Increasing evidence has indicated that prebiotics as an alternative treatment for neuropsychiatric diseases. This study evaluated the prebiotics Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on the modulation of neuroinflammation and cognition in an experimental model of mice high-fat diet fed. Initially, mice were distributed in the following groups: (A) control standard diet (n = 15) and (B) HFD for 18 weeks (n = 30). In the 13th week, the mice were later divided into the following experimental groups: (A) Control (n = 15); (B) HFD (n = 14); and (C) HFD + Prebiotics (n = 14). From the 13th week, the HFD + Prebiotics group received a high-fat diet and a combination of FOS and GOS. In the 18th week, all animals performed the T-maze and Barnes Maze, and were later euthanized. Biochemical and molecular analyzes were performed to assess neuroinflammation, neurogenesis, synaptic plasticity, and intestinal inflammation. Mice fed HFD had higher blood glucose, triglyceridemia, cholesterolemia, and higher serum IL-1β associated with impaired learning and memory. These obese mice also showed activation of microglia and astrocytes and significant immunoreactivity of neuroinflammatory and apoptosis markers, such as TNF-α, COX-2, and Caspase-3, in addition to lower expression of neurogenesis and synaptic plasticity markers, such as NeuN, KI-67, CREB-p, and BDNF. FOS and GOS treatment significantly improved the biochemistry profile and decreased serum IL-1β levels. Treatment with FOS and GOS also reduced TNF-α, COX-2, Caspase-3, Iba-1, and GFAP-positive cells in the dentate gyrus, decreasing neuroinflammation and neuronal death caused by chronic HFD consumption. In addition, FOS and GOS promoted synaptic plasticity by increasing NeuN, p-CREB, BDNF, and KI-67, restoring spatial learning ability and memory. Moreover, FOS and GOS on HFD modulated the insulin pathway, which was proved by up-regulating IRS/PI3K/AKT signaling pathway, followed by a decreasing Aβ plate and Tau phosphorylation. Furthermore, the prebiotic intervention reshaped the HFD-induced imbalanced gut microbiota by modulating the composition of the bacterial community, markedly increasing Bacteroidetes. In addition, prebiotics decreased intestinal inflammation and leaky gut. In conclusion, FOS and GOS significantly modulated the gut microbiota and IRS/PI3K/AKT signaling pathway, decreased neuroinflammation, and promoted neuroplasticity improving spatial learning and memory.

Graphical Abstract

Schematic summarizing of the pathways by FOS and GOS improves memory and learning through the gut-brain axis. FOS and GOS improve the microbial profile, reducing intestinal inflammation and leaky gut in the distal colon. Specifically, the administration of FOS and GOS decreases the expression of TLR4, TNF-α, IL-1β, and MMP9 and increases the expression of occludin and IL-10. Prebiotics inhibit neuroinflammation, neuronal apoptosis, and reactive gliosis in the hippocampus but restore synaptic plasticity, neuronal proliferation, and neurogenesis

中文翻译：

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低聚果糖 (FOS) 和低聚半乳糖 (GOS) 通过上调 IRS/PI3K/AKT 信号通路改善饮食诱导的肥胖小鼠的神经炎症和认知

越来越多的证据表明益生元可以作为神经精神疾病的替代治疗方法。本研究在高脂饮食喂养的小鼠实验模型中评估了益生元低聚果糖 (FOS) 和低聚半乳糖 (GOS) 对神经炎症和认知的调节作用。最初，小鼠被分为以下几组：(A) 对照标准饮食组 (n = 15) 和 (B) HFD 18 周 (n = 30)。第13周，将小鼠分为以下实验组：（A）对照组（n = 15）；(B) HFD (n = 14)；(C) HFD + 益生元 (n = 14)。从第13周开始，HFD+益生元组接受高脂饮食以及FOS和GOS的组合。第18周，所有动物进行T型迷宫和巴恩斯迷宫，随后被安乐死。进行生化和分子分析以评估神经炎症、神经发生、突触可塑性和肠道炎症。喂食 HFD 的小鼠血糖、甘油三酯血症、胆固醇血症以及与学习和记忆受损相关的血清 IL-1β 较高。这些肥胖小鼠还表现出小胶质细胞和星形胶质细胞的激活以及神经炎症和细胞凋亡标记物（例如 TNF-α、COX-2 和 Caspase-3）的显着免疫反应性，以及神经发生和突触可塑性标记物（例如 NeuN）的较低表达。 KI-67、CREB-p 和 BDNF。FOS 和 GOS 治疗显着改善了生化特征并降低了血清 IL-1β 水平。FOS 和 GOS 治疗还减少了齿状回中的 TNF-α、COX-2、Caspase-3、Iba-1 和 GFAP 阳性细胞，从而减少了慢性 HFD 消耗引起的神经炎症和神经元死亡。此外，FOS和GOS通过增加NeuN、p-CREB、BDNF和KI-67来促进突触可塑性，恢复空间学习能力和记忆。此外，HFD 上的 FOS 和 GOS 调节胰岛素通路，这通过上调 IRS/PI3K/AKT 信号通路、随后减少 Aβ 板和 Tau 磷酸化来证明。此外，益生元干预通过调节细菌群落的组成，显着增加拟杆菌，重塑了 HFD 引起的不平衡肠道微生物群。此外，益生元还可以减少肠道炎症和肠漏。总之，FOS 和 GOS 显着调节肠道微生物群和 IRS/PI3K/AKT 信号通路，减少神经炎症，促进神经可塑性，改善空间学习和记忆。

图形概要

FOS 和 GOS 通路的示意图总结通过肠脑轴改善记忆和学习。FOS 和 GOS 改善微生物特征，减少远端结肠的肠道炎症和肠漏。具体而言，施用FOS和GOS会降低TLR4、TNF-α、IL-1β和MMP9的表达，并增加occludin和IL-10的表达。益生元抑制海马体中的神经炎症、神经元凋亡和反应性神经胶质增生，但恢复突触可塑性、神经元增殖和神经发生