Chen Guorong, Qi Hongying, Jiang Li, Sun Shijie, Zhang Junhai, Yu Jiali, Liu Fang, Zhang Yanli, Du Shiyu
Department of Gastroenterology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, 100029, China.
Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.
J Transl Med. 2024 Dec 20;22(1):1121. doi: 10.1186/s12967-024-05934-w.
Ulcerative colitis (UC) is a persistent inflammatory bowels disease (IBD) characterized by immune response dysregulation and metabolic disruptions. Tryptophan metabolism has been believed as a significant factor in UC pathogenesis, with specific metabolites influencing immune modulation and gut microbiota interactions. However, the precise regulatory mechanisms and key genes involved remain unclear.
AUCell, Ucell, and other functional enrichment algorithms were utilized to determine the activation patterns of tryptophan metabolism at the UC cell level. Differential analysis identified key genes associated with tryptophan metabolism. Five machine learning algorithms, including Random Forest, Boruta algorithm, LASSO, SVM-RFE, and GBM were integrated to identify and categorize disease-specific characteristic genes.
We observed significant heterogeneity in tryptophan metabolism activity across cell types in UC, with the highest activity levels in macrophages and fibroblasts. Among the key tryptophan metabolism-related genes, CTSS, S100A11, and TUBB were predominantly expressed in macrophages and significantly upregulated in UC, highlighting their involvement in immune dysregulation and inflammation. Cross-analysis with bulk RNA data confirmed the consistent upregulation of these genes in UC samples, highly indicating their relevance in UC pathology and potential as targets for therapeutic intervention.
This study is the first to reveal the heterogeneity of tryptophan metabolism at the single-cell level in UC, with macrophages emerging as key contributors to inflammatory processes. The identification of CTSS, S100A11, and TUBB as key regulators of tryptophan metabolism in UC underscores their potential as biomarkers and therapeutic targets.
溃疡性结肠炎（UC）是一种持续性炎症性肠病（IBD），其特征为免疫反应失调和代谢紊乱。色氨酸代谢被认为是UC发病机制中的一个重要因素，特定代谢产物会影响免疫调节和肠道微生物群相互作用。然而，具体的调控机制和涉及的关键基因仍不清楚。
利用AUCell、Ucell和其他功能富集算法来确定UC细胞水平上色氨酸代谢的激活模式。差异分析确定了与色氨酸代谢相关的关键基因。整合了包括随机森林、Boruta算法、LASSO、支持向量机递归特征消除法（SVM-RFE）和梯度提升机（GBM）在内的五种机器学习算法，以识别和分类疾病特异性特征基因。
我们观察到UC中不同细胞类型的色氨酸代谢活性存在显著异质性，巨噬细胞和成纤维细胞中的活性水平最高。在关键的色氨酸代谢相关基因中，组织蛋白酶S（CTSS）、钙结合蛋白A11（S100A11）和微管蛋白β（TUBB）主要在巨噬细胞中表达，且在UC中显著上调，突出了它们在免疫失调和炎症中的作用。与批量RNA数据的交叉分析证实了这些基因在UC样本中的一致上调，高度表明它们与UC病理学的相关性以及作为治疗干预靶点的潜力。
本研究首次揭示了UC单细胞水平上色氨酸代谢的异质性，巨噬细胞是炎症过程的关键贡献者。CTSS、S100A11和TUBB被确定为UC色氨酸代谢的关键调节因子，突出了它们作为生物标志物和治疗靶点的潜力。
