Departments of Nutrition, University of California, Davis, CA, USA; Environmental Toxicology, University of California, Davis, CA, USA.
Pharmanex Research, NSE Products, Inc., Provo, UT, USA.
Redox Biol. 2019 Sep;26:101269. doi: 10.1016/j.redox.2019.101269. Epub 2019 Jul 5.
The gastrointestinal (GI) tract can play a critical role in the development of pathologies associated with overeating, overweight and obesity. We previously observed that supplementation with anthocyanins (AC) (particularly glycosides of cyanidin and delphinidin) mitigated high fat diet (HFD)-induced development of obesity, dyslipidemia, insulin resistance and steatosis in C57BL/6J mice. This paper investigated whether these beneficial effects could be related to AC capacity to sustain intestinal monolayer integrity, prevent endotoxemia, and HFD-associated dysbiosis. The involvement of redox-related mechanisms were further investigated in Caco-2 cell monolayers. Consumption of a HFD for 14 weeks caused intestinal permeabilization and endotoxemia, which were associated with a decreased ileum expression of tight junction (TJ) proteins (occludin, ZO-1 and claudin-1), increased expression of NADPH oxidase (NOX1 and NOX4) and NOS2 and oxidative stress, and activation of redox sensitive signals (NF-κB and ERK1/2) that regulate TJ dynamics. AC supplementation mitigated all these events and increased GLP-2 levels, the intestinal hormone that upregulates TJ protein expression. AC also prevented, in vitro, tumor necrosis factor alpha-induced Caco-2 monolayer permeabilization, NOX1/4 upregulation, oxidative stress, and NF-κB and ERK activation. HFD-induced obesity in mice caused dysbiosis and affected the levels and secretion of MUC2, a mucin that participates in intestinal cell barrier protection and immune response. AC supplementation restored microbiota composition and MUC2 levels and distribution in HFD-fed mice. Thus, AC, particularly delphinidin and cyanidin, can preserve GI physiology in HFD-induced obesity in part through redox-regulated mechanisms. This can in part explain AC capacity to mitigate pathologies, i.e. insulin resistance and steatosis, associated with HFD-associated obesity.
胃肠道（GI）在与暴饮暴食、超重和肥胖相关的病理学发展中起着关键作用。我们之前观察到，补充花色苷（AC）（特别是矢车菊素和天竺葵素的糖苷）可减轻 C57BL/6J 小鼠高脂肪饮食（HFD）诱导的肥胖、血脂异常、胰岛素抵抗和脂肪肝的发展。本文研究了这些有益影响是否与 AC 维持肠道单层完整性、防止内毒素血症和 HFD 相关的菌群失调的能力有关。还进一步在 Caco-2 单层细胞中研究了与氧化还原相关的机制。14 周的 HFD 消耗导致肠道通透性增加和内毒素血症，这与回肠紧密连接（TJ）蛋白（occludin、ZO-1 和 claudin-1）表达减少、NADPH 氧化酶（NOX1 和 NOX4）和 NOS2 表达增加以及氧化应激有关，并且激活了调节 TJ 动力学的氧化还原敏感信号（NF-κB 和 ERK1/2）。AC 补充缓解了所有这些事件，并增加了 GLP-2 水平，GLP-2 是上调 TJ 蛋白表达的肠道激素。AC 还可防止 TNF-α诱导的 Caco-2 单层通透性增加、NOX1/4 上调、氧化应激以及 NF-κB 和 ERK 的激活。在肥胖小鼠中，HFD 诱导的肥胖引起菌群失调，并影响 MUC2 的水平和分泌，MUC2 是一种参与肠道细胞屏障保护和免疫反应的粘蛋白。AC 补充恢复了 HFD 喂养小鼠的微生物群落组成和 MUC2 水平和分布。因此，AC，特别是矢车菊素和天竺葵素，可通过氧化还原调节机制部分维持 HFD 诱导肥胖的胃肠道生理学。这可以部分解释 AC 减轻与 HFD 相关肥胖相关的病理的能力，即胰岛素抵抗和脂肪肝。
