The intestinal mucin isoform landscape reveals region-specific biomarker panels for inflammatory bowel disease patient stratification.

Wout Arras, Tom Breugelmans, Baptiste Oosterlinck, Joris G De Man, Surbhi Malhotra-Kumar, Steven Abrams, Steven Van Laere, Elisabeth Macken, Michaël Somers, Aranzazu Jauregui-Amezaga, Benedicte Y De Winter, Annemieke Smet
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Abstract

Background and aims: Mucosal healing is considered as a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the mucosal barrier function that give rise to structurally diverse isoforms. Unraveling disease-associated mucin isoforms that could act as an indication for barrier function would greatly enhance IBD management.

Methods: We present the intestinal mucin RNA isoform landscape in IBD and control patients using a targeted mucin isoform sequencing approach on a discovery cohort (n = 106). Random Forest modeling (n = 1683 samples) with external validation (n = 130 samples) identified unique mucin RNA isoform panels that accurately stratified IBD patients in multiple subpopulations based on inflammation, IBD subtype (Crohn's disease (CD), ulcerative colitis (UC)), and anatomical location of the intestinal tract (i.e. ileum, proximal colon, distal colon, rectum).

Results: Particularly, the mucin RNA isoform panels obtained from the inflamed UC and CD distal colon showed high performance in distinguishing inflamed biopsies from their control counterparts (AUC of 93.3% and 91.1% in the training, 95.0% and 96.0% in the test, and 89.5% and 78.3% in the external validation datasets, respectively). Furthermore, the differentially expressed MUC4 (PB.1238.363), MUC5AC (PB.2811.15), MUC16 (ENST00000397910.8) and MUC1 (ENST00000462317.5, ENST00000620103.4) RNA isoforms frequently occurred throughout the different panels highlighting their role in IBD pathogenesis.

Conclusion: We unveiled region-specific mucin RNA isoform panels capturing the heterogeneity of the IBD patient population and showing great potential to indicate barrier function in IBD patients.

肠粘蛋白同工酶结构揭示了用于炎症性肠病患者分层的区域特异性生物标记物面板。
背景和目的:粘膜愈合被认为是炎症性肠病(IBD)的关键治疗终点,包括内镜下炎症的改善,而不考虑屏障愈合。粘蛋白是粘膜屏障功能的关键成分,可产生结构多样的异构体。揭示与疾病相关的粘蛋白同工酶,作为屏障功能的指示剂,将大大提高 IBD 的治疗效果:方法:我们在发现队列(n = 106)中使用靶向粘蛋白同工酶测序方法,展示了 IBD 患者和对照组患者的肠粘蛋白 RNA 同工酶结构。随机森林建模(n = 1683 个样本)和外部验证(n = 130 个样本)确定了独特的粘蛋白 RNA 同工酶面板,根据炎症、IBD 亚型(克罗恩病 (CD)、溃疡性结肠炎 (UC))和肠道解剖位置(即回肠、近端结肠、远端结肠、直肠)准确地将 IBD 患者分为多个亚群:特别是,从有炎症的 UC 和 CD 远端结肠中获得的粘蛋白 RNA 同工酶组在区分有炎症的活检组织和对照组方面表现出很高的性能(训练数据集的 AUC 分别为 93.3% 和 91.1%,测试数据集的 AUC 分别为 95.0% 和 96.0%,外部验证数据集的 AUC 分别为 89.5% 和 78.3%)。此外,差异表达的 MUC4(PB.1238.363)、MUC5AC(PB.2811.15)、MUC16(ENST00000397910.8)和 MUC1(ENST00000462317.5、ENST00000620103.4)RNA 同工酶经常出现在不同的数据集中,这突显了它们在 IBD 发病机制中的作用:我们揭示了区域特异性粘蛋白 RNA 同工酶组,捕捉到了 IBD 患者群体的异质性,并显示出显示 IBD 患者屏障功能的巨大潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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