Dahlgren David, Lennernäs Hans
Department of Pharmaceutical Biosciences Uppsala University, Uppsala, Sweden.
Department of Pharmaceutical Biosciences Uppsala University, Uppsala, Sweden.
Biomed Pharmacother. 2023 Jun;162:114644. doi: 10.1016/j.biopha.2023.114644. Epub 2023 Apr 3.
Chemotherapy kills fast-growing cells including gut stem cells. This affects all components of the physical and functional intestinal barrier, i.e., the mucus layer, epithelium, and immune system. This results in an altered intestinal permeability of toxic compounds (e.g., endotoxins) as well as luminal bacterial translocation into the mucosa and central circulation. However, there is uncertainty regarding the relative contributions of the different barrier components for the development of chemotherapy-induced gut toxicity. This review present an overview of the intestinal mucosal barrier determined with various types of molecular probes and methods, and how they are affected by chemotherapy based on reported rodent and human data. We conclude that there is overwhelming evidence that chemotherapy increases bacterial translocation, and that it affects the mucosal barrier by rendering the mucosa more permeable to large permeability probes. Chemotherapy also seems to impede the intestinal mucus barrier, even though this has been less clearly evaluated from a functional standpoint but certainly plays a role in bacteria translocation. Combined, it is however difficult to outline a clear temporal or succession between the different gastrointestinal events and barrier functions, especially as chemotherapy-induced neutropenia is also involved in intestinal immunological homeostasis and bacterial translocation. A thorough characterization of this would need to include a time dependent development of neutropenia, intestinal permeability, and bacterial translocation, ideally after a range of chemotherapeutics and dosing regimens.
化疗会杀死包括肠道干细胞在内的快速生长细胞。这会影响肠道物理和功能屏障的所有组成部分，即黏液层、上皮细胞和免疫系统。这会导致有毒化合物（如内毒素）的肠道通透性改变，以及肠腔内细菌易位至黏膜和体循环。然而，关于不同屏障成分在化疗诱导的肠道毒性发展中的相对作用尚不确定。本综述概述了用各种类型的分子探针和方法测定的肠道黏膜屏障，以及根据已报道的啮齿动物和人类数据它们如何受到化疗的影响。我们得出结论，有压倒性的证据表明化疗会增加细菌易位，并且它通过使黏膜对大通透性探针更具通透性来影响黏膜屏障。化疗似乎也会阻碍肠道黏液屏障，尽管从功能角度对此评估得不太清楚，但它肯定在细菌易位中起作用。然而，综合来看，很难勾勒出不同胃肠道事件和屏障功能之间清晰的时间顺序或先后顺序，特别是因为化疗诱导的中性粒细胞减少也参与肠道免疫稳态和细菌易位。对此进行全面表征需要包括中性粒细胞减少、肠道通透性和细菌易位的时间依赖性发展，理想情况下是在一系列化疗药物和给药方案之后。
