Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA.
Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA.
Brain Behav Immun. 2021 Jan;91:350-368. doi: 10.1016/j.bbi.2020.10.013. Epub 2020 Oct 21.
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.
慢性应激会破坏免疫稳态，而肠道微生物衍生的代谢物则可减轻炎症，从而促进机体对应激引起的免疫和行为异常的适应。慢性应激会导致外周和大脑区域的免疫反应出现特定的适应性改变，这些改变产生了相互关联的机制考虑因素，是设计预防应激引起的心理损伤的新型治疗策略所必需的。本研究表明，益生菌和富含多酚的益生元的组合（合生素）可减轻慢性应激引起的回肠和前额叶皮质的炎症反应，从而提高雄性小鼠对随后出现的抑郁和焦虑样行为的适应能力。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。使用慢性不可预测应激模型，行为异常与回肠中强烈的免疫细胞激活和募集有关，而炎症小体途径则与前额叶皮质和海马体有关。慢性应激还上调了肝脏和回肠中激活的促炎性辅助性 T 细胞 17（Th17）与调节性 T 细胞（Treg）的比例，而通过 ingenuity 通路分析预测，芳基烃受体（AHR）可能是合生素对回肠应激炎症反应产生影响的驱动因素。合生素治疗可不分青红皂白地减轻回肠和大脑中应激引起的免疫和行为异常，而在肠道-免疫共培养模型中，合生素的特异性代谢物通过 AHR 促进抗炎活性。总体而言，本研究描述了一种新型合生素治疗方案，可用于治疗慢性应激引起的行为损伤，并定义了一种调节外周和大脑免疫系统的潜在肠道微生物-宿主相互作用机制。
