Feng Jing, He Li-Na, Yao Ruchen, Qiao Yuqi, Yang Tian, Cui Zhe, Meng Xiangjun, Tong Jinlu, Jia Keyu, Zuo Zhixiang, Shen Jun
Department of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Inflammatory Bowel Disease Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
J Adv Res. 2024 Dec 26. doi: 10.1016/j.jare.2024.12.042.
In Crohn's disease (CD), lesions are mainly distributed in a segmental manner, with the primary sites of involvement being the ileum and colon. Heterogeneity in colon and ileum results in location-specific clinical presentations and therapeutic responses. Mucosal healing tends to be more readily and quickly achieved in the colon than in the ileum, where lesions are more likely to develop into complex behaviors. The heterogeneity of colon and ileum in CD, which is essential for tailored therapeutic approaches, has not yet been systematically illustrated.
CD presents with unique intestinal lesions, mainly impacting the terminal ileum and colon. It is essential to comprehend the diversity in pathogenesis and treatment response among various segments.
We conducted comparative single-cell RNA sequencing analysis in treatment-naïve CD patients, concentrating on the colon and ileum.
A novel subset of epithelial cells expressing high levels of DUOX2 and DUOXA2 (DUOX2-epi) was discovered. This DUOX2-epi subcluster predominantly distributed in the tip epithelium of the inflamed colon, potentially in response to microbial infection, as evidenced by the significant enrichment of inflammatory and microbial response pathways. The colonic and ileal DUOX2-epi subsets trigger inflammatory responses through distinct mechanisms. The colonic DUOX2-epi primarily affects monocytes via the SAA1-FPR2 ligand-receptor interaction, whereas the ileal DUOX2-epi directly interacts with regulate T cells through the CXCL16-CXCR6 ligand-receptor pair. Moreover, the cell-cell communication networks involving DUOX2-epi in the colon and ileum can help predict the location-specific effects of biological therapies.
This study delves into the heterogeneity within the ileum and colon of Crohn's disease at the single-cell level, identifying a new epithelial subset DUOX2-epi. Predictive gene modules tailored to different locations for biological therapies are developed as well, based on the cell-cell communication network modulated by DUOX2-epi.
在克罗恩病（CD）中，病变主要呈节段性分布，主要受累部位为回肠和结肠。结肠和回肠的异质性导致了特定部位的临床表现和治疗反应。与回肠相比，结肠黏膜愈合往往更容易、更快实现，回肠病变更易发展为复杂病变。CD中结肠和回肠的异质性对于个性化治疗方法至关重要，但尚未得到系统阐述。
CD具有独特的肠道病变，主要影响回肠末端和结肠。了解不同节段发病机制和治疗反应的多样性至关重要。
我们对未经治疗的CD患者进行了比较单细胞RNA测序分析，重点关注结肠和回肠。
发现了一个表达高水平双氧化酶2（DUOX2）和双氧化酶激活因子2（DUOXA2）的新型上皮细胞亚群（DUOX2-上皮细胞）。该DUOX2-上皮细胞亚群主要分布在炎症结肠的顶端上皮，可能是对微生物感染的反应，炎症和微生物反应通路的显著富集证明了这一点。结肠和回肠的DUOX2-上皮细胞亚群通过不同机制引发炎症反应。结肠DUOX2-上皮细胞主要通过血清淀粉样蛋白A1（SAA1）-甲酰肽受体2（FPR2）配体-受体相互作用影响单核细胞，而回肠DUOX2-上皮细胞则通过CXC趋化因子配体16（CXCL16）-CXC趋化因子受体6（CXCR6）配体-受体对直接与调节性T细胞相互作用。此外，涉及结肠和回肠中DUOX2-上皮细胞的细胞间通讯网络有助于预测生物疗法的部位特异性效果。
本研究在单细胞水平深入探讨了克罗恩病回肠和结肠内的异质性，鉴定出一个新的上皮亚群DUOX2-上皮细胞。基于DUOX2-上皮细胞调节的细胞间通讯网络，还开发了针对生物疗法不同部位的预测性基因模块。
