathways. Targeting ERβ activation could be a promising therapeutic strategy for treating intestinal fibrosis.

Keywords: Crohn’s disease; TGF-β; TLR4; estrogen receptor β; intestinal fibrosis.

Plain language summary

Imagine your gut is like a garden hose. In Crohn’s disease, parts of this “hose” get narrow and blocked. Scientists found less of a helpful protein, ERβ, in these narrow areas. In an experiment with mice, boosting ERβ lessened the gut damage and reduced the buildup of collagen—the “blockage” in our hose analogy. Also, ERβ calmed overactive cells causing these issues, acting like a peacemaker. This protein “talks” to cells through channels called TGF-β/Smad and TLR4/NF-κB, telling them to relax. This could be a new way to tackle such gut problems!

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