Abstract Background Disruption of the epithelial barrier and mucosal immune homeostasis is central to ulcerative colitis (UC) pathogenesis. Although single-cell RNA sequencing (scRNA-seq) has enhanced understanding of intestinal cellular heterogeneity, data on anti–tumor necrosis factor (anti-TNF)–related cellular responses in Asian UC patients remain limited. This study aimed to characterize mucosal immune, stromal, and epithelial cell subsets associated with responsiveness to anti-TNF therapy in Korean UC patients. Methods This prospective two-center study enrolled biologic-naïve patients with moderate-to-severe UC before initiation of anti-TNF therapy. Sigmoid colon biopsies from 11 patients underwent scRNA-seq. Clinical response at 52 weeks defined treatment groups: responders maintained clinical remission (Mayo ≤2, with no individual subscore 1), whereas non-responders required biologic switch due to uncontrolled disease activity. Cell clustering identified major immune, stromal, and epithelial compartments, and cell composition was compared between responders and non-responders. Results scRNA-seq revealed distinct mucosal cellular landscapes between responders and non-responders. Among immune cells, CD8 naïve T cells differed significantly between the two groups (p 0.05), and CD4 naïve T cells were markedly increased in non-responders. These findings suggest preserved immune regulation in responders but inefficient T-cell differentiation and persistent inflammatory signaling in non-responders. Stromal analysis demonstrated decreased lamina propria and subepithelial fibroblasts in non-responders, indicating impaired structural recovery and reduced tissue support. In the epithelial compartment, colonic enterocytes were significantly reduced in non-responders (p 0.05), reflecting sustained epithelial barrier damage. Tuft and enteroendocrine cells appeared more abundant in non-responders, suggesting compensatory but functionally insufficient activation (Figure 1). Conclusion Anti-TNF responsiveness in UC is governed by the coordinated restoration of immune balance, stromal integrity, and epithelial repair. Responders exhibited normalization of naïve T-cell composition and partial preservation of epithelial structure, whereas non-responders showed naïve CD4 accumulation, enterocyte loss, and stromal depletion—reflecting persistent fibro-epithelial dysfunction uncorrected by TNF blockade. Conflict of interest: Kim, Jin-Oh: No conflict of interest Prof. Dr. Jeon, Seong Ran: Source of funding: This work was supported by the National Research Foundation (NRF) of Korea grant funded by the Korea government (MSIT) (RS-2021-NR066198) and the Research Supporting Program of the Korean Association for the Study of Intestinal Diseases for 2023 (2023-2025). Jung, Yunho: No conflict of interest Kim, Hyun Gun: No conflict of interest Park, Jung-Bin: No conflict of interest Ko, Bong Min: No conflict of interest Hwang, Woo Chang: No conflict of interest
Kim et al. (Thu,) studied this question.