Chronic stress disrupts immune homeostasis while gut microbiota-derived metabolites attenuate inflammation, thus promoting resilience to stress-induced immune and behavioral abnormalities. There are both peripheral and brain region-specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of stress-induced psychological impairment. This study shows that a combination of probiotics and polyphenol-rich prebiotics, a synbiotic, attenuates the chronic-stress induced inflammatory responses in the ileum and the prefrontal cortex promoting resilience to the consequent depressive- and anxiety-like behaviors in male mice. Pharmacokinetic studies revealed that this effect may be attributed to specific synbiotic-produced metabolites including 4-hydroxyphenylpropionic, 4-hydroxyphenylacetic acid and caffeic acid. Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the prefrontal cortex and hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic's effect on the ileum's inflammatory response to stress. Synbiotic treatment indiscriminately attenuated the stress-induced immune and behavioral aberrations in both the ileum and the brain while in a gut-immune co-culture model, the synbiotic-specific metabolites promoted anti-inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic-stress induced behavioral impairments while defining a putative mechanism of gut-microbiota host interaction for modulating the peripheral and brain immune systems.

中文翻译：

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微生物群代谢物调节 T 辅助 17 至调节性 T 细胞 (Th17/Treg) 失衡，促进对压力诱导的焦虑和抑郁样行为的恢复能力

慢性压力会破坏免疫稳态，而肠道微生物群衍生的代谢物会减轻炎症，从而增强对压力引起的免疫和行为异常的恢复能力。对慢性压力的免疫反应存在外周和大脑区域特异性的适应不良，这些不良反应产生了设计预防压力引起的心理障碍的新型治疗策略所需的相互关联的机制考虑。这项研究表明，益生菌和富含多酚的益生元（一种合生元）的组合可减弱回肠和前额叶皮层中慢性压力诱导的炎症反应，从而促进雄性小鼠对随之而来的抑郁和焦虑样行为的恢复能力。药代动力学研究表明，这种作用可能归因于特定的合生素产生的代谢物，包括 4-羟基苯丙酸、4-羟基苯乙酸和咖啡酸。使用慢性不可预测的压力模型，行为异常与回肠中强烈的免疫细胞激活和募集有关，而炎症小体通路与前额叶皮层和海马体有关。慢性应激还上调了肝脏和回肠中激活的促炎性 T 辅助细胞 17 (Th17) 与调节性 T 细胞 (Treg) 的比例，并且通过独创性途径分析预测，芳烃受体 (AHR) 可能驱动合生元对回肠对压力的炎症反应。合生元治疗不分青红皂白地减弱了回肠和大脑中压力引起的免疫和行为异常，而在肠道免疫共培养模型中，合生元特异性代谢物通过 AHR 促进抗炎活性。总体而言，这项研究描述了一种针对慢性压力引起的行为障碍的新型合生元治疗方法，同时定义了肠道-微生物群宿主相互作用以调节外周和大脑免疫系统的推定机制。