Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM-CSIC/UVa), 47003 Valladolid, Spain.
Laboratory of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
Int J Mol Sci. 2023 Mar 4;24(5):4977. doi: 10.3390/ijms24054977.
Multiple sclerosis (MS) is a CNS inflammatory demyelinating disease. Recent investigations highlight the gut-brain axis as a communication network with crucial implications in neurological diseases. Thus, disrupted intestinal integrity allows the translocation of luminal molecules into systemic circulation, promoting systemic/brain immune-inflammatory responses. In both, MS and its preclinical model, the experimental autoimmune encephalomyelitis (EAE) gastrointestinal symptoms including "leaky gut" have been reported. Oleacein (OLE), a phenolic compound from extra virgin olive oil or olive leaves, harbors a wide range of therapeutic properties. Previously, we showed OLE effectiveness preventing motor defects and inflammatory damage of CNS tissues on EAE mice. The current studies examine its potential protective effects on intestinal barrier dysfunction using MOG-induced EAE in C57BL/6 mice. OLE decreased EAE-induced inflammation and oxidative stress in the intestine, preventing tissue injury and permeability alterations. OLE protected from EAE-induced superoxide anion and accumulation of protein and lipid oxidation products in colon, also enhancing its antioxidant capacity. These effects were accompanied by reduced colonic IL-1β and TNFα levels in OLE-treated EAE mice, whereas the immunoregulatory cytokines IL-25 and IL-33 remained unchanged. Moreover, OLE protected the mucin-containing goblet cells in colon and the serum levels of iFABP and sCD14, markers that reflect loss of intestinal epithelial barrier integrity and low-grade systemic inflammation, were significantly reduced. These effects on intestinal permeability did not draw significant differences on the abundance and diversity of gut microbiota. However, OLE induced an EAE-independent raise in the abundance of family. Consistently, using Caco-2 cells as an in vitro model, we confirmed that OLE protected against intestinal barrier dysfunction induced by harmful mediators present in both EAE and MS. This study proves that the protective effect of OLE in EAE also involves normalizing the gut alterations associated to the disease.
多发性硬化症（MS）是一种中枢神经系统炎症性脱髓鞘疾病。最近的研究强调了肠道-大脑轴作为一种通讯网络，对神经疾病具有至关重要的影响。因此，肠道完整性的破坏允许腔分子易位进入体循环，促进全身/大脑免疫炎症反应。在 MS 及其临床前模型实验性自身免疫性脑脊髓炎（EAE）中，均有报道胃肠道症状，包括“肠漏”。橄榄苦苷（OLE）是特级初榨橄榄油或橄榄叶中的一种酚类化合物，具有广泛的治疗特性。以前，我们表明 OLE 可有效预防 EAE 小鼠的运动缺陷和中枢神经系统组织的炎症损伤。本研究使用 MOG 诱导的 C57BL/6 小鼠 EAE 模型，研究其对肠道屏障功能障碍的潜在保护作用。OLE 降低了 EAE 引起的肠道炎症和氧化应激，防止了组织损伤和通透性改变。OLE 可防止 EAE 引起的超氧阴离子和蛋白质及脂质氧化产物在结肠中的积累，同时增强其抗氧化能力。这些作用伴随着 OLE 治疗的 EAE 小鼠结肠中 IL-1β和 TNFα水平的降低，而免疫调节细胞因子 IL-25 和 IL-33 保持不变。此外，OLE 还保护了结肠中的粘蛋白含量丰富的杯状细胞，血清中 iFABP 和 sCD14 的水平显著降低，这些标志物反映了肠道上皮屏障完整性的丧失和低度全身炎症。这些对肠道通透性的影响并没有对肠道微生物群的丰度和多样性产生显著差异。然而，OLE 诱导了一种与 EAE 无关的增加，即家族的丰度增加。一致地，使用 Caco-2 细胞作为体外模型，我们证实 OLE 可防止 EAE 及 MS 中存在的有害介质引起的肠道屏障功能障碍。这项研究证明，OLE 在 EAE 中的保护作用还涉及到使与疾病相关的肠道改变正常化。
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