Department of Biomedicine, Unity of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal.
Department of Internal Medicine, Tâmega e Sousa Hospital Center, Padre Américo Hospital, Penafiel, Portugal.
Inflamm Bowel Dis. 2021 Jun 15;27(7):1153-1165. doi: 10.1093/ibd/izaa324.
The roles dipeptidyl peptidase 4 (DPP4), aminopeptidase N (APN), and their substrates in autoimmune diseases are being increasingly recognized. However, their significance in inflammatory bowel diseases (IBD) is not entirely understood. This systematic review aims to discuss the pathophysiological processes related to these ectopeptidases while comparing findings from preclinical and clinical settings.
This review was conducted according to the PRISMA guidelines. We performed a literature search in PubMed, SCOPUS, and Web of Science to identify all reports from inception until February 2020. The search included validated animal models of intestinal inflammation and studies in IBD patients. Quality assessment was performed using SYRCLE's risk of bias tool and CASP qualitative and cohort checklists.
From the 45 included studies, 36 were performed in animal models and 12 in humans (3 reports included both). Overall, the methodological quality of preclinical studies was acceptable. In animal models, DPP4 and APN inhibition significantly improved intestinal inflammation.Glucagon-like peptide (GLP)-1 and GLP-2 analogs and GLP-2-relase-inducing drugs also showed significant benefits in recovery from inflammatory damage. A nonsignificant trend toward disease remission with the GLP-2 analog teduglutide was observed in the sole interventional human study. All human studies reported an inverse correlation between soluble DPP4/CD26 levels and disease severity, in accordance with the proposal of DPP4 as a biomarker for IBD.
The use of DPP4 inhibitors and analogs of its substrates has clear benefits in the treatment of experimentally induced intestinal inflammation. Further research is warranted to validate their potential diagnostic and therapeutic applications in IBD patients.
二肽基肽酶 4（DPP4）和氨基肽酶 N（APN）及其底物在自身免疫性疾病中的作用正日益受到关注。然而，它们在炎症性肠病（IBD）中的意义尚不完全清楚。本系统评价旨在讨论这些外肽酶的病理生理过程，并比较临床前和临床研究的结果。
本研究按照 PRISMA 指南进行。我们在 PubMed、SCOPUS 和 Web of Science 中进行了文献检索，以确定自成立以来至 2020 年 2 月的所有报告。检索包括验证的肠道炎症动物模型和 IBD 患者的研究。使用 SYRCLE 的偏倚风险工具以及 CASP 定性和队列检查表对质量进行评估。
从 45 项纳入的研究中，36 项在动物模型中进行，12 项在人类中进行（3 项报告同时包含这两项）。总体而言，临床前研究的方法学质量是可以接受的。在动物模型中，DPP4 和 APN 抑制显著改善了肠道炎症。胰高血糖素样肽（GLP）-1 和 GLP-2 类似物以及 GLP-2 释放诱导药物在恢复炎症损伤方面也显示出显著的益处。唯一一项干预性人类研究观察到 GLP-2 类似物 teduglutide 有疾病缓解的趋势，但无统计学意义。所有人类研究均报告可溶性 DPP4/CD26 水平与疾病严重程度呈负相关，这与 DPP4 作为 IBD 生物标志物的假设一致。
DPP4 抑制剂和其底物的类似物在治疗实验性诱导的肠道炎症方面具有明显的益处。需要进一步的研究来验证它们在 IBD 患者中的潜在诊断和治疗应用。
