Introduction

Endoscopic submucosal dissection (ESD) is an effective treatment for superficial esophageal cancer, but postoperative stenosis remains a significant concern. Particularly, probability of the stenosis is less investigated in cases with a 50%-75% circumferential mucosal defect.

Aims & Methods

This study aimed to identify influential factors for postoperative stenosis after the moderate circumferential resection in esophageal ESD. This multi-center retrospective observational study analyzed data from 513 patients across 19 institutions who underwent esophageal ESD from April 2018 to March 2022 and showed 50% to 75% of the circumferential mucosal defect. We firstly overviewed the current status on the postoperative stenosis, the steroid use, and postoperative adverse events in these patients. Subsequently, we identified influential factors for postoperative stenosis. Patients were categorized into stenosis and no stenosis groups, and univariate and multivariate analyses were performed for each parameter. We further investigated influential factors of stenosis in two cohorts: steroid and no steroid groups. Finally, the parameters were compared between the steroid and no steroid groups to assess the tendency of the steroid use in general practice.

Results

Postoperative stenosis was observed in 28 cases (5%). Univariate analysis comparing the stenosis group (n = 28) and no stenosis group (n = 485) revealed significant differences in the prior endoscopic treatment near the lesion (p = 0.02), cervical esophageal location (p = 0.04), defect circumference (p =0.01), and procedure duration (p = 0.02). There was no significant difference in the steroid use between two groups. Multivariate analyses identified history of prior endoscopic treatment close to the lesion (p = 0.01, odds ratio [OR], 5.10), cervical esophageal lesions (p = 0.03, OR, 3.97), large circumferential defect (p <0.01, OR, 3.78), and longer procedure duration (p <0.01, OR, 3.83) as independent risk factors for stenosis formation. Among the steroid group, significant associations of the postoperative stenosis were revealed with the prior endoscopic treatment near the lesion (p = 0.02), cervical esophageal location (p = 0.04), and >5/8 of defect circumference (p = 0.02). In the no steroid group, only the procedure duration (p = 0.01) showed a significant difference between the stenosis and non-stenosis groups. Comparison between the steroid (n = 223) and no steroid groups (n = 290) revealed significant differences in the prior endoscopic treatment near the lesion (p <0.01), cervical esophageal lesions (p <0.01), and resected specimen dimensions (p <0.01). The stenosis rates were 7% in the steroid group and 4% in the no steroid group, without a significant difference. No significant difference in adverse events was observed between the two groups.

Conclusion

In esophageal ESD with a 50%-75% circumferential mucosal defect, the steroid was used in over 40% of patients, and postoperative stenosis still occurred in 5%. Because wider circumference, location of the cervical esophagus, prior endoscopic treatment close to the lesion, and prolonged operative time were identified as independent risk factors on the stenosis, steroid therapy should be preferred in these cases. Particularly, lesions with a history of endoscopic treatment, on cervical esophagus, and with >5/8 of defect circumference should require more aggressive countermeasures than currently applied.

Introduction

Epithelial barrier dysfunction is a hallmark of inflammatory bowel diseases (IBD), contributing to increased permeability, microbial translocation, and sustained mucosal inflammation^1,2. Targeting barrier restoration has emerged as a promising therapeutic strategy³. Gallic acid, a dietary polyphenol with known anti-inflammatory and antioxidative properties, has shown potential in modulating mucosal responses⁴. To investigate its impact on epithelial integrity under inflammatory stress, we utilized intestinal organoids as a physiologically relevant ex vivo model system.

Aims & Methods

The aim of this study was to investigate the potential of gallic acid to restore intestinal epithelial barrier function under inflammatory conditions, using colonic epithelial organoids and integrating transcriptomic and permeability analyses.
The study was approved by the Kaunas Regional Biomedical Research Ethics Committee (protocol no. BE-2-31). Inflamed differentiated colonic epithelial organoids were established from a patient with ulcerative colitis (UC) and non-IBD control individual by exogenous stimulation with TNF-α and IFN-γ (10 ng/mL each) for 24 hours. For gallic acid (GA) screening, organoids were pre-treated with metabolite (100 μM) for 1 hour prior to inflammation induction and co-treated during the induction period. Subsequently, organoids were either processed for mRNA sequencing (1×75 bp, NextSeq 550, Illumina) or subjected to a FITC-Dextran (4kDa) assay. RNA-seq data was processed, analyzed, and visualized using nf-core/RNAseq pipeline and RStudio. Images for permeability assay analysis were acquired using an inverted fluorescence microscope (Zeiss Axio Observer 7), processed with ImageJ, and analyzed and visualized in RStudio.

Results

Principal component analysis of transcriptomic profiles from both UC and non-IBD organoids revealed clear sample clustering driven by stimulation. Differential gene expression and Gene set enrichment (GSEA) analyses indicated a more pronounced cell response to both treatments in UC organoids compared to non-IBD organoids. Inflammation activated immune (CXCL9/10/11, CX3CL1), interferon (IFI44, SOCS1, NOS2), and defense genes (GBP4, GBP5, OAS2), while downregulating metabolic genes (FABP6, CFTR, HMGCS2) in both groups. Gene Ontology-based GSEA confirmed immune pathway enrichment and lipid metabolism suppression in inflamed cultures. In total, 3,148 and 1,479 DEGs were identified in inflamed UC and non-IBD organoids, respectively. GA treatment modulated 2,144 and 384 genes (e.g., LYPD8, MKI67, MT-ATP6, CXCL14, CCL22) in these groups, suggesting potential to rebalance inflammation and metabolism. GA co-treatment enhanced epithelial integrity in UC organoids via upregulation of cell junction, peptide hormone processing, and immune-related pathways. In non-IBD organoids, GA promoted cell adhesion pathways, supporting epithelial cohesion. Functional permeability analysis confirmed GA’s protective role, as supported by transcriptomic data. Mean percentages of FITC-Dextran-permeable organoids were 16.02% (untreated), 86.08% (inflamed), and 42.58% (inflamed + GA). A trend toward statistical significance (Wilcoxon p = 0.125) was observed in both untreated vs. inflamed and inflamed vs. inflamed + GA comparisons.

Conclusion

In conclusion, gallic acid modulates inflammatory and metabolic pathways during colonic inflammation and enhances epithelial barrier integrity.
Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470).

References

¹Jostins, L., et al. (2012). Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119–124. https://doi.org/10.1038/nature11582
²Cleynen, I., et al. (2016). Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: A genetic association study. The Lancet, 387(10014), 156–167. https://doi.org/10.1016/S0140-6736(15)00465-1
³Vieujean, S., et al. (2025). Understanding the therapeutic toolkit for inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology. Online ahead of print. https://doi.org/10.1038/s41575-024-01035-7
⁴Tian, B., Ye, P., Zhou, X., Hu, J., Wang, P., Cai, M., Yang, K., Sun, P., & Zou, X. (2025). Gallic acid ameliorated chronic DSS-induced colitis through gut microbiota modulation, intestinal barrier improvement, and inflammation. Molecular Nutrition & Food Research. Online ahead of print. https://doi.org/10.1002/mnfr.70024