破坏肠上皮屏障是克罗恩病（CD）的一个主要原因。肠上皮屏障的新型分子靶点对于CD的治疗至关重要。跨膜和免疫球蛋白结构域含蛋白1（TMIGD1）是一种调节细胞黏附、迁移和肠上皮细胞分化的黏附分子。然而，TMIGD1在CD和肠上皮屏障中的功能和机制鲜为人知。此外，TMIGD1与CD的临床特征之间的关联仍不清楚。我们通过对CD患者和健康个体的结肠粘膜进行转录组分析，以识别失调基因。将IBD 1000队列包括基因组学、肠道活检的转录组学和血清蛋白组学进行多组学整合，以确定基因与CD特征之间的关联。通过细胞系、器官样和肠特异性Tmigd1基因敲除（Tmigd1INT-KO）小鼠中的细胞因子产生评估炎症。通过透过电阻（TEER）、细胞间隙通透性和顶部连接复合物（AJC）表达评估上皮屏障完整性。采用共免疫沉淀、GST pull-down实验、质谱、蛋白组学和转录组分析探索下游机制。多组学整合提示TMIGD1与CD的炎症特征呈负相关。TMIGD1在CD患者和小鼠结肠炎模型的炎症肠粘膜中下调。Tmigd1INT-KO小鼠对化学诱导性结肠炎更易感。在上皮细胞系和结肠器官样中，TMIGD1敲减导致肠道屏障完整性受损，表现为加大的细胞间通透性，降低的TEER和AJC表达。肠上皮细胞中TMIGD1敲减也可诱导炎症性细胞因子产生。在机制上，TMIGD1直接与胞浆内核组装因子1（BANF1）相互作用，抑制NF-κB活化。TMIGD1和BANF1的外源表达在体内和体外恢复了肠道屏障功能并抑制了炎症。TMIGD1表达预测CD患者对抗TNF治疗的反应。我们的研究证明了TMIGD1维持肠道屏障完整性和抑制炎症，因此是CD的潜在治疗靶点。© 2023年，BioMed Central Ltd.，Springer Nature的一部分。

Disrupted intestinal epithelial barrier is one of the major causes of Crohn's disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear.Transcriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms.Multi-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD.Our study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.© 2023. BioMed Central Ltd., part of Springer Nature.