Tran Minh Tuan
Indian Springs School, Pelham, AL, United States.
Front Genet. 2024 Aug 21;15:1376123. doi: 10.3389/fgene.2024.1376123. eCollection 2024.
Inflammatory Bowel Disease (IBD) is believed to be a risk factor for Small Intestinal Neuroendocrine Tumors (SI-NET) development; however, the molecular relationship between IBD and SI-NET has yet to be elucidated. In this study, we use a systems biology approach to uncover such relationships. We identified a more similar transcriptomic-wide expression pattern between Crohn's Disease (CD) and SI-NET whereas a higher proportion of overlapping dysregulated genes between Ulcerative Colitis (UC) and SI-NET. Enrichment analysis indicates that extracellular matrix remodeling, particularly in epithelial-mesenchymal transition and intestinal fibrosis mediated by TIMP1, is the most significantly dysregulated pathway among upregulated genes shared between both IBD subtypes and SI-NET. However, this remodeling occurs through distinct regulatory molecular mechanisms unique to each IBD subtype. Specifically, myofibroblast activation in CD and SI-NET is mediated through IL-6 and ciliary-dependent signaling pathways. Contrarily, in UC and SI-NET, this phenomenon is mainly regulated through immune cells like macrophages and the NCAM signaling pathway, a potential gut-brain axis in the context of these two diseases. In both IBD and SI-NET, intestinal fibrosis resulted in significant metabolic reprogramming of fatty acid and glucose to an inflammatory- and cancer-inducing state. This altered metabolic state, revealed through enrichment analysis of downregulated genes, showed dysfunctions in oxidative phosphorylation, gluconeogenesis, and glycogenesis, indicating a shift towards glycolysis. Also known as the Warburg effect, this glycolytic switch, in return, exacerbates fibrosis. Corresponding to enrichment analysis results, network construction and subsequent topological analysis pinpointed 7 protein complexes, 17 hub genes, 11 microRNA, and 1 transcription factor related to extracellular matrix accumulation and metabolic reprogramming that are candidate biomarkers in both IBD and SI-NET. Together, these biological pathways and candidate biomarkers may serve as potential therapeutic targets for these diseases.
炎症性肠病（IBD）被认为是小肠神经内分泌肿瘤（SI-NET）发生的一个危险因素；然而，IBD与SI-NET之间的分子关系尚未阐明。在本研究中，我们采用系统生物学方法来揭示这种关系。我们发现克罗恩病（CD）和SI-NET之间存在更相似的全转录组表达模式，而溃疡性结肠炎（UC）和SI-NET之间重叠的失调基因比例更高。富集分析表明，细胞外基质重塑，特别是在由TIMP1介导的上皮-间质转化和肠道纤维化过程中，是IBD两个亚型和SI-NET共有的上调基因中失调最显著的途径。然而，这种重塑是通过每种IBD亚型独特的调控分子机制发生的。具体而言，CD和SI-NET中肌成纤维细胞的激活是通过IL-6和纤毛依赖的信号通路介导的。相反，在UC和SI-NET中，这种现象主要通过巨噬细胞等免疫细胞和NCAM信号通路调节，这在这两种疾病的背景下是一个潜在的肠-脑轴。在IBD和SI-NET中，肠道纤维化导致脂肪酸和葡萄糖的显著代谢重编程，转变为炎症诱导和癌症诱导状态。通过对下调基因的富集分析揭示的这种改变的代谢状态，显示氧化磷酸化、糖异生和糖原合成功能障碍，表明向糖酵解转变。这种糖酵解转换也称为瓦伯格效应，反过来又会加剧纤维化。与富集分析结果相对应，网络构建及随后的拓扑分析确定了7种蛋白质复合物、17个枢纽基因、11种 microRNA和1个与细胞外基质积累和代谢重编程相关的转录因子，它们是IBD和SI-NET中的候选生物标志物。总之，这些生物学途径和候选生物标志物可能成为这些疾病的潜在治疗靶点。
