F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Janssen Research and Development, LLC, Spring House, Pennsylvania.
Gastroenterology. 2021 Feb;160(3):809-822.e7. doi: 10.1053/j.gastro.2020.10.041. Epub 2020 Nov 5.
The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls.
Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted.
ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders.
Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.
严重急性呼吸综合征冠状病毒 2 的宿主受体血管紧张素转换酶 2（ACE2）在小肠（SB）中高度表达。我们的目的是确定影响克罗恩病（CD）、溃疡性结肠炎（UC）和非炎症性肠病（IBD）对照患者肠道 ACE2 表达的因素。
使用来自组织样本的批量 RNA 测序或微阵列转录组学（4 个 SB 和 2 个结肠队列；n=495；n=387 UC；n=94 非 IBD），我们分析了 ACE2 与人口统计学和疾病活动及预后的关系。我们检查了 3 项临床试验中抗肿瘤坏死因子和抗白细胞介素-12/白细胞介素-23 治疗对 SB 和结肠 ACE2 表达的影响。拟合了单变量和多变量回归模型。
与非 IBD 对照相比，SB CD 中的 ACE2 水平持续降低，而结肠 UC 中的 ACE2 水平升高。SB ACE2 升高也与与 COVID-19 不良结局相关的人口统计学特征（年龄和体重指数升高）有关。在 CD 中，随后发生复杂疾病的患者 SB ACE2 减少。在 UC 中，活跃疾病和随后需要抗肿瘤坏死因子挽救治疗的患者中，结肠 ACE2 升高。在活跃的 CD 和 UC 中，SB 和结肠 ACE2 的表达通过抗细胞因子治疗得到恢复，尤其是在应答者中。
IBD 中 SB 的 ACE2 水平降低但结肠 ACE2 水平升高与炎症和严重疾病相关，但在用抗细胞因子治疗后恢复正常，这表明 ACE2 相关生物学在 SB 和结肠炎症中存在分区。用抗细胞因子治疗恢复 ACE2 表达可能在严重急性呼吸综合征冠状病毒 2 感染的背景下很重要，并且可能解释了在接受抗细胞因子治疗的 IBD 患者中 COVID-19 发病率降低的报告。
