Zietek Tamara, Giesbertz Pieter, Ewers Maren, Reichart Florian, Weinmüller Michael, Urbauer Elisabeth, Haller Dirk, Demir Ihsan Ekin, Ceyhan Güralp O, Kessler Horst, Rath Eva
Chair of Nutritional Physiology, Technische Universität München, Munich, Germany.
Pediatric Nutritional Medicine, Klinikum Rechts der Isar, Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Technische Universität München, Munich, Germany.
Front Bioeng Biotechnol. 2020 Sep 11;8:577656. doi: 10.3389/fbioe.2020.577656. eCollection 2020.
Intestinal transport and sensing processes and their interconnection to metabolism are relevant to pathologies such as malabsorption syndromes, inflammatory diseases, obesity and type 2 diabetes. Constituting a highly selective barrier, intestinal epithelial cells absorb, metabolize, and release nutrients into the circulation, hence serving as gatekeeper of nutrient availability and metabolic health for the whole organism. Next to nutrient transport and sensing functions, intestinal transporters including peptide transporter 1 (PEPT1) are involved in the absorption of drugs and prodrugs, including certain inhibitors of angiotensin-converting enzyme, protease inhibitors, antivirals, and peptidomimetics like β-lactam antibiotics. Here, we verify the applicability of 3D organoids for investigation of intestinal biochemical processes related to transport and metabolism of nutrients and drugs. Establishing a variety of methodologies including illustration of transporter-mediated nutrient and drug uptake and metabolomics approaches, we highlight intestinal organoids as robust and reliable tool in this field of research. Currently used models to study intestinal nutrient absorption, drug transport and enterocyte metabolism, such as Caco-2 cells or rodent explant models are of limited value due to their cancer and non-human origin, respectively. Particularly species differences result in poorly correlative data and findings obtained in these models cannot be extrapolated reliably to humans, as indicated by high failure rates in drug development pipelines. In contrast, human intestinal organoids represent a superior model of the intestinal epithelium and might help to implement the 3Rs (Reduction, Refinement and Replacement) principle in basic science as well as the preclinical and regulatory setup.
肠道转运和传感过程及其与代谢的相互联系与诸如吸收不良综合征、炎症性疾病、肥胖症和2型糖尿病等病理状况相关。肠道上皮细胞构成了一道高度选择性的屏障，吸收、代谢营养物质并将其释放到循环系统中，因此作为整个生物体营养供应和代谢健康的把关者。除了营养物质转运和传感功能外，包括肽转运体1（PEPT1）在内的肠道转运体还参与药物和前体药物的吸收，这些药物包括某些血管紧张素转换酶抑制剂、蛋白酶抑制剂、抗病毒药物以及β-内酰胺抗生素等拟肽物。在此，我们验证了三维类器官在研究与营养物质和药物转运及代谢相关的肠道生化过程中的适用性。我们建立了多种方法，包括说明转运体介导的营养物质和药物摄取以及代谢组学方法，强调肠道类器官是该研究领域强大且可靠的工具。目前用于研究肠道营养物质吸收、药物转运和肠上皮细胞代谢的模型，如Caco-2细胞或啮齿动物外植体模型，分别因其癌症起源和非人类来源而价值有限。特别是物种差异导致数据相关性较差，并且在这些模型中获得的研究结果无法可靠地外推至人类，这在药物研发流程中的高失败率中得到了体现。相比之下，人肠道类器官代表了一种更优越的肠道上皮模型，可能有助于在基础科学以及临床前和监管设置中贯彻3R（减少、优化和替代）原则。
