Our previous studies showed that high fructose diet (HFrD)-driven gut dysbiosis caused fecal short-chain fatty acids (SCFAs) reduction and intestinal epithelial barrier (IEB) damage in mice, which might play an important role in hippocampal neuroinflammatory injury. Mulberroside A is reported to have neuroprotective effects in animal experiments, while the underlying mechanisms are not yet fully elucidated. Here, we investigated whether and how mulberroside A prevented HFrD-induced neuroinflammatory injury. HFrD-fed mice were treated orally with mulberroside A (20 and 40 mg/kg) for 8 weeks. Mulberroside A was found to inhibit hippocampal neuroinflammation and neurogenesis reduction in HFrD-fed mice. It reshaped gut dysbiosis, increased fecal and serum SCFAs contents, reactivated signaling of the colonic NLR family, pyrin domain containing 6 (NLRP6) inflammasome, and up-regulated Muc2 expression to prevent IEB damage, as well as subsequently, reduced serum endotoxin levels in this animal model. Additionally, mulberroside A inhibited oxidative stress in colon of HFrD-fed mice and hydrogen peroxide (H₂O₂)-stimulated Caco-2 cells. Blood–brain barrier (BBB) structure defects were also observed in HFrD-driven hippocampal neuroinflammatory injury of mice. Interestingly, mulberroside A maintained astrocyte morphology and up-regulated tight junction proteins to repair BBB structure defects in hippocampus dentate gyrus (DG). Our results demonstrated that mulberroside A was capable of preventing HFrD-induced damage of IEB and BBB in mice, which might contribute to the suppression of hippocampal neuroinflammatory injury.

中文翻译：

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Mulberroside A 修复高果糖饮食诱导的小鼠肠上皮和血脑屏障损伤：预防海马神经炎症损伤的潜力

我们之前的研究表明，高果糖饮食 (HFrD) 驱动的肠道菌群失调导致小鼠粪便短链脂肪酸 (SCFA) 减少和肠上皮屏障 (IEB) 损伤，这可能在海马神经炎症损伤中起重要作用。据报道，桑葚苷 A 在动物实验中具有神经保护作用，但其潜在机制尚未完全阐明。在这里，我们研究了桑树苷 A 是否以及如何预防 HFrD 诱导的神经炎症损伤。HFrD 喂养的小鼠用桑葚苷 A（20 和 40 毫克/千克）口服治疗 8 周。发现 Mulberroside A 抑制 HFrD 喂养小鼠的海马神经炎症和神经发生减少。它重塑肠道生态失调，增加粪便和血清 SCFAs 含量，重新激活结肠 NLR 家族的信号，pyrin 结构域含有 6 (NLRP6) 炎症小体，并上调 Muc2 表达以防止 IEB 损伤，以及随后降低该动物模型中的血清内毒素水平。此外，桑树苷 A 抑制了 HFrD 喂养小鼠结肠中的氧化应激和过氧化氢（H₂ O ₂ )-刺激的 Caco-2 细胞。在 HFrD 驱动的小鼠海马神经炎症损伤中也观察到血脑屏障 (BBB) 结构缺陷。有趣的是，桑树苷 A 维持星形胶质细胞形态并上调紧密连接蛋白以修复海马齿状回 (DG) 中的 BBB 结构缺陷。我们的研究结果表明，桑椹苷 A 能够预防 HFrD 诱导的小鼠 IEB 和 BBB 损伤，这可能有助于抑制海马神经炎症损伤。