Histopathologic Evaluation and Single-Cell Spatial Transcriptomics of the Colon Reveal Cellular and Molecular Abnormalities Linked to J-Pouch Failure in Patients with Inflammatory Bowel Disease.

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-06-24 DOI:10.1016/j.jcmgh.2025.101563

Andrea D Olivas, Paul Chak Mou Ngai, Emily Schahrer, Junjie Xing, Mobarakeh Ghadiri, Kinga S Olortegui, John F Cursio, Shintaro Akiyama, Eugene B Chang, Le Shen, Konstantin Umanskiy, David T Rubin, David Zemmour, Christopher R Weber

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引用次数: 0

Abstract

Background and aims: Total abdominal colectomy (TAC) with a staged ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis (UC). However, a significant percentage of patients experience pouch failure, leading to morbidity. This retrospective case-control study identified histopathological features of the TAC specimen associated with pouch failure and investigated the molecular mechanisms of this susceptibility using single-cell spatial transcriptomics.

Methods: We analyzed a cohort of 417 patients who underwent IPAA between 2000-2010 at the University of Chicago Medical Center for up to 18 years. Histological examination of TAC specimens focused on disease activity, depth of inflammation, and specific features, including granulomas and deep ulcers. A subset of patients was profiled using single-cell spatial transcriptomics to map gene expression and immune cell interactions in relation to the risk of pouch failure.

Results: The 18-year pouch failure risk was 23%, with post-procedure clinical features of Crohn's disease as a major risk factor (HR = 4.3, 95% CI: 2.3-8.1) as well as high-risk histologic features, including deep chronic inflammation (HR = 21, 95% CI: 11-41) and severe disease activity (HR = 14, 95% CI: 5.7-32) in TAC specimens. Spatial transcriptomics showed immune infiltration of T and myeloid cells, reduced myocyte-glial interactions, and cytokine signaling pathways such as IL-10, IL-1β, and type I/II interferons, associated with an increased risk of pouch failure. CD68 immunohistochemistry confirmed that deep CD68⁺ macrophage infiltration is associated with increased risk of future pouch failure.

Conclusion: Histological features including CD68 IHC and spatial molecular profiling are predictive of IPAA failure. These findings support the use of histologic evaluation and targeted molecular analysis of the TAC specimen to identify high-risk patients and improve IPAA outcomes.

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组织病理学评估和结肠单细胞空间转录组学揭示炎症性肠病患者j -袋衰竭相关的细胞和分子异常

背景与目的：全腹结肠切除术（TAC）联合分期回肠袋-肛门吻合术（IPAA）是治疗溃疡性结肠炎（UC）的常用手术方法。然而，很大比例的患者经历眼袋衰竭，导致发病。这项回顾性病例对照研究确定了与眼袋破裂相关的TAC标本的组织病理学特征，并利用单细胞空间转录组学研究了这种易感性的分子机制。方法：我们分析了2000-2010年间在芝加哥大学医学中心接受IPAA治疗长达18年的417例患者。TAC标本的组织学检查侧重于疾病活动性、炎症深度和特定特征，包括肉芽肿和深部溃疡。使用单细胞空间转录组学对一部分患者进行分析，绘制基因表达和免疫细胞相互作用与眼袋衰竭风险的关系。结果：18年的眼袋衰竭风险为23%，手术后临床特征为克罗恩病的主要危险因素（HR = 4.3, 95% CI: 2.3-8.1）以及高危组织学特征，包括TAC标本的深度慢性炎症（HR = 21, 95% CI: 11-41）和严重疾病活动性（HR = 14, 95% CI: 5.7-32）。空间转录组学显示，T细胞和髓细胞的免疫浸润，肌细胞-神经胶质相互作用减少，细胞因子信号通路如IL-10、IL-1β和I/II型干扰素，与眼袋衰竭的风险增加有关。CD68免疫组化证实深部CD68+巨噬细胞浸润与未来眼袋衰竭风险增加相关。结论：包括CD68免疫组化和空间分子谱在内的组织学特征可预测IPAA失败。这些发现支持使用TAC标本的组织学评估和靶向分子分析来识别高危患者并改善IPAA结果。

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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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.